This cohort study investigates the biometric factors associated with the development of angle closure disease in individuals with eyes at risk of primary angle closure after treatment with laser peripheral iridotomy.
Key Points
Question
What biometric factors predict development of angle closure disease in primary angle closure suspect (PACS) eyes after treatment with laser peripheral iridotomy (LPI)?
Findings
In this cohort analysis of data from 878 eyes of 878 participants from the Zhongshan Angle Closure Prevention trial, PACS eyes with persistent angle narrowing by anterior-segment optical coherence tomography (AS-OCT) or cumulative gonioscopy score 2 weeks after LPI were at higher risk of primary angle closure (PAC) and acute angle closure.
Meaning
These findings suggest that AS-OCT or gonioscopy may be performed after LPI to identify patients at higher risk for angle closure disease who may benefit from more intensive follow-up.
Abstract
Importance
Laser peripheral iridotomy (LPI) is the most common primary treatment for primary angle closure disease (PACD). However, there are sparse data guiding the longitudinal care of PAC suspect (PACS) eyes after LPI.
Objective
To elucidate the anatomic effects of LPI that are associated with a protective outcome against progression from PACS to PAC and acute angle closure (AAC) and to identify biometric factors that predict progression after LPI.
Design, Setting, and Participants
This was a retrospective analysis of data from the Zhongshan Angle Closure Prevention (ZAP) trial, a study of mainland Chinese people aged 50 to 70 years with bilateral PACS who received LPI in 1 randomly selected eye. Gonioscopy and anterior-segment optical coherence tomography (AS-OCT) imaging were performed 2 weeks after LPI. Progression was defined as the development of PAC or an acute angle closure (AAC) attack. Cohort A included a random mix of treated and untreated eyes, and cohort B included only eyes treated with LPI. Univariable and multivariable Cox regression models were developed to assess biometric risk factors for progression in cohorts A and B. Data were analyzed from January 4 to December 22, 2022.
Main Outcome and Measure
Six-year progression to PAC or AAC.
Results
Cohort A included 878 eyes from 878 participants (mean [SD] age, 58.9 [5.0] years; 726 female [82.7%]) of whom 44 experienced progressive disease. In a multivariable analysis, treatment (hazard ratio [HR], 0.67; 95% CI, 0.34-1.33; P = .25) was no longer associated with progression after adjusting for age and trabecular iris space area at 500 μm (TISA at 500 μm) at the 2-week visit. Cohort B included 869 treated eyes from 869 participants (mean [SD] age, 58.9 [5.0] years; 717 female [82.5%]) of whom 19 experienced progressive disease. In multivariable analysis, TISA at 500 μm (HR, 1.33 per 0.01 mm2 smaller; 95% CI, 1.12-1.56; P = .001) and cumulative gonioscopy score (HR, 1.25 per grade smaller; 95% CI, 1.03-1.52; P = .02) at the 2-week visit were associated with progression. Persistent angle narrowing on AS-OCT (TISA at 500 μm ≤0.05 mm2; HR, 9.41; 95% CI, 3.39-26.08; P <.001) or gonioscopy (cumulative score ≤6; HR, 2.80; 95% CI, 1.13-6.93; P =.04) conferred higher risk of progression.
Conclusions and Relevance
Study results suggest that persistent angle narrowing detected by AS-OCT or cumulative gonioscopy score was predictive of disease progression in PACS eyes after LPI. These findings suggest that AS-OCT and gonioscopy may be performed to identify patients at high risk of developing angle closure who may benefit from closer monitoring despite patent LPI.
Introduction
Primary angle closure glaucoma (PACG) is a relatively common cause of permanent vision loss, currently affecting approximately 20 million people worldwide.1 Although primary open-angle glaucoma (POAG) is more common than PACG, PACG confers 2.5 times higher odds of blindness than POAG.2 Angle closure occurs when there is obstruction of the trabecular meshwork (TM) by the peripheral iris, which can lead to impaired aqueous outflow,3 elevated intraocular pressure (IOP), and glaucomatous optic neuropathy. PAC disease (PACD) occurs on a spectrum, progressing from PAC suspect (PACS) to PAC to PACG.4 Treatment with laser and lens extraction surgery can alleviate angle closure, lower IOP, and reduce risk of developing PACG. Although there is consensus that eyes with PAC and PACG should receive laser or surgical treatment, the benefit of treating PACS eyes is less clear.5,6,7,8,9 Therefore, ongoing research in the field of angle closure is focused on identifying predictive factors to guide care of PACS eyes.10
The most common primary treatment for angle closure is laser peripheral iridotomy (LPI), a procedure that creates an alternative pathway for aqueous flow between the anterior and posterior chambers. LPI widens the angle by relieving pupillary block, a key anatomic mechanism underlying angle closure.11,12 The Zhongshan Angle Closure Prevention (ZAP) trial found that LPI effectively halves the risk of progression from PACS to PAC or acute angle closure (AAC) over a 6-year period.9 Although it is intuitive that this lowered progression risk is associated with the angle-widening effects of LPI, to our knowledge, this has not been demonstrated experimentally. The ZAP trial also found that progression occurred in LPI-treated eyes at a rate of 0.4% per eye year.9 Although narrower angle width and flatter iris curvature predict angle closure progression in untreated PACS eyes, it is unclear if these risk factors extend to PACS eyes after LPI treatment.10
In this study, we use data from the ZAP trial to assess the role of anterior-segment optical coherence tomography (AS-OCT) and gonioscopy in evaluating PACS eyes after treatment with LPI. First, we assessed biometric factors that are associated with angle closure progression in treated vs untreated eyes, which could help elucidate the protective mechanism(s) of LPI. We also assessed which biometric factors predict progression of PACS eyes after LPI. Although biometric predictors of anatomic changes after LPI are well studied, biometric predictors of longitudinal clinical outcomes (eg, more severe PACD) after LPI remain unclear.13
Methods
The ZAP trial was approved by the ethical review board of Sun Yat-sen University, the ethical committee of Zhongshan Ophthalmic Center, and the institutional review boards of Moorfields Eye Hospital and Johns Hopkins University. The University of Southern California institutional review board approved the present study. All study procedures adhered to the Declaration of Helsinki, and all study participants provided written informed consent; study participants did not receive a stipend to participate. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Data for the current study were derived from the ZAP trial, a single-center randomized clinical trial conducted in Guangzhou, China. Demographic information from study participants were self-reported. In brief, the ZAP trial recruited participants aged 50 to 70 years with bilateral PACS, defined as eyes with 2 or more quadrants of nonvisibility of pigmented TM on manual gonioscopy in the absence of peripheral anterior synechiae, IOP more than 21 mm Hg, and glaucomatous optic neuropathy. One eye per participant was randomly assigned to treatment with LPI. The other eye was monitored without treatment and served as the control eye. Participants underwent complete baseline examinations before LPI treatment, including AS-OCT imaging, gonioscopy, and ultrasound A-scan biometry. Participants were reexamined 2 weeks after the baseline visit. Gonioscopy and AS-OCT data used in this study were derived from the 2-week visit to assess the outcomes of LPI. Study end points included the development of PAC, which was defined as IOP greater than 24 mm Hg on 2 separate occasions, development of 1 or more clock hours of peripheral anterior synechiae, or an AAC attack. Data were censored if participants received cataract surgery during the 72-month follow-up.
Static gonioscopy was performed under dark ambient lighting standardized at less than 1 lux illumination (EA30 EasyView Light Meter [Extech Instruments]) with a 1-mm light beam and a Goldmann-type 1-mirror goniolens (Haag-Streit AG) before pupillary dilation. Gonioscopy was performed by 1 of 2 fellowship-trained glaucoma specialists with high intergrader agreement (weighted κ > 0.80).14 Care was taken to avoid light falling on the pupil, inadvertent indentation of the globe, and tilting of the lens of more than 10°. The angle was graded in each quadrant accordingly: grade 0, no structures visible; grade 1, nonpigmented TM visible; grade 2, pigmented TM visible; grade 3, scleral spur visible; and grade 4, ciliary body visible. Cumulative gonioscopy score was calculated as the sum of gonioscopy grades from all 4 quadrants.
AS-OCT imaging was performed along the horizontal (temporal-nasal) and vertical (superior-inferior) meridians with the Visante AS-OCT system (Carl Zeiss Meditec Inc) under dark ambient lighting standardized at less than 1 lux illumination before pupillary dilation. During imaging, eyelids were retracted gently, taking care to avoid inadvertent pressure on the globe. Ultrasound A-scan biometry (CineScan A/B [Quantel Medical]) was performed to measure axial length and lens thickness.
AS-OCT Image Analysis
AS-OCT images were analyzed using the custom Zhongshan Angle Assessment Program, which automatically segmented anterior-segment structures and produced biometric measurements after the scleral spurs were marked.15 Five certified graders who were masked to examination results and intervention assignments confirmed the segmentation and marked the scleral spurs in each image.
In total, 13 biometric parameters describing the anterior segment were measured in each AS-OCT image obtained at the 2-week visit. A representative AS-OCT image is available in eFigure in Supplement 1. These included (1) an angle-opening distance 500 μm and 750 μm anterior to the scleral spur (AOD at 500 μm and AOD at 750 μm, respectively); (2) trabecular iris space area bounded by AOD at 500 μm or AOD at 750 μm (TISA at 500 μm and TISA at 750 μm, respectively): posteriorly by a line drawn from the scleral spur perpendicular to the plane of the inner scleral wall to the opposing iris, superiorly by the inner corneoscleral wall, and inferiorly by the iris surface; (3) iris thickness at 750 μm and 2000 um from the scleral spur (IT at 750 μm and IT at 2000 μm, respectively); (4) iris area (IA); (5) iris curvature (IC); (6) lens vault; (7) anterior chamber depth; (8) anterior chamber width (ACW); (9) anterior chamber area (ACA); and (10) pupillary diameter (PD). A set of 20 images from 20 eyes was selected randomly and graded independently by all 5 graders. Intergrader agreement in the form of intraclass correlation coefficients (ICCs) were excellent for all AS-OCT parameters (ICC >0.83).
Cohort Selection
Cohort A included 1 eye chosen at random from each ZAP trial participant who had bilateral progression or nonprogression. Among participants with unilateral progression, the eye that progressed to PAC or AAC was selectively chosen for analysis. Cohort A was created using a mix of treated and untreated eyes to elucidate the protective mechanism(s) associated with a reduced risk of progression in treated eyes. Cohort B included only treated eyes of ZAP trial participants. Cohort B was created to assess the clinical and ocular biometric predictors of angle closure progression in eyes after LPI.
Statistical Analysis
For parameters with 2 measurements per image (eg, AOD at 750 μm), horizontal and vertical measurements of biometric parameters were averaged. Differences between means of continuous variables were compared between those with angle closure progression and nonprogression using the unpaired t test, whereas categorical variables were compared using the χ2 test. Only horizonal AS-OCT measurements were included in the analyses.
Univariable and multivariable Cox regression models were developed to investigate the associations between clinical and biometric parameters assessed 2 weeks after randomization and angle closure progression in a time-dependent manner for both cohorts A and B. Only 1 AS-OCT measure of angle width was included in multivariable analysis due to multicollinearity, and TISA at 500 μm was ultimately included in multivariable analysis. Multivariable models A, B, and C were limited to 4 variables, and models D, E, and F were limited to 2 variables due to the number of participants with progression in cohorts A and B. Multivariable models A, B, and C were developed to elucidate the anatomic outcomes of LPI that protect against progression, and multivariable models D, E, and F were developed to identify biometric risk factors for progression. Multivariable models G, H, and J were developed to assess the association between progression and persistent narrowing after LPI, defined as angle width based on the lowest quartile of angle width based on horizontal TISA at 500 μm measurements (≤0.05 mm2), gonioscopic angle status (closed = gonioscopy grade 0 or 1 in ≥2 quadrants), or cumulative gonioscopy scores (≤6). Data were analyzed from January 4 to December 22, 2022, using SAS, version 9.4 (SAS Institute). Statistical analyses were conducted using a significance level of <.05; all P values were 2-sided but were not adjusted for multiple analyses.
Results
Among the 889 ZAP trial participants, 11 participants were excluded due to missing 2-week AS-OCT data. Cohort A included 878 eyes of 878 participants (mean [SD] age, 58.9 [5.0] years; 726 female [82.7%]; 152 male [17.3%]), of whom 44 experienced progressive disease. There were 433 untreated eyes and 445 treated eyes in cohort A (13 eyes [29.6%] treated with LPI), 31 (70.4%) of whom were untreated. When comparing vertical AS-OCT measurements in participants with progression of disease and those without progression, there was no difference found. In mixed cohort A, participants who experienced angle closure progression had significantly older age (mean [SD], 60.4 [5.5] years vs 58.8 [5.0] years; P ≤ .03), smaller cumulative gonioscopy score (mean [SD], 3.77 [1.87] vs 5.78 [2.86]; P <.001), and smaller measurements of horizontal AOD at 500 μm (mean [SD], 0.07 [0.07] mm vs 0.12 [0.06] mm; P <.001), horizontal AOD at 750 μm (mean [SD], 0.12 [0.09] mm vs 0.16 [0.07] mm; P =.002), and horizontal TISA at 500 μm (mean [SD], 0.04 [0.03] mm2 vs 0.07 [0.04] mm2; P <.001) at the 2-week visit (Table 1 and Table 2). A smaller proportion of PACS eyes that progressed were treated with an LPI compared with PACS eyes that did not progress (29.6% [13 of 44] vs 51.8% [432 of 834]; P = .004).
Table 1. Differences in Clinical and Biometric Measures Between Those With Angle Closure Progression and Nonprogression Among a Mixed Sample of Treated and Untreated Eyes at 2 Weeks After Laser Peripheral Iridotomy (Cohort A).
| Variable | Mean (SD) | Difference (95% CI) | P value | |
|---|---|---|---|---|
| Nonprogression (n = 834) | Progression (n = 44) | |||
| Age, y | 58.78 (4.96) | 60.43 (5.54) | −1.65 (−3.16 to −0.13) | .03 |
| Sex, No. (%) | ||||
| Female | 690 (82.7) | 36 (81.8) | NA | .88 |
| Male | 144 (17.3) | 8 (18.2) | NA | |
| Treatment, No. (%) | ||||
| Yes | 432 (51.8) | 13 (29.6) | NA | .004 |
| No | 402 (48.2) | 31 (70.4) | NA | |
| IOP, mm Hg | 15.07 (3.29) | 15.48 (3.20) | −0.41 (−1.40 to 0.59) | .42 |
| Cumulative gonioscopy | 5.78 (2.86) | 3.77 (1.87) | 2.01 (1.15 to 2.87) | <.001 |
| Horizontal AOD at 500 μm, mm | 0.12 (0.06) | 0.07 (0.07) | 0.05 (0.03 to 0.07) | <.001 |
| Horizontal AOD at 750 μm, mm | 0.16 (0.07) | 0.12 (0.09) | 0.04 (0.02 to 0.07) | .002 |
| Horizontal TISA at 500 μm, mm2 | 0.07 (0.04) | 0.04 (0.03) | 0.03 (0.02 to 0.04) | <.001 |
| Horizontal TISA at 750 μm, mm2 | 0.12 (0.07) | 0.10 (0.10) | 0.02 (−0.002 to 0.04) | .08 |
| Horizontal IA, mm2 | 1.59 (0.22) | 1.57 (0.20) | 0.02 (−0.05 to 0.10) | .50 |
| Horizontal IT at 750 μm, mm | 0.50 (0.07) | 0.50 (0.06) | 0.00 (−0.02 to 0.02) | .78 |
| Horizontal IT at 2000 μm, mm | 0.62 (0.08) | 0.61 (0.09) | 0.00 (−0.02 to 0.03) | .91 |
| Horizontal IC, mm | 0.31 (0.12) | 0.31 (0.12) | 0.00 (−0.04 to 0.04) | .97 |
| Horizontal ACD, mm | 2.21 (0.20) | 2.17 (0.24) | 0.05 (−0.02 to 0.11) | .17 |
| Horizontal PD, mm | 4.39 (0.72) | 4.53 (0.78) | −0.14 (−0.37 to 0.10) | .26 |
| Horizontal ACW, mm | 11.55 (0.38) | 11.57 (0.42) | −0.01 (−0.14 to 0.12) | .87 |
| Horizontal LV, mm | 0.73 (0.24) | 0.72 (0.29) | 0.01 (−0.06 to 0.09) | .72 |
| Horizontal ACA, mm2 | 16.13 (2.01) | 15.71 (2.48) | 0.42 (−0.25 to 1.08) | .22 |
| LT, mm | 4.87 (0.31) | 4.95 (0.38) | −0.08 (−0.17 to 0.020) | .12 |
| AXL, mm | 22.50 (0.72) | 22.38 (0.69) | 0.12 (−0.10 to 0.34) | .28 |
Abbreviations: ACA, anterior chamber area; ACD, anterior chamber depth; ACW, anterior chamber width; AOD, angle opening distance from the scleral spur; AXL, axial length; IA, iris area; IC, iris curvature; IOP, intraocular pressure; IT, iris thickness from the scleral spur; LT, lens thickness; LV, lens vault; NA, not applicable; PD, pupillary diameter; TISA, trabecular-iris space area from the scleral spur.
Table 2. Univariable and Multivariable Cox Regression Models of Clinical and Biometric Predictors of Progression Among a Mixed Sample of Treated and Untreated Eyes at 2 Weeks After Laser Peripheral Iridotomy (Cohort A).
| Variable | Univariable | Multivariable model A, tdAUROC = 0.75 at 72 mo | Multivariable model B, tdAUROC = 0.74 at 72 mo | Multivariable model C, tdAUROC = 0.79 at 72 mo | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | 1.07 (1.00-1.14) | .04 | 1.08 (1.01-1.15) | .03 | 1.08 (1.01-1.15) | .02 | 1.08 (1.02-1.15) | .01 |
| Sex | 0.96 (0.44-2.09) | .92 | NA | |||||
| IOP | 1.06 (0.96-1.16) | .24 | NA | |||||
| Treatment | 0.40 (0.21-0.77) | .006 | 0.67 (0.34-1.33) | .25 | 1.51 (0.65-3.50) | .34 | 1.59 (0.68-3.76) | .29 |
| Horizontal AOD at 750 μm | 0.91 (0.86-0.98) | .008 | NA | |||||
| Horizontal AOD at 500 μm | 0.86 (0.80-0.93) | <.001 | NA | |||||
| Cumulative gonioscopy | 0.74 (0.66-0.83) | <.001 | NA | NA | 0.70 (0.61-0.80) | <.001 | 0.76 (0.64-0.92) | .003 |
| Horizontal IC | 0.94 (0.07-12.93) | .96 | NA | |||||
| Horizontal IA | 0.59 (0.15-2.32) | .45 | NA | |||||
| Horizontal TISA at 750 μm | 0.95 (0.86-1.05) | .32 | NA | |||||
| Horizontal TISA at 500 μm | 0.71 (0.62-0.82) | <.001 | 0.73 (0.63-0.83) | <.001 | NA | NA | 0.75 (0.66-0.85) | <.0001 |
| Horizontal IT at 750 μm | 0.99 (0.95-1.04) | .78 | NA | |||||
| Horizontal IT at 2000 μm | 0.86 (0.02-32.23) | .94 | NA | |||||
| Horizontal ACD | 0.31 (0.05-1.81) | .20 | NA | |||||
| Horizontal LV | 1.00 (1.00,1.00) | .07 | NA | |||||
| PD | 1.49 (0.78-2.81) | .23 | NA | |||||
| LT | 2.22 (0.64-7.65) | .21 | NA | |||||
| AXL | 0.80 (0.53-1.20) | .29 | NA | |||||
Abbreviations: ACD, anterior chamber depth; AXL, axial length; AOD, angle opening distance from the scleral spur; HR, hazard ratio; IA, iris area; IC, iris curvature IOP, intraocular pressure; IT, iris thickness from the scleral spur; LT, lens thickness; LV, lens vault; PD, pupillary diameter; NA, not applicable; tdAUROC, time-dependent area under the receiver operating characteristic curve; TISA, trabecular-iris space area from the scleral spur.
In multivariable model A (time-dependent area under the receiver operating characteristic curve [tdAUROC] = 0.75 at 72 months), older age (hazard ratio [HR], 1.08 per 1 year; 95% CI, 1.01-1.15; P = .03) and smaller horizontal TISA at 500 μm (HR, 1.37 per 0.01 mm2; 95% CI, 1.20-1.59; P < .001) at the 2-week visit were associated with progression, whereas treatment with LPI (HR, 0.67; 95% CI, 0.34-1.33; P = .25) was no longer protective (Table 2). In multivariable model B (tdAUROC = 0.74 at 72 months), older age (HR, 1.08 per 1 year; 95% CI, 1.01-1.15; P = .02) and smaller cumulative gonioscopy score (HR, 1.43 per 1 grade; 95% CI, 1.25-1.64; P < .001) at the 2-week visit were associated with progression, whereas treatment with LPI was no longer protective (Table 2). In multivariable model C (tdAUROC = 0.79 at 72 months), older age (HR, 1.08 per 1 year; 95% CI, 1.02-1.15; P = .01), smaller cumulative gonioscopy score (HR, 1.32 per 1 grade; 95% CI, 1.09-1.56; P = .004), and smaller horizontal TISA at 500 μm (HR, 1.33 per 0.01 mm2; 95% CI, = 1.18-1.52; P < .001) measured at the 2-week visit were associated with progression, whereas treatment with LPI was no longer associated (Table 2).
Cohort B included 869 treated eyes of 869 participants (mean [SD] age, 58.9 [5.0] years; 717 female [82.5%]; 152 male [17.5%]) of the ZAP trial, of whom 19 experienced progressive disease. Twenty participants from the original 889 were excluded due to missing AS-OCT data. In treated cohort B, participants who experienced angle closure progression had significantly smaller horizontal AOD at 500 μm (mean [SD], 0.09 [0.07] mm vs 0.14 [0.06] mm; P =.002), horizontal AOD at 750 μm (mean [SD], 0.16 [0.11] mm vs 0.20 [0.07] mm; P =.03), horizontal TISA at 500 μm (mean [SD], 0.04 [0.03] mm2 vs 0.07 [0.04] mm2; P <.001), horizonal TISA at 750 μm (mean [SD], 0.08 [0.05] mm2 vs 0.13 [0.07] mm2; P =.002), cumulative gonioscopy scores (mean [SD], 6.16 [1.89] vs 7.84 [2.23]; P =.001), and larger lens vault (mean [SD], 0.85 [0.23] mm vs 0.73 [0.25] mm; P =.04) 2 weeks after LPI than those without progression (Table 3 and Table 4).
Table 3. Differences in Clinical and Biometric Measures Between Those With Angle Closure Progression and Nonprogression Among Treated Eyes at 2 Weeks After LPI (Cohort B).
| Variable, units | Mean (SD) | Difference (95% CI) | P value | |
|---|---|---|---|---|
| Nonprogression (n = 850) | Progression (n = 19) | |||
| Age, y | 58.86 (4.98) | 61.00 (5.83) | −2.14 (−4.42 to 0.13) | .06 |
| Sex, No. (%) | ||||
| Female | 702 (82.6) | 15 (78.9) | NA | .68 |
| Male | 148 (17.4) | 4 (21.1) | NA | |
| Treatment, No. (%) | 850 (97.8) | 19 (2.2) | ||
| IOP, mm Hg | 15.26 (3.35) | 15.63 (3.85) | −0.37 (−1.90 to 1.16) | .64 |
| Cumulative gonioscopy | 7.84 (2.23) | 6.16 (1.89) | 1.68 (0.67 to 2.69) | .001 |
| Horizontal AOD at 500 μm, mm | 0.14 (0.06) | 0.09 (0.07) | 0.04 (0.02 to 0.07) | .002 |
| Horizontal AOD at 750 μm, mm | 0.20 (0.07) | 0.16 (0.11) | 0.04 (0.004 to 0.07) | .03 |
| Horizontal TISA at 500 μm, mm2 | 0.07 (0.04) | 0.04 (0.03) | 0.03 (0.02 to 0.05) | <.001 |
| Horizontal TISA at 750 μm, mm2 | 0.13 (0.07) | 0.08 (0.05) | 0.05 (0.02 to 0.08) | .002 |
| Horizontal IA, mm2 | 1.59 (0.21) | 1.56 (0.20) | 0.03 (−0.06 to 0.13) | .50 |
| Horizontal IT at 750 μm, mm | 0.50 (0.07) | 0.48 (0.06) | 0.02 (−0.01 to 0.05) | .24 |
| Horizontal IT at 2000 μm, mm | 0.61 (0.09) | 0.60 (0.07) | 0.01 (−0.03 to 0.05) | .74 |
| Horizontal IC, mm | 0.23 (0.09) | 0.23 (0.07) | 0.00 (−0.04 to 0.04) | .88 |
| Horizontal ACD, mm | 2.22 (0.20) | 2.19 (0.26) | 0.03 (−0.06 to 0.12) | .52 |
| Horizontal PD, mm | 4.35 (0.72) | 4.43 (0.85) | −0.08 (−0.41 to 0.25) | .62 |
| Horizontal ACW, mm | 11.58 (0.37) | 11.68 (0.50) | −0.10 (−0.27 to 0.07) | .25 |
| Horizontal LV, mm | 0.73 (0.25) | 0.85 (0.23) | −0.12 (−0.23 to −0.003) | .04 |
| Horizontal ACA, mm2 | 16.50 (1.94) | 16.35 (2.45) | 0.15 (−0.74 to 1.04) | .74 |
| Horizontal LT, mm | 4.87 (0.33) | 4.89 (0.31) | −0.02 (−0.16 to 0.13) | .84 |
| Horizontal AXL, mm | 22.50 (0.72) | 22.38 (0.89) | 0.12 (−0.21 to 0.45) | .46 |
Abbreviations: ACA, anterior chamber area; ACD, anterior chamber depth; ACW, anterior chamber width; AOD, angle opening distance from the scleral spur; AXL, axial length; IA, iris area; IC, iris curvature; IOP, intraocular pressure; IT, iris thickness from the scleral spur; LT, lens thickness; LV, lens vault; NA, not applicable; PD, pupillary diameter; TISA, trabecular-iris space area from the scleral spur.
Table 4. Univariable and Multivariable Cox Regression Models of Clinical and Biometric Predictors of Progression Among Treated Eyes at 2 Weeks After Laser Peripheral Iridotomy (Cohort B).
| Variable | Univariable | Multivariable model D, tdAUROC = 0.76 at 72 mo | Multivariable model E, tdAUROC = 0.69 at 72 mo | Multivariable model F, tdAUROC = 0.78 at 72 mo | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | 1.09 (0.98-1.21) | .10 | 1.10 (1.00-1.21) | .06 | 1.10 (0.99-1.22) | .08 | NA | NA |
| Sex | ||||||||
| Female | 0.81 (0.27-2.43) | .70 | NA | |||||
| Male | Reference | |||||||
| IOP | 1.05 (0.89-1.23) | .57 | NA | |||||
| Horizontal AOD at 750 μm | 0.93 (0.83-1.03) | .17 | NA | |||||
| Horizontal AOD at 500 μm | 0.88 (0.80-0.97) | .01 | NA | |||||
| Cumulative gonioscopy score | 1.60 (1.21-2.11) | .001 | NA | NA | 0.72 (0.61-0.84) | <.001 | 0.80 (0.66-0.97) | .02 |
| Horizontal IC | 0.57 (0.01-52.32) | .81 | NA | |||||
| Horizontal IA | 0.46 (0.06-3.42) | .44 | NA | |||||
| PD | 1.06 (0.46-2.42) | .90 | NA | |||||
| Horizontal TISA at 500 μm | 0.72 (0.61-0.84) | <.001 | 0.72 (0.62-0.83) | <.001 | NA | NA | 0.75 (0.64-0.89) | .001 |
| Horizontal TISA at 750 μm | 0.81 (0.71-0.92) | .001 | NA | |||||
| Horizontal IT at 750 μm | 0.02 (0.00-7.42) | .19 | NA | |||||
| Horizontal IT at 2000 μm | 0.44 (0.01-18.11) | .67 | NA | |||||
| Horizontal ACD | 0.48 (0.04-6.45) | .58 | NA | |||||
| Horizontal LV | 1.00 (1.00-1.00) | .06 | NA | |||||
| LT | 1.13 (0.31-4.10) | .85 | NA | |||||
| AXL | 0.79 (0.37-1.71) | .55 | NA | |||||
Abbreviations: ACD, anterior chamber depth; AOD, angle opening distance from the scleral spur; AXL, axial length; HR, hazard ratio; IA, iris area; IC, iris curvature; IT, iris thickness from the scleral spur; IOP, intraocular pressure; LT, lens thickness; LV, lens vault; NA, not applicable; PD, pupillary diameter; tdAUROC, time-dependent area under the receiver operating characteristic curve; TISA, trabecular-iris space area from the scleral spur.
In multivariable model D (tdAUROC = 0.76 at 72 months), among eyes treated with LPI, smaller horizontal TISA at 500 μm (HR, 1.39 per 0.01 mm2; 95% CI, 1.20-1.61; P < .001) was associated with progression, whereas age was not associated (Table 4). In multivariable model E (tdAUROC = 0.69 at 72 months), smaller cumulative gonioscopy score (HR, 1.39 per 1 grade; 95% CI, 1.19-1.64; P < .001) was associated with progression, and age was not associated (Table 4). In multivariable model F (tdAUROC = 0.78 at 72 months), smaller cumulative gonioscopy score (HR, 1.25 per 1 grade; 95% CI, 1.03-1.52; P = .02) and horizontal TISA at 500 μm (HR, 1.33 per 0.01 mm2; 95% CI, 1.12-1.56; P = .001) were associated with progression (Table 4).
In multivariable models G, H, and J, the outcomes of persistent angle narrowing were assessed (Table 5). In multivariable model G (tdAUROC = 0.79 at 72 months), horizontal TISA at 500 μm (≤0.05 mm2) in the lowest quartile (25.0%) after LPI was predictive of progression (HR, 9.41; 95% CI, 3.39-26.08; P < .001). The progression rate of eyes with TISA of 0.05 mm2 or less was 1.15% per eye year compared with 0.15% per eye year in eyes with TISA greater than 0.05 mm2. In multivariable model H (tdAUROC = 0.62 at 72 months), the lowest quartile of gonioscopic angle status (closed) approached but did not reach significance. In multivariable model J (tdAUROC = 0.68 at 72 months), cumulative gonioscopy score (≤6) in the lowest quartile (25.2%) was predictive of progression (HR, 2.80; 95% CI, 1.13-6.93; P = .04). The progression rate of eyes with cumulative gonioscopy score of 6 or less was 0.68% per eye year compared with 0.25% per eye year in eyes with cumulative gonioscopy score greater than 6.
Table 5. Age-Adjusted Cox Regression Models of the Association Between Disease Progression and Categorical Measures (Lowest Quartile) of Horizontal TISA at 500 Micrometers, Gonioscopic Angle Status, and Cumulative Gonioscopy Score Among Treated Eyes at 2 Weeks After Laser Peripheral Iridotomy (Cohort B).
| Variable | Model G, tdAUROC = 0.79 at 72 mo | Model H, tdAUROC = 0.62 at 72 mo | Model J, tdAUROC = 0.68 at 72 mo | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | 1.11 (1.00-1.22) | .06 | 1.09 (0.99-1.21) | .10 | 1.09 (0.99-1.21) | .09 |
| Horizontal TISA at 500 μm (≤0.05 mm2) | 9.41 (3.39-26.08) | <.001 | NA | NA | NA | NA |
| Gonioscopic angle status (closed) | NA | NA | 2.28 (0.91-5.67) | .08 | NA | NA |
| Cumulative gonioscopy score (≤6) | NA | NA | NA | NA | 2.80 (1.13-6.93) | .04 |
Abbreviations: HR, hazard ratio; NA, not applicable; tdAUROC, time-dependent area under the receiver operating characteristic curve; TISA, trabecular-iris space area from the scleral spur.
Discussion
In this cohort study, which used data from the ZAP trial, findings suggest that LPI was associated with protection against progression from PACS to PAC or AAC primarily through its angle-widening effect, and that among LPI-treated eyes, smaller angle width and cumulative gonioscopy score 2 weeks after LPI were independent predictors of progression. Our findings provide insight into the protective mechanism of LPI and suggest the utility of AS-OCT and gonioscopic assessments of angle width for identifying eyes at higher risk of angle closure progression after LPI.
The presumed anatomic benefit of LPI is relief of pupillary block, which leads to angle widening, reduction of IOP, and decreased risk of angle closure progression.9,12,13,16,17 Our findings suggest support of this theory. In the univariable analysis of treated and untreated eyes, treatment with LPI was significantly associated with protection against progression. However, in the multivariable analysis, when LPI treatment status was adjusted for horizontal TISA at 500 μm or cumulative gonioscopy score after LPI, treatment was no longer associated with progression. This suggests that it is primarily the angle-widening effect of LPI that was associated with the protection of PACS eyes from progression. Interestingly, when all 3 of these factors were included in a single model, both horizontal TISA at 500 μm and cumulative gonioscopy score remained significant predictors of progression, which suggests that AS-OCT and gonioscopy provide independent information that may be useful for predicting progression when performed after LPI.
Although LPI reduced the risk of progression by 47% in the ZAP trial, treated eyes still progressed to a study end point at a rate of 0.4% per eye year, highlighting the need to identify factors associated with progression in these eyes.9 Although smaller angle width and flatter iris curvature were predictive of progression in untreated PACS eyes, it was unclear if these anatomic risk factors were conserved after LPI.10 In the univariable analysis of LPI-treated eyes, AS-OCT measurements of angle width and cumulative gonioscopy score after LPI were predictive of progression; however, iris curvature was not. The significant risk conferred by narrower angle width regardless of treatment status is intuitive; narrower angles increase the risk of iridotrabecular contact and obstruction of aqueous outflow. The lack of association between iris curvature and progression risk after LPI could be explained by the iris-flattening effect of LPI and a convergence of iris profiles overall.18 In addition, other anatomic mechanisms of angle closure, including plateau iris configuration and anteriorized lens, likely predominate in determining progression risk after pupillary block is relieved.19,20
There is sparse evidence to guide longitudinal care of PACS eyes after treatment with LPI. Guidelines published by the American Academy of Ophthalmology recommend repeat gonioscopy after LPI, although the precise rationale behind this recommendation is unclear.5 There is no recommendation to perform AS-OCT imaging before or after LPI. Previous studies21,22 identified biometric factors that predicted longitudinal anatomic changes; however, it is difficult to base practice patterns on anatomic outcomes measures alone. Our study results suggest for the first time, to our knowledge, that persistent angle narrowing on AS-OCT and gonioscopy 2 weeks after LPI were predictive of angle closure progression. The progression rate among eyes with persistent angle narrowing on AS-OCT was 1.15% per eye year, which exceeds the rate observed even among untreated eyes (0.8% per eye year). In contrast, progression was exceedingly rare among treated eyes without persistent angle narrowing on AS-OCT (0.15% per eye year). These findings suggest the clinical utility of measuring angle width with AS-OCT or at least assessing cumulative gonioscopy score after LPI; however, the same may not hold true for simply identifying the angle as open or closed. By extension, eyes with persistent angle narrowing by AS-OCT measurements or cumulative gonioscopy score after LPI may benefit from more intensive follow-up, whereas eyes without persistent angle narrowing may require less intensive follow-up.
Although AS-OCT measurements of angle width at the 2-week visit were predictive of progression in both LPI-treated and untreated eyes, cumulative gonioscopy score was only predictive in LPI-treated eyes.10 This finding highlights differences between AS-OCT and gonioscopic angle assessments and provides insight into when each method provides clinically useful information. Although AS-OCT measurements of angle width and cumulative gonioscopy score are well correlated overall, they are poorly correlated among angle closure eyes.23,24 In addition, IOP appears to be better correlated with AS-OCT measurements of angle width than gonioscopy grades.25,26 The disagreement between AS-OCT and gonioscopy in eyes with narrow angles is likely associated with factors independent of angle width that make visualization of the TM on gonioscopy more difficult, such as high iris curvature or shallow anterior-chamber depth.27,28 In the case of progression among PACS eyes, gonioscopic assessments of angle width appeared to be more useful for risk stratification when there was a wider range of angle widths (eg, post-LPI eyes) than a narrower range (eg, untreated eyes).
Older age is a well-established risk factor for more severe PACD and progression in untreated eyes.29 The association of older age with angle closure progression was not statistically significant in univariable or multivariable analyses of post-LPI eyes. The lack of significance could be related to the relatively small number of treated eyes with progression (n = 19), causing our analysis to have insufficient power to capture the association of age. Nevertheless, age-associated changes in ocular biometrics, such as increased lens thickness and lens vault and decreased anterior-chamber depth, contribute to progression of angle closure and remain an important factor in the management of post-LPI eyes.17,18,19
Limitations
Our study has several limitations. First, there were a relatively low number of eyes with progression in our analysis of LPI-treated eyes. This limited our multivariable analysis to 2 variables and may have prevented us from identifying other significant but weakly predictive factors. However, this is an inherent limitation of longitudinal studies on progression from PACS to PAC or AAC, which remains a rare event, especially after LPI treatment. Second, our relatively simple multivariable models predicting progression produced only moderate predictive performance. The development of more robust models, perhaps using machine learning methods, may help with more precise detection of high-risk eyes. Finally, our study population was comprised of only Chinese people aged between 50 to 70 years with bilateral PACS and clear lenses or nonvisually significant cataracts. Therefore, our findings may not be generalizable to other demographic groups or patients with more severe angle closure and/or cataracts, and additional studies in independent cohorts are needed to validate the observed variables associated with progression.
Conclusions
In conclusion, this cohort study highlights the potential importance of post-LPI angle assessments and provides initial evidence toward establishing clearer guidelines about long-term monitoring of PACS eyes after primary treatment with LPI. These topics merit further investigation as LPI remains the first-line treatment for many patients with PACD without visually significant cataracts, despite recent trends moving away from LPI and toward earlier lens extraction.7,8,9 Further research directed toward optimizing anatomic outcomes after LPI may also be beneficial for delivering precision care to patients with PACS and mitigating the risk of PACG-associated blindness.
eFigure. Representative AS‐OCT Image With AS‐OCT Measurements Labeled
Data Sharing Statement
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Associated Data
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Supplementary Materials
eFigure. Representative AS‐OCT Image With AS‐OCT Measurements Labeled
Data Sharing Statement