Faculty Bibliography

PURPOSE:To determine whether peripapillary atrophy (PPA) area is an indicator of glaucomatous structural and functional damage and progression. METHODS:In this retrospective longitudinal analysis from ongoing prospective study we qualified 71 eyes (50 subjects) with glaucoma. All subjects had a comprehensive ophthalmic examination, visual field (VF), and spectral-domain optical coherence tomography (OCT) testing in at least three visits. PPA was manually delineated on en face OCT optic nerve head scans, while observing the corresponding cross-sectional images, as the hyper-reflective area contiguous with the optic disc. RESULTS:The mean follow-up duration was 4.4 ± 1.4 years with an average of 6.8 ± 2.2 visits. At baseline, PPA area was significantly associated only with VF's mean deviation (MD; P = 0.041), visual field index (VFI; P = 0.041), superior ganglion cell inner plexiform layer (GCIPL; P = 0.011), and disc area (P = 0.011). Longitudinally, PPA area was negatively and significantly associated with MD (P = 0.015), VFI (P = 0.035), GCIPL (P = 0.009), superior GCIPL (P = 0.034), and disc area (P = 0.007, positive association). CONCLUSIONS:Longitudinal change in PPA area is an indicator of glaucomatous structural and functional progression but PPA area at baseline cannot predict future progression. TRANSLATIONAL RELEVANCE:Longitudinal changes in peripapillary atrophy area measured by OCT can be an indicator of structural and functional glaucoma progression.

PURPOSE/UNASSIGNED:To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures. METHODS/UNASSIGNED:Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography. dMRI parameters of microstructural integrity in the optic radiation and MRS-derived neurochemical levels in the visual cortex were compared among early glaucoma, advanced glaucoma, and healthy controls. Multivariate regression was used to correlate neuroimaging metrics with 16 archetypal VF loss patterns. We also ranked neuroimaging, ophthalmic, and demographic attributes in terms of their information gain to determine their importance to glaucoma. RESULTS/UNASSIGNED:In dMRI, decreasing fractional anisotropy, radial kurtosis, and tortuosity and increasing radial diffusivity correlated with greater overall VF loss bilaterally. Regionally, decreasing intra-axonal space and extra-axonal space diffusivities correlated with greater VF loss in the superior-altitudinal area of the right eye and the inferior-altitudinal area of the left eye. In MRS, both early and advanced glaucoma patients had lower gamma-aminobutyric acid (GABA), glutamate, and choline levels than healthy controls. GABA appeared to associate more with superonasal VF loss, and glutamate and choline more with inferior VF loss. Choline ranked third for importance to early glaucoma, whereas radial kurtosis and GABA ranked fourth and fifth for advanced glaucoma. CONCLUSIONS/UNASSIGNED:Our findings highlight the importance of non-invasive neuroimaging biomarkers and analytical modeling for unveiling glaucomatous neurodegeneration and how they reflect complementary VF loss patterns.

PURPOSE/UNASSIGNED:To establish generalizable pointwise spatial relationship between structure and function through occlusion analysis of a deep-learning (DL) model for predicting the visual field (VF) sensitivities from 3-dimensional (3D) OCT scan. DESIGN/UNASSIGNED:Retrospective cross-sectional study. PARTICIPANTS/UNASSIGNED:A total of 2151 eyes from 1129 patients. METHODS/UNASSIGNED:A DL model was trained to predict 52 VF sensitivities of 24-2 standard automated perimetry from 3D spectral-domain OCT images of the optic nerve head (ONH) with 12 915 OCT-VF pairs. Using occlusion analysis, the contribution of each individual cube covering a 240 × 240 × 31.25 μm region of the ONH to the model's prediction was systematically evaluated for each OCT-VF pair in a separate test set that consisted of 996 OCT-VF pairs. After simple translation (shifting in x- and y-axes to match the ONH center), group t-statistic maps were derived to visualize statistically significant ONH regions for each VF test point within a group. This analysis allowed for understanding the importance of each super voxel (240 × 240 × 31.25 μm covering the entire 4.32 × 4.32 × 1.125 mm ONH cube) in predicting VF test points for specific patient groups. MAIN OUTCOME MEASURES/UNASSIGNED:The region at the ONH corresponding to each VF test point and the effect of the former on the latter. RESULTS/UNASSIGNED:The test set was divided to 2 groups, the healthy-to-early-glaucoma group (792 OCT-VF pairs, VF mean deviation [MD]: -1.32 ± 1.90 decibels [dB]) and the moderate-to-advanced-glaucoma group (204 OCT-VF pairs, VF MD: -17.93 ± 7.68 dB). Two-dimensional group t-statistic maps (x, y projection) were generated for both groups, assigning related ONH regions to visual field test points. The identified influential structural locations for VF sensitivity prediction at each test point aligned well with existing knowledge and understanding of structure-function spatial relationships. CONCLUSIONS/UNASSIGNED:This study successfully visualized the global trend of point-by-point spatial relationships between OCT-based structure and VF-based function without the need for prior knowledge or segmentation of OCTs. The revealed spatial correlations were consistent with previously published mappings. This presents possibilities of learning from trained machine learning models without applying any prior knowledge, potentially robust, and free from bias. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE/UNASSIGNED:Prior evidence suggests racial disparities in the utilization of visual field testing (VFT) for the diagnosis and monitoring of glaucoma. In this study, we considered the effect of baseline glaucoma severity and socioeconomic disadvantage along with other potential confounders such as test reliability, ancillary tests, and glaucoma surgeries on racial disparity in the frequency of VFT. METHODS/UNASSIGNED:The records of all subjects with a diagnosis of glaucoma who received VFT at an academic, tertiary care facility from January 2018 to December 2021 were accessed. Analysis was performed to compare VFT frequency, the total number of office visits (DoS), and the ratio of VFT frequency to DoS (VFT/DoS) across self-reported races while controlling for sex, age, socioeconomic disadvantage (Area Deprivation Index), VF reliability indicators and baseline mean deviation, optical coherence tomography frequency, and glaucoma surgeries. RESULTS/UNASSIGNED:Among the 2654 subjects (1515 White, 782 Black, and 357 Asian) included in this study, Black subjects had the worst socioeconomic status and disease severity at baseline. They also experienced a 3% lower VFT/DoS ratio compared to White subjects (P = 0.031). Asian subjects had a 5% lower VFT/DoS ratio compared to White subjects (P = 0.015). DISCUSSION/UNASSIGNED:We identified racial disparity in performing VFT in subjects with glaucoma even when multiple confounders were considered. Further investigation is necessary to identify other race-associated factors to work toward reducing racial disparities in VFT. TRANSLATIONAL RELEVANCE/UNASSIGNED:Black and Asian subjects with glaucoma receive fewer VFT per visit compared to White subjects even when considering socioeconomic disadvantage and disease severity.

Excitotoxicity from the impairment of glutamate uptake constitutes an important mechanism in neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and Parkinson's disease. Within the eye, excitotoxicity is thought to play a critical role in retinal ganglion cell death in glaucoma, diabetic retinopathy, retinal ischemia, and optic nerve injury, yet how excitotoxic injury impacts different retinal layers is not well understood. Here, we investigated the longitudinal effects of N-methyl-D-aspartate (NMDA)-induced excitotoxic retinal injury in a rat model using deep learning-assisted retinal layer thickness estimation. Before and after unilateral intravitreal NMDA injection in nine adult Long Evans rats, spectral-domain optical coherence tomography (OCT) was used to acquire volumetric retinal images in both eyes over 4 weeks. Ten retinal layers were automatically segmented from the OCT data using our deep learning-based algorithm. Retinal degeneration was evaluated using layer-specific retinal thickness changes at each time point (before, and at 3, 7, and 28 days after NMDA injection). Within the inner retina, our OCT results showed that retinal thinning occurred first in the inner plexiform layer at 3 days after NMDA injection, followed by the inner nuclear layer at 7 days post-injury. In contrast, the retinal nerve fiber layer exhibited an initial thickening 3 days after NMDA injection, followed by normalization and thinning up to 4 weeks post-injury. Our results demonstrated the pathological cascades of NMDA-induced neurotoxicity across different layers of the retina. The early inner plexiform layer thinning suggests early dendritic shrinkage, whereas the initial retinal nerve fiber layer thickening before subsequent normalization and thinning indicates early inflammation before axonal loss and cell death. These findings implicate the inner plexiform layer as an early imaging biomarker of excitotoxic retinal degeneration, whereas caution is warranted when interpreting the ganglion cell complex combining retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses in conventional OCT measures. Deep learning-assisted retinal layer segmentation and longitudinal OCT monitoring can help evaluate the different phases of retinal layer damage upon excitotoxicity.

PURPOSE/UNASSIGNED:Broken stick analysis is a widely used approach for detecting unknown breakpoints where the association between measurements is nonlinear. We propose LIMBARE, an advanced linear mixed-effects breakpoint analysis with robust estimation, especially designed for longitudinal ophthalmic studies. LIMBARE accommodates repeated measurements from both eyes and over time, and it effectively addresses the presence of outliers. METHODS/UNASSIGNED:The model setup of LIMBARE and the computing algorithm for point and confidence interval estimates of the breakpoint were introduced. The performance of LIMBARE and other competing methods was assessed via comprehensive simulation studies and application to a longitudinal ophthalmic study with 216 eyes (145 subjects) followed for an average of 3.7 ± 1.3 years to examine the longitudinal association between structural and functional measurements. RESULTS/UNASSIGNED:In simulation studies, LIMBARE showed the smallest bias and mean squared error for estimating the breakpoint, with an empirical coverage probability of corresponding confidence interval estimates closest to the nominal level for scenarios with and without outlier data points. In the application to the longitudinal ophthalmic study, LIMBARE detected two breakpoints between visual field mean deviation (MD) and retinal nerve fiber layer thickness and one breakpoint between MD and cup-to-disc ratio, whereas the cross-sectional analysis approach detected only one and none, respectively. CONCLUSIONS/UNASSIGNED:LIMBARE enhances breakpoint estimation accuracy in longitudinal ophthalmic studies, and the cross-sectional analysis approach is not recommended for future studies. TRANSLATIONAL RELEVANCE/UNASSIGNED:Our proposed method and companion R package provide a valuable computational tool for advancing longitudinal ophthalmology research and exploring the association relationships among ophthalmic variables.

The cellular-level visualization of retinal microstructures such as blood vessel wall components, not available with other imaging modalities, is provided with unprecedented details by dark-field imaging configurations; however, the interpretation of such images alone is sometimes difficult since multiple structural disturbances may be present in the same time. Particularly in eyes with retinal pathology, microstructures may appear in high-resolution retinal images with a wide range of sizes, sharpnesses, and brightnesses. In this paper we show that motion contrast and phase gradient imaging modalities, as well as the simultaneous acquisition of depth-resolved optical coherence tomography (OCT) images, provide additional insight to help understand the retinal neural and vascular structures seen in dark-field images and may enable improved diagnostic and treatment plans.

OBJECTIVE:To assess the feasibility of remotely training glaucoma patients to take a 10-session clustered virtual reality (VR) visual field (VF) test (Vivid Vision Perimetry [VVP-10]) at home, analyze results for test-retest variability, and assess correspondence with conventional perimetry. DESIGN/METHODS:Cross-sectional study. SUBJECTS/METHODS:Twenty-one subjects with glaucoma were enrolled and included in the feasibility assessment of remote training. Thirty-six eyes were used for test-retest analysis and determination of concordance with the Humphrey Field Analyzer (HFA). METHODS:Subjects were provided with a mobile VR headset containing the VVP-10 test software and trained remotely via video conferencing. Subjects were instructed to complete 10 sessions over a 14-day period. MAIN OUTCOME MEASURES/METHODS:Feasibility was determined by the number of subjects who were able to independently complete VVP-10 over the 14-day period after 1 remote training session. The intraclass correlation coefficient (ICC) for average fraction seen across 10 sessions and the standard error (SE) of the mean were primary outcome measures for assessing test-retest variability. Correlation with HFA mean sensitivity (MS) across eyes, was a secondary outcome measure. RESULTS:Twenty subjects (95%) successfully completed the VVP-10 test series after 1 training session. The ICC for VVP-10 was 0.95 (95% confidence interval [CI], 0.92-0.97). The mean SE in units of fraction seen was 0.012. The Spearman correlations between VVP-10 average fraction seen and HFA MS were 0.87 (95% CI, 0.66-0.98) for moderate-to-advanced glaucoma eyes, and decreased to 0.67 (95% CI, 0.28-0.94) when all eyes were included. CONCLUSIONS:Remote training of patients at home is feasible, and subsequent remote clustered VF testing using VVP-10 by patients on their own, without any further interactions with caregivers or study staff, was possible. At-home VVP-10 results demonstrated low test-retest variability. Future studies must be conducted to determine if VVP-10, taken at home as convenient for the patient, may be a viable supplement to provide equivalent or complementary results to that of standard in-clinic assessment of visual function in glaucoma. FINANCIAL DISCLOSURE(S)/BACKGROUND:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

OBJECTIVE:To examine the longitudinal postoperative outcomes of open versus closed conjunctiva implantation of the XEN45 gel stent. DESIGN/METHODS:Retrospective multicenter study. SUBJECTS/METHODS:One hundred ninety-three patients with glaucoma underwent XEN45 implantation via an open or closed conjunctiva approach. METHODS:Data on patient demographics; diagnoses; preoperative and postoperative clinical data; outcome measures, including intraocular pressure (IOP); use of glaucoma medications; visual acuity; and complications were collected. Statistical analyses were performed with P < 0.05 as significant. MAIN OUTCOME MEASURES/METHODS:Failure was defined as < 20% reduction in IOP from the medicated baseline or a IOP of > 21 mmHg at 2 consecutive visits at postoperative month 1 and beyond, the need for subsequent operative intervention or additional glaucoma surgery, or a catastrophic event, such as loss of light perception. Eyes that had not failed by these criteria and were not on glaucoma medications were considered complete successes. Overall success was defined as those who achieved success either with or without topical medications. RESULTS:Patients were followed for an average of 17 months. Complete success was achieved in 42.5% and 24.7% of the open and closed groups, respectively (P = 0.01). Overall success was achieved in 64.2% and 37.0% of the open and closed groups, respectively (P < 0.001) at the last follow-up. Bleb needling was performed in 12.4% of eyes in the open group compared with 40% of eyes in the closed group. An IOP spike of ≥ 10 mmHg was twice as likely to occur in the closed group compared with the open group during the postoperative period (40% vs. 18%; P = 0.001). CONCLUSIONS:Implantation of XEN45 with opening of the conjunctiva resulted in a lower IOP with greater success and lower needling rate compared with those achieved with the closed conjunctiva technique. Similar rates of postoperative complications and vision loss were noted in each group. Although both procedures provide substantial IOP reduction, the open technique appears to result in higher success rates and fewer postoperative interventions. FINANCIAL DISCLOSURE(S)/BACKGROUND:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE/UNASSIGNED:stimation, especially designed for longitudinal ophthalmic studies. LIMBARE accommodates repeated measurements from both eyes and overtime, and effectively address the presence of outliers. METHODS/UNASSIGNED:The model setup of LIMBARE and computing algorithm for point and confidence interval estimates of the breakpoint was introduced. The performance of LIMBARE and other competing methods was assessed via comprehensive simulation studies and application to a longitudinal ophthalmic study with 216 eyes (145 subjects) followed for an average of 3.7±1.3 years to examine the longitudinal association between structural and functional measurements. RESULTS/UNASSIGNED:In simulation studies, LIMBARE showed the smallest bias and mean squared error (MSE) for estimating the breakpoint, with empirical coverage probability of corresponding CI estimate closest to the nominal level for scenarios with and without outlier data points. In the application to the longitudinal ophthalmic study, LIMBARE detected two breakpoints between visual field mean deviation (MD) and retinal nerve fiber layer thickness (RNFL) and one breakpoint between MD and cup to disc ratio (CDR), while the cross-sectional analysis approach only detected one and none, respectively. CONCLUSIONS/UNASSIGNED:LIMBARE enhances breakpoint estimation accuracy in longitudinal ophthalmic studies, while cross-sectional analysis approach is not recommended for future studies. TRANSLATIONAL RELEVANCE/UNASSIGNED:Our proposed method and companion software R package provides a valuable computational tool for advancing longitudinal ophthalmology research and exploring the association relationships between ophthalmic variables.