Biometric Risk Factors for Angle Closure Progression After Laser Peripheral Iridotomy.

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.

Angle closure extent, anterior segment dimensions and intraocular pressure.

AIM: To investigate the association between the extent of iridotrabecular contact and other quantitative anterior segment dimensions measured by swept-source optical coherence tomography (SS-OCT; CASIA SS-1000, Tomey, Nagoya, Japan) with intraocular pressure (IOP). METHODS: Cross-sectional study. All subjects who were ≥50 years with no history of glaucoma, ocular surgery or trauma, underwent SS-OCT imaging (eight equally spaced radial scans), Goldman applanation tonometry and gonioscopy on the same day. We measured iridotrabecular contact (ITC) index and area, total volume of trabeculo-iris space area and angle opening distance at 500 and 750 from the scleral spur (TISA 500 and 750, AOD 500 and 750, respectively), anterior chamber depth (ACD), volume, area and width, pupil diameter, lens vault and iris volume.Their relationship with IOP (dependent variable) was assessed by locally weighted scatterplot smoothing (Lowess) regression with change-point analysis and generalised additive models adjusted for confounders. RESULTS: 2027 right eyes of mostly Chinese Singaporeans (90%) were analysed. ITC index above a threshold of ~60% (95% CI 34% to 92%) was significantly associated with higher IOP. Independent of the extent of ITC, ACD was also significantly associated with higher IOP below a threshold of 2.5 mm (95% CI 2.33 mm to 2.71 mm). Greater ITC index and shallower ACD had a joint association with IOP. A model including ACD and ITC index was more predictive of IOP than a model considering these variables separately, particularly for women with gonioscopically closed angles (R2 52.7%, p<0.05). CONCLUSIONS: The extent of angle closure and the ACD below a certain threshold had a significant joint association with IOP. These parameters, as biometrical surrogates of mechanical obstruction of the aqueous outflow, may jointly contribute to elevated IOP, particularly in women with gonioscopic angle closure.

Generalisability and performance of an OCT-based deep learning classifier for community-based and hospital-based detection of gonioscopic angle closure.

PURPOSE: To assess the generalisability and performance of a deep learning classifier for automated detection of gonioscopic angle closure in anterior segment optical coherence tomography (AS-OCT) images. METHODS: A convolutional neural network (CNN) model developed using data from the Chinese American Eye Study (CHES) was used to detect gonioscopic angle closure in AS-OCT images with reference gonioscopy grades provided by trained ophthalmologists. Independent test data were derived from the population-based CHES, a community-based clinic in Singapore, and a hospital-based clinic at the University of Southern California (USC). Classifier performance was evaluated with receiver operating characteristic curve and area under the receiver operating characteristic curve (AUC) metrics. Interexaminer agreement between the classifier and two human examiners at USC was calculated using Cohen's kappa coefficients. RESULTS: The classifier was tested using 640 images (311 open and 329 closed) from 127 Chinese Americans, 10 165 images (9595 open and 570 closed) from 1318 predominantly Chinese Singaporeans and 300 images (234 open and 66 closed) from 40 multiethnic USC patients. The classifier achieved similar performance in the CHES (AUC=0.917), Singapore (AUC=0.894) and USC (AUC=0.922) cohorts. Standardising the distribution of gonioscopy grades across cohorts produced similar AUC metrics (range 0.890-0.932). The agreement between the CNN classifier and two human examiners (Ò =0.700 and 0.704) approximated interexaminer agreement (Ò =0.693) in the USC cohort. CONCLUSION: An OCT-based deep learning classifier demonstrated consistent performance detecting gonioscopic angle closure across three independent patient populations. This automated method could aid ophthalmologists in the assessment of angle status in diverse patient populations.

Towards 'automated gonioscopy': a deep learning algorithm for 360° angle assessment by swept-source optical coherence tomography.

AIMS: To validate a deep learning (DL) algorithm (DLA) for 360° angle assessment on swept-source optical coherence tomography (SS-OCT) (CASIA SS-1000, Tomey Corporation, Nagoya, Japan). METHODS: This was a reliability analysis from a cross-sectional study. An independent test set of 39 936 SS-OCT scans from 312 phakic subjects (128 SS-OCT meridional scans per eye) was analysed. Participants above 50 years with no previous history of intraocular surgery were consecutively recruited from glaucoma clinics. Indentation gonioscopy and dark room SS-OCT were performed. Gonioscopic angle closure was defined as non-visibility of the posterior trabecular meshwork in ≥180° of the angle. For each subject, all images were analysed by a DL-based network based on the VGG-16 architecture, for gonioscopic angle-closure detection. Area under receiver operating characteristic curves (AUCs) and other diagnostic performance indicators were calculated for the DLA (index test) against gonioscopy (reference standard). RESULTS: Approximately 80% of the participants were Chinese, and more than half were women (57.4%). The prevalence of gonioscopic angle closure in this hospital-based sample was 20.2%. After analysing a total of 39 936 SS-OCT scans, the AUC of the DLA was 0.85 (95% CI:0.80 to 0.90, with sensitivity of 83% and a specificity of 87%) to classify gonioscopic angle closure with the optimal cut-off value of >35% of circumferential angle closure. CONCLUSIONS: The DLA exhibited good diagnostic performance for detection of gonioscopic angle closure on 360° SS-OCT scans in a glaucoma clinic setting. Such an algorithm, independent of the identification of the scleral spur, may be the foundation for a non-contact, fast and reproducible 'automated gonioscopy' in future.

Ocular Biometric Risk Factors for Progression of Primary Angle Closure Disease: The Zhongshan Angle Closure Prevention Trial.

PURPOSE: To assess baseline ocular biometric risk factors for progression from primary angle closure suspect (PACS) to primary angle closure (PAC) or acute angle closure (AAC). DESIGN: Prospective, observational study. PARTICIPANTS: Six hundred forty-three mainland Chinese with untreated PACS. METHODS: Participants underwent baseline clinical examinations, including gonioscopy, anterior segment OCT (AS-OCT) imaging, and A-scan ultrasound biometry as part of the Zhongshan Angle Closure Prevention (ZAP) Trial. Primary angle closure suspect was defined as an inability to visualize pigmented trabecular meshwork in 2 or more quadrants based on static gonioscopy. Primary angle closure was defined as development of intraocular pressure above 24 mmHg or peripheral anterior synechiae. Progression was defined as development of PAC or an AAC attack. Multivariable logistic regression models were developed to assess biometric risk factors for progression. MAIN OUTCOME MEASURES: Six-year progression from PACS to PAC or AAC. RESULTS: Six hundred forty-three untreated eyes (609 nonprogressors, 34 progressors) of 643 participants were analyzed. In a multivariable model with continuous parameters, narrower horizontal angle opening distance of 500 µm from the scleral spur (AOD500; odds ratio [OR], 1.10 per 0.01-mm decrease; P = 0.03), flatter horizontal iris curvature (IC; OR, 1.96 per 0.1-mm decrease; P = 0.01), and older age (OR, 1.11 per 1-year increase; P = 0.01) at baseline were associated significantly with progression (area under the receiver operating characteristic curve [AUC], 0.73). Smaller cumulative gonioscopy score was not associated with progression (OR, 1.03 per 1-modified Shaffer grade decrease; P = 0.85) when replacing horizontal AOD500 in the multivariable model. In a separate multivariable model with categorical parameters, participants in the lowest quartile of horizontal AOD500 (OR, 3.10; P = 0.002) and IC (OR, 2.48; P = 0.014) measurements and 59 years of age or older (OR, 2.68; P = 0.01) at baseline showed higher odds of progression (AUC, 0.72). CONCLUSIONS: Ocular biometric measurements can help to risk-stratify patients with early angle closure for more severe disease. Anterior segment OCT measurements of biometric parameters describing the angle and iris are predictive of progression from PACS to PAC or AAC, whereas gonioscopy grades are not.

Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome.

PURPOSE: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation. DESIGN: Retrospective case study. PARTICIPANTS: A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort. METHODS: Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account. MAIN OUTCOME MEASURES: Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation. RESULTS: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001). CONCLUSIONS: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Non-optical coherence tomography modalities for assessment of angle closure.

Primary angle closure glaucoma is a leading cause of irreversible blindness, particularly in Asia. Its pathophysiology is based in the closure of the anterior chamber angle (ACA). In addition to gonioscopy (current reference standard), in the past decade, anterior segment optical coherence tomography (AS-OCT) has been incorporated in routine ophthalmic practice to help assess the configuration of the ACA. Especially in nonspecialist ophthalmology practice, gonioscopy may be less frequently performed and AS-OCT may not be available, leading to the need of other anterior segment evaluation methods. Evaluating the anterior chamber depth (ACD) has long been recognized as screening tool for primary angle-closure glaucoma. It can be measured with several devices, such as Scheimpflug photography and the scanning peripheral ACD analyzer. It can also be estimated with the oblique flashlight test and van Herick technique (limbal ACD assessment). More recently, goniophotographic systems have been developed to produce images of the ACA similar to those seen with manual gonioscopy. NGS-1 automated gonioscope (NIDEK Co, Gamagori, Japan) and the RetCam (Natus Medical Incorporated, Pleasanton, CA) are commercially available. However, NGS-1 is the only one with a specialized software for ACA imaging. Several prototype devices are currently being developed, such as the GonioPEN and axicon lens assisted gonioscopy. This article aims to review different modalities of ACA assessment, beyond AS-OCT, and compare their relative advantages and disadvantages.

Evaluation of meridional scans for angle closure assessment with anterior segment swept-source optical coherence tomography.

BACKGROUND/AIMS: As swept-source optical coherence tomography (SS-OCT) simultaneously obtains 128 meridional scans, it is important to identify which scans are playing the main role in classifying gonioscopic angle closure to simplify the analysis. We aimed to evaluate the diagnostic performance of every meridional scan in its ability to detect gonioscopic angle closure. METHODS: Observational study with 2027 phakic subjects consecutively recruited from a community polyclinic. Gonioscopy and SS-OCT were performed. Gonioscopic angle closure was defined as non-visibility of the posterior trabecular meshwork in ≥180° of the angle, while SS-OCT was defined as iridotrabecular contact anterior to the scleral spur. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic performance of each single scan, the sequential anticlockwise cumulative effect of those single scans and different combinations of them. RESULTS: The AUCs of each scan ranged from 0.73 to 0.82. The single scan at 80°-260° had the highest AUC (0.82, 95% CI 0.79 to 0.84) and performed significantly better than most of the temporonasal scans (from 0° to 52° and from 153° to 179°). The superoinferior scans achieved higher AUCs compared with the temporonasal ones. When assessing the cumulative effect of adding individual scans consecutively, the peak AUC (0.80) was obtained when considering the superoinferior scans closer to 80°-85°, but no further positive cumulative effect was seen when adding the rest of the temporonasal scans of the circumference. CONCLUSIONS: In conclusion, the single SS-OCT scan at 80°-260° had the highest diagnostic performance. Our study suggests that the 360° evaluation may not translate to better clinical utility for detection of gonioscopic angle closure.

Understanding diagnostic disagreement in angle closure assessment between anterior segment optical coherence tomography and gonioscopy.

BACKGROUND/AIMS: Although being a more objective tool for assessment and follow-up of angle closure, reliability studies have reported a moderate diagnostic performance for anterior segment optical coherence tomography (OCT) technologies when comparing with gonioscopy as the reference standard. We aim to determine factors associated with diagnostic disagreement in angle closure when assessed by anterior segment swept source OCT (SS-OCT, CASIA SS-1000; Tomey, Nagoya, Japan) and gonioscopy. METHODS: Cross-sectional study. A total of 2027 phakic subjects aged ≥50 years, with no relevant previous ophthalmic history, were consecutively recruited from a community polyclinic in Singapore. Gonioscopy and SS-OCT (128 radial scans) for the entire circumference of the angle were performed for each subject. A two-quadrant closed gonioscopic definition was used. On SS-OCT images, angle closure was defined as iridotrabecular contact (ITC) to the extent of ≥35%, ≥50% and ≥75% of the circumferential angle. Diagnostic disagreements between both methods, that is, false positives or overcalls and false negatives or undercalls were defined, respectively, as gonioscopic open/closed angles inversely assessed as closed/open by SS-OCT. RESULTS: Two hundred and seventy-two (14.7%) resulted in overcall results (false positives) when ≥50% of the angle circumference was closed using SS-OCT. These eyes had significantly wider (anterior chamber width, 11.7 vs 11.6 mm, p<0.001) and deeper (anterior chamber depth (ACD), 2.4 vs 2.2 mm, p<0.001) anterior chambers than eyes assessed by both methods as closed (true positives). Deeper ACD (OR 9.31) and lower lens vault (LV) (OR 0.04) were significantly associated with a false positive diagnosis in the multivariate analysis. Most of these cases had short (52.6%) or irregular (39%) ITC in SS-OCT images. CONCLUSIONS: We found that anterior chamber dimensions, determined by ACD and LV, were factors significantly associated with diagnostic disagreement between anterior segment SS-OCT and gonioscopy in angle closure assessment.

Recent advances in anterior chamber angle imaging.

Differentiating the two main forms of primary glaucoma (open-angle and closed-angle glaucoma) depends on the correct assessment of the anterior chamber angle (ACA). This assessment will determine the management plan and prognosis for the disease. The standard method of examining the angle has been, for many years, slit-lamp gonioscopy. This method, although clinically still useful, is less robust for patient follow up and clinical research, given its low reproducibility. Several imaging technologies have been developed in recent years to improve the evaluation of the ACA and overcome the shortcomings of gonioscopy. These recent advances include three-dimensional and 360° analysis by Swept-Source OCT (SS-OCT, CASIA, Tomey, Nagoya, Japan), the introduction of deep learning algorithms for automatic imaging classification and new goniophotographic systems. SS-OCT allows for the first time the assessment of the circumferential extension of angle closure with moderate to good diagnostic performance compared with gonioscopy. Deep learning algorithms are showing promising results for the automation of imaging analysis, and may potentially save physicians' time in regards of the interpretation of the images. Lastly, goniophotograph systems have the distinct advantage of recordability of gonioscopic findings and are most closely matched to the findings of slit-lamp gonioscopy.

Assessment of Circumferential Angle Closure with Swept-Source Optical Coherence Tomography: a Community Based Study.

PURPOSE: To evaluate the diagnostic performance of swept-source optical coherence tomography (SS-OCT, CASIA SS-1000; Tomey Corporation, Nagoya, Japan) for angle closure detection, in comparison with gonioscopy, in a community setting. DESIGN: Reliability analysis. METHODS: A total of 2027 phakic subjects aged ≥50 years, with no previous history of glaucoma, laser (including peripheral iridotomy), intraocular surgery, or ocular trauma, were consecutively recruited from a community polyclinic in Singapore. Gonioscopy was performed by a single trained ophthalmologist. SS-OCT angle scans, which obtain radial scans for the entire circumference of the angle, were analyzed by a single examiner, masked to the subject's clinical details. On SS-OCT images, angle closure was defined as contact between the iris and any part of the angle wall anterior to the scleral spur. Different cutoff values of the degree of circumferential angle closure (≥35%, ≥50%, and ≥75%) were taken for analysis to assess SS-OCT performance in detecting angle closure. RESULTS: A total of 1857 subjects (91.6%) were included in the final analysis after excluding poor-quality SS-OCT scans. Almost 90% of the subjects were Chinese, with a mean age of 61.8 ± 6.7 years, and more than half were women (63.5%). The overall AUC of SS-OCT manual grading against gonioscopy was 0.84 (95% confidence interval, 0.81-0.88). The prevalence of angle closure on SS-OCT was 26.1% for the ≥35% definition, with an area under the curve of 0.80 (0.77-0.84), sensitivity of 82.5% (75.3%-88.4%), and specificity of 78.5% (76.5%-80.4%). The first-order agreement coefficient statistics for the 2-quadrant gonioscopic definition of angle-closure with corresponding ≥35%, ≥50%, and ≥75% angle closure definitions for SS-OCT were good at 0.89 (0.83-0.93), 0.88 (0.842-0.93), and 0.88 (0.831-0.99), respectively. CONCLUSIONS: In this large community-based study, SS-OCT exhibited moderate performance for angle closure detection compared to gonioscopy as the reference standard.

Role of anterior segment optical coherence tomography in angle-closure disease: a review.

This article aims to review the published literature pertaining to the use of anterior segment optical coherence tomography (AS-OCT) in the evaluation of angle-closure disease. Searches on the available published literature were last conducted on 15 June 2017. Rated as Level I evidence, we found that AS-OCT has shown good sensitivity and moderate diagnostic accuracy to detect narrow angles when compared with gonioscopy. AS-OCT quantitative and qualitative parameters demonstrated strong association with the presence of gonioscopically closed angles. This technology provides an objective non-contact method of assessing the angle that is well tolerated by the patient and correlates well with the information provided by gonioscopy.