Randomized Trial to Evaluate the Efficacy of the Nanodropper Device for Pupillary Dilation and Cycloplegia in Children.

PURPOSE: We evaluated the noninferiority of 10.4 µl of eye drops eluted with a commercially available eye drop adapter, the Nanodropper (Nanodropper, Inc), on pupillary dilation and cycloplegia in children compared with the standard of care (SOC), 50 µl of eye drops. DESIGN: Prospective randomized trial. PARTICIPANTS: Pediatric patients scheduled for routine pupillary dilation at the University of California, San Francisco, at the Pediatric Ophthalmology Clinic were enrolled. Each participant provided 1 eye for the intervention group (Nanodropper) and 1 eye for the control group (SOC). METHODS: Participants were randomized to receive small-volume dilating drops in 1 eye (Nanodropper) and SOC dilating drops in the other eye. Dilation was performed using 1 drop each of 1% cyclopentolate, 1% tropicamide, and 2.5% phenylephrine. Refraction and pupillometry were obtained before and 30 minutes after dilation. A noninferiority analysis was performed to assess change from before to after dilation in spherical equivalent and in pupil constriction percentage and maximum pupil diameter after dilation. MAIN OUTCOME MEASURES: Spherical equivalent, maximum pupil diameter, and pupil constriction percentage. RESULTS: One hundred eyes of 50 patients were included, with a mean ± standard deviation age of 9 ± 3 years. After controlling for baseline measurements, the spherical equivalent after dilation was 0.05 diopter (D) more (95% confidence interval [CI], -0.28 to 0.37 D) in the Nanodropper arm, which did not achieve noninferiority. Maximum pupil diameter after dilation was lower in the Nanodropper group (mean, -0.01 mm; 95% CI, -0.20 to -0.03), which did achieve noninferiority. Constriction percentage after dilation was 0.57 percentage points more (95% CI, -1.38 to 2.51 percentage points) in the Nanodropper group, which did not achieve noninferiority. CONCLUSIONS: Administration of eye drops using a small-volume adapter demonstrated similar efficacy to SOC in a pediatric population. Strict noninferiority was met only for pupillary dilation and not for cycloplegia or constriction percentage; however, the small differences in the effect of the Nanodropper versus SOC on all primary outcomes were not clinically significant. We conclude that small-volume eye drops have the potential to decrease unnecessary medical waste and medication toxicity while maintaining therapeutic effect. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Biomarkers for primary open-angle glaucoma progression.

Glaucoma is a heterogeneous group of progressive optic neurodegenerative. Although most patients with primary open angle glaucoma (POAG) are stable for many years, certain subgroups of POAG patients could progress over time even with treatment. This study is to identify aqueous humor (AH) biomarkers that may be associated with disease progression in POAG patients. Gene differential expression study of prospectively collected AH from patients with stable or progressive POAG. Metagenomic deep sequencing (MDS) was performed on the aqueous fluid of 20 patients with stable POAG and 20 patients with progressive POAG. Differential gene expression analysis was performed to identify host transcriptome signatures. A total of 21 transcripts were differentially expressed between groups. Differential transcripts identified by MDS. Twenty transcripts were up-regulated and 1 transcript was down-regulated in progressive POAG patients compared to stable patients. Of those, 11 transcripts were eye-related, and 5 transcripts were related to glaucomatous phenotypes (Fibronectin type III domain containing 3B (FNDC3B), Clusterin (CLU), Proprotein convertase subtilisin/kexin type 6 (PCSK6), Cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), and Rho guanine nucleotide exchange factor 4 (ARHGEF4)). Biomarkers associated with POAG progression can be identified from aqueous fluid. Identification of the biomarkers may improve glaucoma surveillance for progressive POAG.

The Relationship Between Health Insurance Status and Diabetic Retinopathy Progression.

Objective: To determine if baseline diabetic retinopathy (DR) severity mediates the relationship between health insurance status and DR progression. Design: Retrospective cohort study. Subjects: Seven hundred sixteen patients aged ≥ 18 years with a diagnosis of type 1 or 2 diabetes mellitus, and a diagnosis of nonproliferative DR (NPDR) were identified from the electronic health record of a tertiary academic center between June 2012 and February 2022. Methods: NPDR severity at baseline was the proposed mediator in the relationship between insurance status and proliferative DR (PDR) progression. Logistic regression was used to determine the association between insurance status and NPDR severity at baseline, and Cox proportional hazards regression was used to assess the association between insurance status and time to PDR progression. To analyze the mediation effect of NPDR severity at baseline, a counterfactual approach, which decomposes a total effect into a natural direct effect and a natural indirect effect was applied. Main Outcome Measures: Time to progression from first NPDR diagnosis to first PDR diagnosis. Results: Of the 716 patients, 581 (81%) had Medicare or private insurance, 107 (15%) had Medicaid, and 28 (4.0%) were uninsured at their baseline eye visit. Uninsured or Medicaid patients had a higher proportion of moderate or severe NPDR at their baseline eye visit and a higher proportion of progression to PDR. After adjusting for confounders and NPDR severity at baseline, patients who were uninsured had significantly greater risk of progression to PDR compared with that of patients with Medicare/private insurance (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.10-6.25). Patients with Medicaid also had an increased risk of progression to PDR compared with that of patients with Medicare/private insurance, although not statistically significant (HR: 1.53; 95% CI: 0.81-2.89). NPDR severity at baseline mediated 41% of the effect of insurance status (uninsured vs. Medicare/private insurance) on PDR progression. Conclusions: Patients who were uninsured were more likely to have an advanced stage of NPDR at their baseline eye visit and were at significantly greater risk of progression to PDR compared with patients who had Medicare or were privately insured. Mediation analysis revealed that differences in baseline NPDR severity by insurance explained a significant proportion of the relationship between insurance status and DR progression. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Deep Learning Classification of Angle Closure based on Anterior Segment OCT.

PURPOSE: To assess the performance and generalizability of a convolutional neural network (CNN) model for objective and high-throughput identification of primary angle-closure disease (PACD) as well as PACD stage differentiation on anterior segment swept-source OCT (AS-OCT). DESIGN: Cross-sectional. PARTICIPANTS: Patients from 3 different eye centers across China and Singapore were recruited for this study. Eight hundred forty-one eyes from the 2 Chinese centers were divided into 170 control eyes, 488 PACS, and 183 PAC + PACG eyes. An additional 300 eyes were recruited from Singapore National Eye Center as a testing data set, divided into 100 control eyes, 100 PACS, and 100 PAC + PACG eyes. METHODS: Each participant underwent standardized ophthalmic examination and was classified by the presiding physician as either control, primary angle-closure suspect (PACS), primary angle closure (PAC), or primary angle-closure glaucoma (PACG). Deep Learning model was used to train 3 different CNN classifiers: classifier 1 aimed to separate control versus PACS versus PAC + PACG; classifier 2 aimed to separate control versus PACD; and classifier 3 aimed to separate PACS versus PAC + PACG. All classifiers were evaluated on independent validation sets from the same region, China and further tested using data from a different country, Singapore. MAIN OUTCOME MEASURES: Area under receiver operator characteristic curve (AUC), precision, and recall. RESULTS: Classifier 1 achieved an AUC of 0.96 on validation set from the same region, but dropped to an AUC of 0.84 on test set from a different country. Classifier 2 achieved the most generalizable performance with an AUC of 0.96 on validation set and AUC of 0.95 on test set. Classifier 3 showed the poorest performance, with an AUC of 0.83 and 0.64 on test and validation data sets, respectively. CONCLUSIONS: Convolutional neural network classifiers can effectively distinguish PACD from controls on AS-OCT with good generalizability across different patient cohorts. However, their performance is moderate when trying to distinguish PACS versus PAC + PACG. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Developing and Validating Models to Predict Progression to Proliferative Diabetic Retinopathy.

Purpose: To develop models for progression of nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and determine if incorporating updated information improves model performance. Design: Retrospective cohort study. Participants: Electronic health record (EHR) data from a tertiary academic center, University of California San Francisco (UCSF), and a safety-net hospital, Zuckerberg San Francisco General (ZSFG) Hospital were used to identify patients with a diagnosis of NPDR, age ≥ 18 years, a diagnosis of type 1 or 2 diabetes mellitus, ≥ 6 months of ophthalmology follow-up, and no prior diagnosis of PDR before the index date (date of first NPDR diagnosis in the EHR). Methods: Four survival models were developed: Cox proportional hazards, Cox with backward selection, Cox with LASSO regression and Random Survival Forest. For each model, three variable sets were compared to determine the impact of including updated clinical information: Static0 (data up to the index date), Static6m (data updated 6 months after the index date), and Dynamic (data in Static0 plus data change during the 6-month period). The UCSF data were split into 80% training and 20% testing (internal validation). The ZSFG data were used for external validation. Model performance was evaluated by the Harrell's concordance index (C-Index). Main Outcome Measures: Time to PDR. Results: The UCSF cohort included 1130 patients and 92 (8.1%) patients progressed to PDR. The ZSFG cohort included 687 patients and 30 (4.4%) patients progressed to PDR. All models performed similarly (C-indices ∼ 0.70) in internal validation. The random survival forest with Static6m set performed best in external validation (C-index 0.76). Insurance and age were selected or ranked as highly important by all models. Other key predictors were NPDR severity, diabetic neuropathy, number of strokes, mean Hemoglobin A1c, and number of hospital admissions. Conclusions: Our models for progression of NPDR to PDR achieved acceptable predictive performance and validated well in an external setting. Updating the baseline variables with new clinical information did not consistently improve the predictive performance. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Relationship Between Optical Coherence Tomography and Anterior Chamber Depth After Pupillary Dilation in Primary Angle Closure Suspects.

PRCIS: Anterior chamber depth (ACD) change after pupillary dilation is correlated with lens vault (LV) and anterior chamber width (ACW), as observed by swept-source optical coherence tomography (SS-OCT) at both horizontal and vertical scans in patients with primary angle closure suspect and cataract. PURPOSE: The purpose of this study is to evaluate the association between ACD and other anterior chamber parameters after pharmacological dilation in patients with primary angle closure suspect and cataract. PATIENTS AND METHODS: SS-OCT was performed for 78 patients at baseline and 1 hour after pharmacological dilation. Measurements were taken at 8 evenly spaced axes at 250, 500, and 750 µm from the scleral spur. Pearson correlation coefficient (ρ) was used to evaluate the relationship between averaged ACD change and other SS-OCT parameters. Multivariable regression analyses were performed to determine the parameters that predict ACD change. RESULTS: Across all 14 dimension and angle parameters, 12 parameters at the 270-degree axis and 10 parameters at the 0-degree axis yielded significant correlations with ACD change (ρ=0.24-0.55, P <0.05). Angle parameters were most significantly correlated to ACD change 750 µm from the scleral spur. The prediction model for ACD change after pharmacological dilation at 0 degree included decreased LV, wider ACW, and increased trabecular iris space area (all P ≤0.001). The prediction model for ACD change at 270 degrees included: decreased LV, wider ACW, larger change in anterior chamber volume, larger baseline anterior chamber volume, and smaller baseline angle opening distance (all P ≤0.03). CONCLUSIONS: LV and ACW, as measured in both vertical and horizontal scans, were found to be determinants of the ACD change after pharmacological pupillary dilation. Examination of these parameters may help identify patients at higher risk of developing angle-closure disease.

Clinical and Visual Field Outcomes Following Minimally Invasive Glaucoma Surgery Combined with Cataract Surgery.

Purpose: To determine the change in Humphrey visual field and clinical parameters after minimally invasive glaucoma surgery combined with cataract surgery. Patients and Methods: Patients undergoing minimally invasive glaucoma surgery combined with cataract surgery in a multicenter retrospective case series between 2013 and 2021 with reliable preoperative and 12 to 18 month postoperative visual field measurements were included. Devices included iStent, XEN, and Hydrus. Clinical parameters were compared with a generalized linear model with generalized estimating equations between preoperative and postoperative visits including best corrected visual acuity, intraocular pressure, number of glaucoma medications and visual fields. Visual field metrics included mean deviation (MD), pattern standard deviation (PSD), visual field index (VFI), and Collaborative Initial Glaucoma Treatment Study (CIGTS) score of total deviation probability and pattern deviation probability. Results: Forty-four eyes from 39 patients were included. During the follow up period, visual acuity improved from 0.23±0.17 to 0.10±0.14 logMAR (mean ± standard deviation, p<0.001), number of glaucoma medications was reduced from 2.68±1.06 to 1.46±1.32 (p<0.001), and intraocular pressure decreased from 17.08±4.23 mmHg to 14.92±3.13 mmHg (p=0.003). Differences across devices were negligible. The only significant difference was a greater reduction in number of glaucoma medications in the XEN group (p<0.001). There were no significant changes in the global parameters of VFI, MD, PSD, or CIGTS. Conclusion: Overall, minimally invasive glaucoma surgery combined with cataract surgery appears to be effective at stabilizing visual field function, reducing intraocular pressure, reducing number of glaucoma medications, and improving visual acuity over a 12 to 18 month follow-up period across MIGS devices.

Anterior Segment OCT in Primary Angle Closure Disease Compared With Normal Subjects With Similar Shallow Anterior Chamber.

PRCIS: Compared with normal subjects with similar shallow anterior chamber depth (ACD), patients with primary angle closure disease (PACD) had narrower angle structures measured by swept-source optical coherence tomography (SS-OCT) at 250 µm from scleral spur (very root of iris), especially along oblique and vertical axis. PURPOSE: To examine anterior segment structures in normal subjects whose ACD was shallow on slit-lamp examination but did not meet the diagnostic criteria of PACD, and to compare them with PACD patients with similar ACD. MATERIALS AND METHODS: Patients were recruited from glaucoma clinic at Zhongshan Ophthalmic Center. A total of 40 eyes from 29 PACD patients and 40 eyes from 34 normal subjects received full ophthalmic examination and CASIA SS-1000 OCT tests. PACD eyes and control eyes were 1:1 matched for ACD at 0 degree of scan. Generalized linear model that accounted for inter-eye correlation was used to compare differences between the 2 groups for intraocular pressure and SS-OCT parameters. P-values were adjusted for multiple comparisons using the Bonferroni method. RESULTS: The PACD and control groups had similar age, but the PACD group had a significantly higher intraocular pressure (18.4 vs. 14.0 mm Hg, P=0.005). Angle parameters, representative of angle area, such as angle recess area and trabecular iris space area measured at 250 µm along axes of 90, 135, 225, and 315 degrees were significantly smaller in PACD group than those of control group (adjusted P<0.05), while most of angle parameters at 500 and 750 µm, volume parameters, and anterior chamber parameters, were similar (adjusted P>0.05). CONCLUSIONS: In PACD patients compared with normal subjects with similar anterior chamber shallowing, OCT findings measured at the iris root 250 µm from the scleral spur, especially in the oblique and vertical axes, including angle recess area and trabecular iris space area, may match gonioscopic findings more closely and provide further insight into mechanisms of PACD.

Survey of the American Glaucoma Society Membership on Current Glaucoma Drainage Device Placement and Postoperative Corticosteroid Use.

Purpose: To assess practice patterns and opinions of glaucoma specialists regarding glaucoma drainage device tube shunt placement and post-operative anti-inflammatory medication use. We also assess the perceived need for a randomized control trial to compare them. Patients and Methods: An online survey was distributed to a group of glaucoma specialists from the American Glaucoma Society via the American Glaucoma Society forum from April to August 2021. Results: One hundred and twenty-eight responses were included. Ninety percent placed tubes in the anterior chamber. Sixty-one percent reported that evidence suggested the superiority of sulcus tube placement over the anterior chamber, whereas 34% reported there was not enough evidence to suggest superiority of either in preventing endothelial cell loss. Comparing these techniques for intraocular pressure control, 49% reported evidence suggested sulcus tube placement superiority whereas 46% reported there was not enough evidence. Over 40% of respondents reported that they were either unfamiliar with literature or that there was not enough evidence to support the superiority of difluprednate 0.05% over prednisolone 1% for post-operative use in preventing endothelial cell loss and for intraocular pressure control. Ninety percent and 81% of respondents respectively would benefit from randomized control trials comparing outcomes of anterior chamber vs sulcus tube placement and post-operative corticosteroid usage. Conclusion: Most glaucoma specialists surveyed place glaucoma drainage device tube in the anterior chamber over the sulcus. A randomized control trial to determine optimal tube placement and post-operative anti-inflammatory medication use for preventing endothelial cell loss would change current glaucoma drainage device practice patterns.