July 2014
Volume 55, Issue 7
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Glaucoma  |   July 2014
Quantitative Analysis of Iris Changes After Physiologic and Pharmacologic Mydriasis in a Rural Chinese Population
Author Affiliations & Notes
  • Ye Zhang
    Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, People's Republic of China
  • Si Zhen Li
    Nanjing Aier Eye Hospital, Nanjing, People's Republic of China
  • Lei Li
    Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, People's Republic of China
  • Ming Guang He
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China
  • Ravi Thomas
    Queensland Eye Institute, Brisbane, Queensland, Australia
    University of Queensland, Brisbane, Queensland, Australia
  • Ning Li Wang
    Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, Beijing, People's Republic of China
    Beijing Institute of Ophthalmology, Beijing, People's Republic of China
  • Correspondence: Ning Li Wang, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Lab, No. 1 Dong Jiao Min Xiang Street, Dongcheng District, Beijing, People's Republic of China, 100730; wningli@vip.163.com
Investigative Ophthalmology & Visual Science July 2014, Vol.55, 4405-4412. doi:10.1167/iovs.13-13782
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      Ye Zhang, Si Zhen Li, Lei Li, Ming Guang He, Ravi Thomas, Ning Li Wang; Quantitative Analysis of Iris Changes After Physiologic and Pharmacologic Mydriasis in a Rural Chinese Population. Invest. Ophthalmol. Vis. Sci. 2014;55(7):4405-4412. doi: 10.1167/iovs.13-13782.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To estimate and compare the change in iris cross-sectional area (IA) and iris volume (IV) following physiologic and pharmacologic pupil dilation in primary angle closure suspects (PACS) and normal subjects.

Methods.: Anterior segment–optical coherence tomography (AS-OCT) measurements in light, dark, and following pharmacologic dilation were obtained on 186 PACS and 224 normal subjects examined during the 5-year follow-up of the Handan Eye Study. Iris cross-sectional area, IV, and other biometric parameters calculated using the Zhongshan angle assessment program in the right eyes of all subjects were analyzed.

Results.: The mean IA and IV decreased in dark compared with light and after pharmacologic dilation in both PACS and normal eyes. This change was statistically significant in normal eyes: light versus pharmacologic dilation for IA (P = 0.038) and for IV, both light versus dark (P = 0.031) and light versus pharmacologic dilation (P = 0.012). A longer axial length (P = 0.028) and a greater change in pupil diameter (PD) (P < 0.001) were associated with a larger decrease of IA for the light to dark comparison. A diagnosis of normal eyes (P = 0.011), larger PD in dark (P = 0.001), and a larger change in PD (P = 0.001) were associated with a larger decrease of IV from light to dark.

Conclusions.: The differences in iris behavior between PACS and normal rural Chinese subjects following physiologic or pharmacologic pupillary dilation may help provide insights into the pathogenesis of angle closure.

Introduction
Primary angle-closure glaucoma (PACG) is one of the leading causes of blindness, and Asians comprise 87% of PACG patients worldwide. 1 Although more people are affected by POAG than PACG, the proportion of those who suffer serious loss of vision is considerably higher in PACG and is responsible for the vast majority (91%) of bilateral glaucoma blindness in China. 1,2  
Previously identified ocular risk factors that predispose individuals to angle closure, include small eyes, shallow central anterior chamber depth (ACD), short axial length (AL), thicker and more anteriorly positioned lens, and lens vault. 37 A shallow ACD is regarded as a cardinal risk factor for angle closure, but data from population-based studies suggest that only a small proportion of those with shallow ACD ultimately develop PACG. 810 There are conflicting reports on the importance of AL and lens position in angle closure. 3,5,11 Asians, particularly Chinese and Mongolians, have a substantially greater risk for angle closure than Europeans and Africans but do not seem to differ in the distribution of their AL or ACD. 1114 The understanding of which small eyes might develop angle closure could lie not just in the static anatomy but in the dynamic responses as well. 15  
Recent reports support the concept that PACG is a multifactorial disease caused by a combination of factors both anatomic and dynamic. 6,7,16 While anatomic factors have been extensively investigated, the dynamic elements and their role is less clear. 1721 Analysis of such dynamic iris behavior may provide clues for the higher prevalence of PACG among Asians. 17 Quigley et al. 17 hypothesized that the high fluid content of iris stroma combined with a change in the capacity for fluid movement could alter iris volume as the pupil dilates, creating a dynamic factor that could predispose some small eyes to angle closure. They report that a smaller iris cross-sectional area (IA) change after pupil dilation could be a potential risk factor for angle closure in those with European ancestry. 17 They also postulate that a lower decrease in iris volume (IV) with dilation may present a higher risk of angle closure. 17 A reduction in the transfer of extracellular fluid from the iris stroma to the anterior chamber was proposed as a mechanism to explain this anatomic change. In French patients, Aptel and Denis 18 demonstrated that the IV, as estimated with anterior segment–optical coherence tomography (AS-OCT), increased after pupil dilation in narrow-angle eyes predisposed to acute angle closure. They also found that this biometric change was associated with angle narrowing, despite a patent laser peripheral iridotomy (LPI) and that the decrease in IV was associated with a change to a larger pupil. 18 In South Indians, Ganeshrao et al. 19 report that IA and IV decrease as the pupil dilates in normal and angle-closure eyes; the loss of IV was lower in angle-closure eyes. 
The objective of this study was 2-fold: (1) quantify changes in IA and IV induced by physiologic and pharmacologic mydriasis and detect any differences between primary angle closure suspects (PACS) and normal controls; and (2) assess whether these changes are associated with demographic and previously reported ocular biometric measurements. 
Methods
Subjects and Ophthalmic Examination
This observational, cross-sectional study was based on the 5-year follow-up of the Handan Eye Study (HES). The Handan Eye Study was conducted on a sample of rural Chinese adults aged 30 years or older living in Handan County, Hebei Province. 22 From May 2012 to June 2013, surviving members of the original HES cohort were reexamined for the 5-year follow-up. Handan Eye Study subjects aged ≥40 years who participated in this follow-up examination between September 2012 and March 2013 and underwent gonioscopy were eligible for inclusion. Gonioscopy was performed on all subjects with a peripheral limbal anterior chamber depth (LACD) ≤ 40% of peripheral corneal thickness (CT) as well as for one in 10 subjects (No. 1, 11, 21, etc.) registered per day. 
Subjects with peripheral anterior synechiae (PAS), raised IOP, cup-disc ratio ≥ 0.6/presence of typical glaucomatous optic neuropathy/field defects, previous intraocular surgery, previous penetrating eye injury or corneal disorders preventing anterior chamber assessment, and persons taking antiglaucoma eyedrops were excluded, as were those who had suffered an episode of acute angle closure (AAC) attack or had undergone LPI or laser iridoplasty. Eyes with an episode of AAC attack were not included because consecutive iris atrophy and sphincter action loss would distort the analysis of IA and IV. Eyes with LPI were excluded as they would affect the dynamic response of the iris to pupil dilation. Also, subjects who were on topical or systemic medication that could affect the iris or angle configuration at the time of the study (cholinergics or anticholinergics, adrenergic agonists or antagonists, serotonin, norepinephrine, and dopamine releasers, their precursors or reuptake inhibitors, monoamine oxidase inhibitors; opioid agonists or antagonists and histamine-receptor antagonists) were excluded. Those included were divided into PACS and control groups. Primary angle closure suspects were defined based on the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) classification, as eyes in which the posterior trabecular meshwork was not visible for at least 180° on static gonioscopy without PAS on indentation/manipulation, IOP ≤ 21 mm Hg, healthy optic nerves, and normal visual fields. 23 The control group comprised age and sex, comparable normal subjects (defined as IOP ≤ 21 mm Hg with open angles, healthy optic nerves, and normal visual fields, no previous surgery, and no family history of glaucoma). 
All participants underwent a comprehensive ophthalmic examination including presenting visual acuity (PVA) and best corrected visual acuity (BCVA), using the Early Treatment Diabetic Retinopathy Study (EDTRS) logMAR E chart, objective and subjective refraction, slit-lamp biomicroscopy, visual field examination, IOP measurement, gonioscopy, A-scan ultrasound biometry, and fundus examination. Refraction was measured using a KR-8800 auto kerato-refractometer (Topcon, Tokyo, Japan), visual field test using the standard 24-2 Swedish Interactive Testing Algorithm (SITA) standard program on a visual field analyzer (Humphrey Visual Field Analyzer 740i or 750i; Carl Zeiss, Jena, Germany), and A-scan ultrasound biometry using an OcuScan RxP (Alcon, Inc., Fort Worth, TX, USA). Static gonioscopy was performed at high magnification (×25) with the eye in the primary gaze position using a Goldmann-type one-mirror lens under the lowest level of ambient illumination that permitted a view of the angle. Dynamic examination (manipulation) was then performed using the same lens. Gonioscopy was performed by one of two observers (ZP and YSH) who were masked to AS-OCT findings. The two observers attained a κ of 0.76 for assessment of occludable angle in 30 eyes (not included in this study). 
The study was approved by the Beijing Tongren Hospital Ethics Committee and performed in accordance with the tenets of the Declaration of Helsinki. All subjects provided verbal and written informed consent. 
AS-OCT Imaging
Anterior segment–optical coherence tomography uses an infrared light with a wavelength of 1310 nm that optimizes anterior chamber angle imaging in the absence of visible light spectrum influence on angle configuration and pupil size. 24,25 This technique enables cross-sectional images of the anterior segment of the eye and is capable of recording transient and dynamic changes of the pupil at low levels of illumination. 24,25 Each eye was imaged with an AS-OCT (Visante; Carl Zeiss Meditec, Inc., Dublin, CA, USA), first under dark conditions (approximately 3 lux, to induce physiologic mydriasis), then with light (approximately 200 lux), and finally 30 minutes after pharmacologic dilation with tropicamide 1% eyedrops. Since PACS eyes have a risk of AAC post dilation, the protocol incorporated precautions to recognize and manage such events. Subjects recording a normal IOP (<21 mm Hg) at least 1 hour after dilation were allowed to leave. Those with an IOP of ≥21 mm Hg received IOP-lowering medications as required. The protocol required those with raised IOP at high risk for an acute event to stay in the central clinic for one night for further observation and management. Doctors in the surrounding towns and villages were made aware of the symptoms that required patients to be sent back to the clinic. 
All images were obtained in the “anterior segment quadrant” mode at 0° to 180°, 45° to 225°, 90° to 270°, and 135° to 315° meridians. For image acquisition of the anterior chamber angle at 6 and 12 o'clock, the operator gently retracted the upper and lower lids as needed taking care to avoid inadvertent pressure on the globe. Imaging was repeated if the scleral spur visibility was poor, and the best set of images were selected. In order to obtain images in a nonaccommodated state, the subject's refractive correction was used to adjust the internal fixation target for their distance correction. Custom software (Zhongshan Angle Assessment Program [ZAAP], Guangzhou, China) was used to calculate IA and IV after the scleral spur was marked on each side of the image. 26  
Angle and anterior chamber configuration, including angle-opening distance at 500 μm (AOD500), trabecular–iris space at 500 μm (TISA500), angle recess area (ARA), ACD, anterior chamber area (ACA), anterior chamber volume (ACV), anterior chamber width (ACW), and pupil diameter (PD) were also analyzed with the same software. Angle opening distance at 500 μm is the distance from the corneal endothelium to the iris surface as determined from a perpendicular to a line drawn at 500 μm from the scleral spur. 27 Trabecular–iris space at 500 μm is the area bounded anteriorly by the AOD500 as determined posteriorly by a line drawn from the scleral spur perpendicular to the plane of the inner scleral wall to the iris, superiorly by the inner corneoscleral wall, and inferiorly by the iris surface. 28 Angle recess area is the area bordered by the anterior iris surface, corneal endothelium, and a line perpendicular to the corneal endothelium drawn to the iris surface from a point at 750 μm anterior to the scleral spur. 29  
Statistical Analysis
The IA, IV, and PD values represented the average of measurements from eight iris cross-sections as obtained from AS-OCT scans; the terms IA and IV are used to designate these average values. Only the right eye of each subject was included for analysis. The one-sample Kolmogorov-Smirnov test was used to assess normality of the measurements. Independent sample t-tests were used to compare differences between normal and PACS eyes. The χ2 test was used for the analysis of qualitative variables. Pearson correlation coefficient or (where indicated) partial correlation coefficient was used to assess the relationship between IA or IV and PD. Linear regression analysis was used to analyze factors associated with IA and IV change (from light to dark). Univariable regression was conducted with changes in IA and IV as the dependent variable and the effects of age, sex, central corneal thickness (CCT), ACD, lens thickness (LT), AL, PD in light, PD in dark, PD change, and diagnosis (PACS or normal) as predictors. Variables that were significant at a level of P < 0.2 were included in a multivariable linear regression model. As this was an explanatory rather than a predictive study, we were prepared to be more inclusive and incorporate variables based on previous reports as well as biologic plausibility. The SPSS statistical software (Version 17.0; SPSS, Inc., Chicago, IL, USA) was used for data analysis. Statistical significance was set at P < 0.05. 
Results
Subjects Characteristics
A total of 485 subjects attending the 5-year HES follow-up were eligible for inclusion. Forty-five eyes (19.5%) in the PACS group and 30 eyes (11.8%) in the normal group were excluded owing to poor image quality and inability to accurately identify the scleral spur. Accordingly, 410 eyes of 410 subjects, including 186 PACS eyes and 224 normal eyes were available for analysis. None of the patients had an episode of AAC on dilation. 
The demographic data and ocular biometric measurements are shown in Table 1. Primary angle closure suspects had worse PVA (P = 0.007), lower IOP (P = 0.043), shallower ACD (P < 0.001), and shorter AL (P < 0.001) than normal subjects. The mean values for AS-OCT parameters and PD of normal and PACS eyes in light, dark, and after pharmacologic dilation along with the differences between the two groups are shown in Tables 2, 3, and 4. The mean values for AOD500, TISA500, ARA, ACD, ACW, ACA, and ACV were significantly lower in the PACS group in all three conditions (P ≤ 0.001). Variables demonstrating a normal distribution are presented as mean (SD), while variables failing to achieve a normal distribution are presented as median (percentiles). 
Table 1
 
Demographic and Biometric Characteristics
Table 1
 
Demographic and Biometric Characteristics
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value
Age, y (SD) 60.5 (8.4) 59.3 (7.4) 59.8 (7.9) 0.110*
Male (%) 66 (32.3) 94 (42.0) 160 (39.0) 0.188†
Female (%) 120 (64.5) 130 (58.0) 250 (61.0)
PVA (IR) 0.30 (0.10, 0.50) 0.20 (0.10, 0.30) 0.20 (0.10, 0.40) 0.007‡
BCVA (IR) 0.00 (0.00, 0.20) 0.00 (0.00, 0.10) 0.00 (0.00, 0.16) 0.085‡
SE (IR) 0.00 (0.00, 1.13) 0.00 (0.00, 0.75) 0.00 (0.00, 0.88) 0.143‡
IOP (IR) 12.0 (10.5, 13.0) 12.5 (11.0, 14.0) 12.0 (11.0, 14.0) 0.043‡
CCT (IR) 528 (516, 548) 531 (517, 547) 530 (516, 547) 0.703‡
Central ACD (IR) 2.49 (2.31, 2.77) 2.73 (2.51, 2.89) 2.62 (2.40, 2.86) <0.001‡
LT (IR) 4.84 (4.54, 5.10) 4.81 (4.49, 5.05) 4.83 (4.51, 5.06) 0.330‡
AL (SD) 22.33 (0.81) 22.74 (0.73) 22.56 (0.79) <0.001*
Table 2
 
AS-OCT in Light
Table 2
 
AS-OCT in Light
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value
AOD500, mm (SD) 0.255 (0.103) 0.333 (0.096) 0.298 (0.107) <0.001*
TISA500, mm2 (IR) 0.103 (0.078, 0.136) 0.132 (0.113, 0.164) 0.123 (0.096, 0.151) <0.001†
ARA500, mm2 (SD) 0.263 (0.099) 0.367 (0.100) 0.320 (0.112) <0.001*
IA, mm2 (SD) 2.90 (0.36) 2.94 (0.35) 2.92 (0.35) 0.315*
IV, mm3 (SD) 28.97 (3.83) 29.46 (3.02) 29.24 (3.42) 0.150*
ACD, mm (SD) 2.276 (0.244) 2.461 (0.222) 2.377 (0.250) <0.001*
ACW, mm (SD) 10.90 (0.41) 11.12 (0.37) 11.02 (0.40) <0.001*
ACA, mm2(SD) 16.13 (2.39) 18.10 (2.33) 17.21 (2.55) <0.001*
ACV, mm3 (SD) 62.61 (12.02) 73.37 (12.33) 68.49 (13.31) <0.001*
PD, mm (SD) 3.99 (0.65) 4.03 (0.64) 4.01 (0.64) 0.529*
Table 3
 
AS-OCT in Dark
Table 3
 
AS-OCT in Dark
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value*
AOD500, mm (SD) 0.252 (0.106) 0.322 (0.100) 0.290 (0.108) <0.001
TISA500, mm2 (SD) 0.102 (0.040) 0.131 (0.039) 0.117 (0.042) <0.001
ARA500, mm2 (SD) 0.248 (0.099) 0.334 (0.102) 0.295 (0.109) <0.001
IA, mm2 (SD) 2.70 (0.37) 2.70 (0.32) 2.70 (0.35) 0.787
IV, mm3 (SD) 28.28 (4.13) 28.53 (3.21) 28.41 (3.65) 0.496
ACD, mm (SD) 2.285 (0.264) 2.457 (0.224) 2.379 (0.257) <0.001
ACW, mm (SD) 10.89 (0.43) 11.09 (0.35) 11.00 (0.40) <0.001
ACA, mm2 (SD) 16.60 (2.53) 18.49 (2.33) 17.63 (2.60) <0.001
ACV, mm3 (SD) 64.65 (12.61) 74.83 (12.29) 70.21 (13.42) <0.001
PD, mm (SD) 4.71 (0.70) 4.78 (0.64) 4.75 (0.67) 0.244
Table 4
 
AS-OCT After Pharmacologic Dilation
Table 4
 
AS-OCT After Pharmacologic Dilation
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value*
AOD500, mm (SD) 0.236 (0.094) 0.386 (0.100) 0.318 (0.122) <0.001
TISA500, mm2 (SD) 0.094 (0.032) 0.149 (0.034) 0.124 (0.043) <0.001
ARA500, mm2 (SD) 0.269 (0.106) 0.425 (0.121) 0.354 (0.138) <0.001
IA, mm2 (SD) 1.80 (0.31) 1.77 (0.26) 1.79 (0.28) 0.357
IV, mm3 (SD) 21.45 (3.33) 21.40 (2.88) 21.42 (3.09) 0.886
ACD, mm (SD) 2.358 (0.265) 2.546 (0.243) 2.461 (0.270) <0.001
ACW, mm (SD) 11.12 (0.41) 11.25 (0.37) 11.19 (0.39) 0.001
ACA, mm2 (SD) 19.54 (2.73) 21.56 (2.44) 20.64 (2.76) <0.001
ACV, mm3 (SD) 84.42 (14.78) 95.32 (13.32) 90.37 (15.01) <0.001
PD, mm (SD) 7.15 (0.63) 7.26 (0.53) 7.21 (0.58) 0.058
Iris Cross-Sectional Area and Iris Volume Measurements
A summary of mean IAs and IVs from eyes of PACS and normal subjects as measured in light, dark, and after dilation is presented in Tables 2, 3, and 4
Table 5 summarizes changes in IA, IV, and PD in the two groups between light and dark, light and pharmacologic dilation, and dark to pharmacologic dilation. The smaller changes in IA for PACS versus normal eyes were statistically significant for the light to pharmacologic dilation comparison (P = 0.038). The smaller changes in IV for PACS versus normal eyes were statistically significant for both light to dark (P = 0.031) and light to pharmacologic dilation comparisons (P = 0.012). 
Table 5
 
Changes in Iris Area, Iris Volume, and Pupillary Diameter
Table 5
 
Changes in Iris Area, Iris Volume, and Pupillary Diameter
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value*
L to D
 IA change, mm2 (SD) 0.21 (0.21) 0.23 (0.19) 0.22 (0.20) 0.191
 IV change, mm3 (SD) 0.70 (2.24) 1.15 (2.03) 0.95 (2.14) 0.031
 PD change, mm (SD) 0.72 (0.42) 0.76 (0.41) 0.74 (0.41) 0.367
L to P
 IA change, mm2 (SD) 1.10 (0.29) 1.17 (0.30) 1.14 (0.30) 0.038
 IV change, mm3 (SD) 7.53 (3.11) 8.28 (2.88) 7.94 (3.00) 0.012
 PD change, mm (SD) 3.17 (0.72) 3.24 (0.67) 3.21 (0.69) 0.317
D to P
 IA change, mm2 (SD) 0.90 (0.28) 0.93 (0.26) 0.92 (0.27) 0.185
 IV change, mm3 (SD) 6.83 (3.20) 7.12 (2.77) 6.99 (2.97) 0.323
 PD change, mm (SD) 2.45 (0.65) 2.48 (0.60) 2.47 (0.63) 0.609
Iris cross-sectional area and IV decreased with increasing PD over the whole range (light, dark, and after pharmacologic dilation) in both groups (Figs. 1, 2). Pearson correlation coefficients for IA and PD were −0.885 for normal eyes and −0.853 for PACS eyes. Partial correlation coefficients between IV and PD were −0.761 for normal eyes and −0.640 for PACS eyes. 
Figure 1
 
Pupillary diameter versus iris cross-sectional area.
Figure 1
 
Pupillary diameter versus iris cross-sectional area.
Figure 2
 
Pupillary diameter versus iris volume.
Figure 2
 
Pupillary diameter versus iris volume.
Results of univariable and multivariable linear regression analysis of IA and IV change from light to dark are shown in Tables 6 and 7. Longer AL (P = 0.028) and larger PD changes (P < 0.001) were associated with greater decrease in IA. 
Table 6
 
Factors Associated With IA Change (Light to Dark)
Table 6
 
Factors Associated With IA Change (Light to Dark)
Variable Univariable Multivariable
P Value Direction P Value
Age −0.117 0.018 −0.001 0.977
Sex −0.018 0.723 - -
SE −0.098 0.047 −0.041 0.279
CCT −0.006 0.905 - -
ACD 0.099 0.048 0.025 0.534
LT 0.018 0.724 - -
AL 0.120 0.016 Eyes with longer AL had more
IA change
0.082 0.028
PACS vs. normal 0.065 0.191 0.019 0.614
PD; L −0.150 0.002 0.012 0.760
PD; D 0.270 <0.001 0.012 0.760
PD change; L to D 0.667 <0.001 Eyes with larger PD change (L to D)
had more IA change
0.664 <0.001
Table 7
 
Factors Associated With IV Change (Light to Dark)
Table 7
 
Factors Associated With IV Change (Light to Dark)
Variable Univariable Multivariable
P Value Direction P Value
Age −0.073 0.138 0.008 0.866
Sex −0.043 0.382 - -
SE −0.037 0.460 - -
CCT −0.071 0.158 −0.093 0.052
ACD 0.124 0.013 0.075 0.130
LT 0.021 0.670 - -
AL 0.124 0.012 0.070 0.159
PACS vs. normal 0.106 0.031 Healthy eyes had more IV change 0.122 0.011
PD; L 0.063 0.202 - -
PD; D 0.211 <0.001 Eyes with larger PD (D) had more IV change 0.171 0.001
PD change; L to D 0.242 <0.001 Eyes with larger PD change (L to D)
had more IV change
0.178 0.001
Normal eyes showed greater decrease in IV (P = 0.011). Following physiologic dilation in the dark, larger PD was associated with greater decrease in IV (P = 0.001), as was larger change in PD (P = 0.001). 
Both PACS as well as normal eyes had lower IA and IV measurements with pharmacologic compared with physiologic dilation and changes in these parameters were also larger with pharmacologic dilation. Change in PD was greater with pharmacologic dilation. 
Discussion
There are multiple factors that predispose to angle closure; a population-based study reported that only 22% of PACS progressed to primary angle closure (PAC) in 5 years. 30 Clearly, the mechanism through which PACS progresses to PAC is poorly understood. 16,31 We are beginning to recognize that primary angle closure disease (PACD) likely results from an interaction of multiple anatomic factors (that cause narrow angles in different combinations), as well as many dynamic elements. 16,20,32,33 It has also been suggested that the latter may play more of a role in AAC. 16  
Previous studies have hypothesized that change in the volume of the iris with pupillary dilation is a dynamic factor that could predispose some anatomically susceptible eyes to PACD. 1719,3437 The limited number of subjects included in these seminal studies is a limitation and makes it difficult to draw robust conclusions. 
The 5-year follow-up of the population-based HES provided an opportunity to collect data for change in iris with pupillary dilation. To the best of our knowledge, this is the first study investigating the role of dynamic iris changes in PACS in a rural Chinese population. The sample was not strictly population based, but participants were no different from others enrolled in the HES and provided measurements in a large number of PACS and normal subjects. 
Iris cross-sectional area and IV decreased both in PACS and normal eyes after both physiologic and pharmacologic dilation. Pupil diameter and IV showed a negative correlation. This would support the hypotheses that losses in IV with increasing PD occur by transfer of fluid into the anterior chamber by transfer of aqueous through macroscopic and microscopic channels into and out of the iris stoma. 17  
The decrease of IA after physiologic and pharmacologic dilation was less in PACS than normal eyes but was statistically significant only for the light to pharmacologic dilation comparison, which is a larger change in pupillary diameter. Iris volume was also found to decrease less in PACS eyes. The differences in IV between PACS and normal eyes were statistically significant for light to dark and for light to pharmacologic dilation comparisons, but not for the dark to pharmacologic dilation measurements. Ganeshrao et al. 19 and Aptel et al. 35 reported a similar change in IA and IV with pupillary dilation between light and dark. Accordingly, the lack of statistical significance should not detract from the hypothesis that this change reflects transfer of fluid from the iris stroma with pupil dilation. Eyes with more compact or water-retentive stroma would lose less fluid and retain more volume. It is possible that the IOP elevation that occurs with iris apposition and results in PAC/PACG is limited to a subset of irides with the poorest fluid conductivity; the factors required to cause AAC may be different from that of asymptomatic disease. 16 Our results reiterate that the dynamic behavior of the iris is one of the component causes in sufficient component causal models for PACD. 
In all eyes, less IA decrease was associated with a shorter AL and a smaller PD change. Moreover, the degree of IV reduction was less in PACS eyes, shallower ACD, smaller PD (in dark), and smaller PD change. All these findings make biological sense and provide further support for the hypothesis that a diminished tendency to lose IV with dilation contributes to PACD. We suggest that PACS eyes, which display extreme or unusual iris responses may be more likely to close in darkness and predispose to PACD. We accept that “extreme” or “unusual” could be different for anatomically different eyes and remain to be identified with further research. 16 In multifactorial disorders like PAC and PACG, all patients do not share the exact same set of risk factors, and this may be more complex in some ethnicities like the Chinese who seem to have multiple mechanisms of angle closure. Perhaps differences in the amount of physiologic mydriasis in the dark play a role. That the role of IV change in progression to PAC may vary between patients, and more broadly between ethnicities, is compatible with the sufficient component causal model for multifactorial diseases. 16,38 A smaller change of IV with dilation is likely contributory to progression only in a subset of PACS that also have a critical anatomic predisposition, and the components involved in AAC are likely different from that of asymptomatic disease. Longitudinal prospective studies are needed to investigate the risk of an IV change in predicting the development of PAC and PACG in those with varying degrees of anatomic risk factors. 
There is a weakness in our study. The study is not strictly population based. However, there were no significant differences in the characteristics of PACS and normal subjects between our study sample and the larger HES cohort. 39  
In summary, our study showed that despite similar baselines, PACS and normal eyes from a rural Chinese population respond differently to both physiologic and pharmacologic pupillary dilation. Such differences in iris behavior may partly explain why only a small proportion of narrow-angle eyes develop PACD. Longitudinal studies will be required to assess the hypothesis that IV change may identify PACS that are at a higher risk of PACD, thereby identifying those who may benefit from an iridotomy. 
Acknowledgments
Supported by the Research Special Fund of the Ministry of Health of the People's Republic of China, Grant 201002019. 
Disclosure: Y. Zhang, None; S.Z. Li, None; L. Li, None; M.G. He, None; R. Thomas, None; N.L. Wang, None 
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Figure 1
 
Pupillary diameter versus iris cross-sectional area.
Figure 1
 
Pupillary diameter versus iris cross-sectional area.
Figure 2
 
Pupillary diameter versus iris volume.
Figure 2
 
Pupillary diameter versus iris volume.
Table 1
 
Demographic and Biometric Characteristics
Table 1
 
Demographic and Biometric Characteristics
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value
Age, y (SD) 60.5 (8.4) 59.3 (7.4) 59.8 (7.9) 0.110*
Male (%) 66 (32.3) 94 (42.0) 160 (39.0) 0.188†
Female (%) 120 (64.5) 130 (58.0) 250 (61.0)
PVA (IR) 0.30 (0.10, 0.50) 0.20 (0.10, 0.30) 0.20 (0.10, 0.40) 0.007‡
BCVA (IR) 0.00 (0.00, 0.20) 0.00 (0.00, 0.10) 0.00 (0.00, 0.16) 0.085‡
SE (IR) 0.00 (0.00, 1.13) 0.00 (0.00, 0.75) 0.00 (0.00, 0.88) 0.143‡
IOP (IR) 12.0 (10.5, 13.0) 12.5 (11.0, 14.0) 12.0 (11.0, 14.0) 0.043‡
CCT (IR) 528 (516, 548) 531 (517, 547) 530 (516, 547) 0.703‡
Central ACD (IR) 2.49 (2.31, 2.77) 2.73 (2.51, 2.89) 2.62 (2.40, 2.86) <0.001‡
LT (IR) 4.84 (4.54, 5.10) 4.81 (4.49, 5.05) 4.83 (4.51, 5.06) 0.330‡
AL (SD) 22.33 (0.81) 22.74 (0.73) 22.56 (0.79) <0.001*
Table 2
 
AS-OCT in Light
Table 2
 
AS-OCT in Light
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value
AOD500, mm (SD) 0.255 (0.103) 0.333 (0.096) 0.298 (0.107) <0.001*
TISA500, mm2 (IR) 0.103 (0.078, 0.136) 0.132 (0.113, 0.164) 0.123 (0.096, 0.151) <0.001†
ARA500, mm2 (SD) 0.263 (0.099) 0.367 (0.100) 0.320 (0.112) <0.001*
IA, mm2 (SD) 2.90 (0.36) 2.94 (0.35) 2.92 (0.35) 0.315*
IV, mm3 (SD) 28.97 (3.83) 29.46 (3.02) 29.24 (3.42) 0.150*
ACD, mm (SD) 2.276 (0.244) 2.461 (0.222) 2.377 (0.250) <0.001*
ACW, mm (SD) 10.90 (0.41) 11.12 (0.37) 11.02 (0.40) <0.001*
ACA, mm2(SD) 16.13 (2.39) 18.10 (2.33) 17.21 (2.55) <0.001*
ACV, mm3 (SD) 62.61 (12.02) 73.37 (12.33) 68.49 (13.31) <0.001*
PD, mm (SD) 3.99 (0.65) 4.03 (0.64) 4.01 (0.64) 0.529*
Table 3
 
AS-OCT in Dark
Table 3
 
AS-OCT in Dark
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value*
AOD500, mm (SD) 0.252 (0.106) 0.322 (0.100) 0.290 (0.108) <0.001
TISA500, mm2 (SD) 0.102 (0.040) 0.131 (0.039) 0.117 (0.042) <0.001
ARA500, mm2 (SD) 0.248 (0.099) 0.334 (0.102) 0.295 (0.109) <0.001
IA, mm2 (SD) 2.70 (0.37) 2.70 (0.32) 2.70 (0.35) 0.787
IV, mm3 (SD) 28.28 (4.13) 28.53 (3.21) 28.41 (3.65) 0.496
ACD, mm (SD) 2.285 (0.264) 2.457 (0.224) 2.379 (0.257) <0.001
ACW, mm (SD) 10.89 (0.43) 11.09 (0.35) 11.00 (0.40) <0.001
ACA, mm2 (SD) 16.60 (2.53) 18.49 (2.33) 17.63 (2.60) <0.001
ACV, mm3 (SD) 64.65 (12.61) 74.83 (12.29) 70.21 (13.42) <0.001
PD, mm (SD) 4.71 (0.70) 4.78 (0.64) 4.75 (0.67) 0.244
Table 4
 
AS-OCT After Pharmacologic Dilation
Table 4
 
AS-OCT After Pharmacologic Dilation
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value*
AOD500, mm (SD) 0.236 (0.094) 0.386 (0.100) 0.318 (0.122) <0.001
TISA500, mm2 (SD) 0.094 (0.032) 0.149 (0.034) 0.124 (0.043) <0.001
ARA500, mm2 (SD) 0.269 (0.106) 0.425 (0.121) 0.354 (0.138) <0.001
IA, mm2 (SD) 1.80 (0.31) 1.77 (0.26) 1.79 (0.28) 0.357
IV, mm3 (SD) 21.45 (3.33) 21.40 (2.88) 21.42 (3.09) 0.886
ACD, mm (SD) 2.358 (0.265) 2.546 (0.243) 2.461 (0.270) <0.001
ACW, mm (SD) 11.12 (0.41) 11.25 (0.37) 11.19 (0.39) 0.001
ACA, mm2 (SD) 19.54 (2.73) 21.56 (2.44) 20.64 (2.76) <0.001
ACV, mm3 (SD) 84.42 (14.78) 95.32 (13.32) 90.37 (15.01) <0.001
PD, mm (SD) 7.15 (0.63) 7.26 (0.53) 7.21 (0.58) 0.058
Table 5
 
Changes in Iris Area, Iris Volume, and Pupillary Diameter
Table 5
 
Changes in Iris Area, Iris Volume, and Pupillary Diameter
Parameter PACS Subjects, n = 186 Healthy Subjects, n = 224 Total Subjects, n = 410 P Value*
L to D
 IA change, mm2 (SD) 0.21 (0.21) 0.23 (0.19) 0.22 (0.20) 0.191
 IV change, mm3 (SD) 0.70 (2.24) 1.15 (2.03) 0.95 (2.14) 0.031
 PD change, mm (SD) 0.72 (0.42) 0.76 (0.41) 0.74 (0.41) 0.367
L to P
 IA change, mm2 (SD) 1.10 (0.29) 1.17 (0.30) 1.14 (0.30) 0.038
 IV change, mm3 (SD) 7.53 (3.11) 8.28 (2.88) 7.94 (3.00) 0.012
 PD change, mm (SD) 3.17 (0.72) 3.24 (0.67) 3.21 (0.69) 0.317
D to P
 IA change, mm2 (SD) 0.90 (0.28) 0.93 (0.26) 0.92 (0.27) 0.185
 IV change, mm3 (SD) 6.83 (3.20) 7.12 (2.77) 6.99 (2.97) 0.323
 PD change, mm (SD) 2.45 (0.65) 2.48 (0.60) 2.47 (0.63) 0.609
Table 6
 
Factors Associated With IA Change (Light to Dark)
Table 6
 
Factors Associated With IA Change (Light to Dark)
Variable Univariable Multivariable
P Value Direction P Value
Age −0.117 0.018 −0.001 0.977
Sex −0.018 0.723 - -
SE −0.098 0.047 −0.041 0.279
CCT −0.006 0.905 - -
ACD 0.099 0.048 0.025 0.534
LT 0.018 0.724 - -
AL 0.120 0.016 Eyes with longer AL had more
IA change
0.082 0.028
PACS vs. normal 0.065 0.191 0.019 0.614
PD; L −0.150 0.002 0.012 0.760
PD; D 0.270 <0.001 0.012 0.760
PD change; L to D 0.667 <0.001 Eyes with larger PD change (L to D)
had more IA change
0.664 <0.001
Table 7
 
Factors Associated With IV Change (Light to Dark)
Table 7
 
Factors Associated With IV Change (Light to Dark)
Variable Univariable Multivariable
P Value Direction P Value
Age −0.073 0.138 0.008 0.866
Sex −0.043 0.382 - -
SE −0.037 0.460 - -
CCT −0.071 0.158 −0.093 0.052
ACD 0.124 0.013 0.075 0.130
LT 0.021 0.670 - -
AL 0.124 0.012 0.070 0.159
PACS vs. normal 0.106 0.031 Healthy eyes had more IV change 0.122 0.011
PD; L 0.063 0.202 - -
PD; D 0.211 <0.001 Eyes with larger PD (D) had more IV change 0.171 0.001
PD change; L to D 0.242 <0.001 Eyes with larger PD change (L to D)
had more IV change
0.178 0.001
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