Faculty Bibliography

Intracranial pressure (ICP) has been proposed to play an important role in the sensitivity to intraocular pressure (IOP) and susceptibility to glaucoma. However, the in vivo effects of simultaneous, controlled, acute variations in ICP and IOP have not been directly measured. We quantified the deformations of the anterior lamina cribrosa (ALC) and scleral canal at Bruch's membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three adult monkeys were imaged in vivo with OCT under four pressure conditions: IOP and ICP either at baseline or elevated. The BMO and ALC were reconstructed from manual delineations. From these, we determined canal area at the BMO (BMO area), BMO aspect ratio and planarity, and ALC median depth relative to the BMO plane. To better account for the pressure effects on the imaging, we also measured ALC visibility as a percent of the BMO area. Further, ALC depths were analyzed only in regions where the ALC was visible in all pressure conditions. Bootstrap sampling was used to obtain mean estimates and confidence intervals, which were then used to test for significant effects of IOP and ICP, independently and in interaction. Response to pressure manipulation was highly individualized between eyes, with significant changes detected in a majority of the parameters. Significant interactions between ICP and IOP occurred in all measures, except ALC visibility. On average, ICP elevation expanded BMO area by 0.17mm²â€¯at baseline IOP, and contracted BMO area by 0.02 mm²â€¯at high IOP. ICP elevation decreased ALC depth by 10μm at baseline IOP, but increased depth by 7 μm at high IOP. ALC visibility decreased as ICP increased, both at baseline (-10%) and high IOP (-17%). IOP elevation expanded BMO area by 0.04 mm²â€¯at baseline ICP, and contracted BMO area by 0.09 mm²â€¯at high ICP. On average, IOP elevation caused the ALC to displace 3.3 μm anteriorly at baseline ICP, and 22 μm posteriorly at high ICP. ALC visibility improved as IOP increased, both at baseline (5%) and high ICP (8%). In summary, changing IOP or ICP significantly deformed both the scleral canal and the lamina of the monkey ONH, regardless of the other pressure level. There were significant interactions between the effects of IOP and those of ICP on LC depth, BMO area, aspect ratio and planarity. On most eyes, elevating both pressures by the same amount did not cancel out the effects. Altogether our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

Early detection and monitoring are critical to the diagnosis and management of glaucoma, a progressive optic neuropathy that causes irreversible blindness. Optical coherence tomography (OCT) has become a commonly utilized imaging modality that aids in the detection and monitoring of structural glaucomatous damage. Since its inception in 1991, OCT has progressed through multiple iterations, from time-domain OCT, to spectral-domain OCT, to swept-source OCT, all of which have progressively improved the resolution and speed of scans. Even newer technological advancements and OCT applications, such as adaptive optics, visible-light OCT, and OCT-angiography, have enriched the use of OCT in the evaluation of glaucoma. This article reviews current commercial and state-of-the-art OCT technologies and analytic techniques in the context of their utility for glaucoma diagnosis and management, as well as promising future directions.

Purpose : Alterations in retinal oxygen metabolism are implicated in blindness causing diseases, such as diabetic retinopathy and glaucoma. Therefore, a non-invasive clinical tool to assess oxygen saturation (sO2) in retinal vessels is desirable. Recent development of visible-light optical coherence tomography (vis-OCT) enabled non-invasive sO measurements in retinal blood vessels at micrometer-scale resolution by threedimensional (3D) spectroscopic analysis. Nevertheless, such measurements are susceptible to spectral contaminants from the complex retina anatomy and vis-OCT signal detection and processing, decreasing measurement reliability. To overcome limitations posed by spectral contaminants, we developed adaptive-spectroscopic OCT (AS-OCT), a processing technique that enables non-invasive, 3D, environment-independent sO measurements in the human retina. Methods : We used vis-OCT to image the retinas of 18 healthy volunteers. Light exposure in the eye was < 250 muW and imaging acquisition time was 5 sec. We used adaptive spectroscopic OCT (AS-OCT) to identify and remove contaminants from retinal tissues, chromatic aberrations, and spectrally-dependent roll-off. Then, we automatically selected the optimal depths in the vessel for sO measurement. Finally, we measured the attenuation spectrum in the blood vessel and used a least-squares regression fit with known spectra to determine the sO value. Results : We measured sO in 125 unique retinal vessels near the optic disc (vessel diameters ranging from 37 mum to 176 mum). Major arteries had sO2= 97.9 +/-2.9 % (mean +/-standard deviation) (n = 36), small arteries (diameter < 100 had sO2= 93.2 +/-5.0 % (n = 36), and veins had sO2= 58.5 +/-4.3 % (n = 53). Repeated measurement standard deviations were 2.21% and 2.32% for all arteries and veins, respectively. Fig. 1 shows an oximetry map of the optic disc in the retina of a healthy 23 year-old volunteer. Conclusions : AS-OCT enables environment-independent retinal oximetry in the clinical setting. Repeatability in arteries and veins < 2.5 % indicates robust measurements that are promising for clinical use

Purpose : Repetitive transorbital alternating current stimulation (rtACS) is an application of weak electric current near the eyes used in vision rehabilitation of optic neuropathies (ON). Conceptually rtACS entrains neuronal oscillations, augmenting neuronal function. In subjects with ON we evaluated whether rtACS influenced visual structure and function. Methods : 34 subjects with ON enrolled in a prospective trial underwent comprehensive ophthalmic evaluation, visual field (VF) 24-2 and 10-2 tests (Humphrey Field Analyzer) and OCT (Cirrus HD-OCT) retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thicknesses at baseline and follow-up (FU) visits. Subjects received rtACS 30-to 45-minutes daily for 10 days. Sham subjects (n=4) underwent the same procedures but received no current. Point-by-point analyses of VF total deviation (TD) values were conducted between rtACS and sham groups. Regression analyses determined rate of change for each TD point per eye (significant points with positive rate of change defined as improved, negative rate of change as progressed; insignificant rate of change as no change) and the association between RNFL and GCIPL between groups. Results : The number of FU visits with VF tests ranged 2 to 7, with no significant differences detected between rtACS vs sham groups' FU duration. No significant differences were detected between groups' baseline VF 24-2 and 10-2 mean deviation (MD) values (Table 1). The average numbers of improved points (VF 10-2) and progressed points (VF 24-2) were greater for rtACS while the average number of no change points was greater for sham (VF 24-2, p0.05, Table 1). Further analysis of FU duration determined a significant interaction with rtACS; number of improved points (VF 10-2) and progressed points (VF 24-2, p<0.02) were not sustained over time. No significant differences were detected in average RNFL and GCIPL thicknesses between groups. Conclusions : Preliminary analyses of the effect of rtACS in ON indicate initial improvement but not a clear benefit over time. Detection of differences between rtACS vs sham groups may be biased due to the small sham sample and range of FU duration as VF test-to-test variability is known to increase with worsening VF MD. Future analyses will assess interim effect at early vs late FU time points to evaluate the role of rtACS in vision rehabilitation

Purpose : To improve the performance of the feature agnostic AI-based glaucoma detection algorithm by evaluating an uncertainty score for each prediction. Methods : We previously developed a 5-layer 3D Convolutional Neural Network (CNN) in using the OCT scans from both eyes of 134 healthy, 779 glaucoma patients on a Cirrus HDOCT scanner (200x200 ONH Cubes; Zeiss, Dublin CA). In our analysis, we excluded scans with signal strength less than 7 and downsampled the volumes to 64x64x128 voxels. Uncertainty of AI models can be estimated by computing the effect of randomly ignoring a set of parameters within the network. We randomly zeroed 5% of each of the 5 convolutional layers and computed the entropy in the final score over 20 forward passes. The performance of the approach was assessed using a 10-fold cross validation study. Results : Over the 10-folds, the model showed an AUC of 0.91+/-0.027. In analysing the uncertainty and the probabilistic scores generated by the model (Softmax function) for one fold (see Fig. 1), we observed that a threshold of 0.8 can be used to flag 75% of the false positives and false negatives for further review. On the other hand, only 25% of the healthy controls and 20% of glaucoma patients showed an uncertainty score above that threshold. Fig. 2 summarises the overall uncertainties scores and indicates that low scores are associated with the correctly identified cases while the errors show higher uncertainty scores. Conclusions : The quantitative uncertainty measure provides supplementary information to clinicians and can be used to flag difficult cases automatically. Given that the dataset used in this work is highly imbalanced (more positive cases compared to normal cases) the uncertainty score for true negative cases is significantly higher compared to true positive cases. We expect to achieve lower uncertainty scores for normal cases if more data for normal eyes are available. The uncertainty analysis presented here may aid clinical interpretations of AI-based glaucoma detection outcomes. A separate study will be run to measure this improvement and compare the result with experts' level of uncertainty

Purpose : Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that exhibits a number of neuroprotective effects on the brain and the eye. Here, we investigated the neurobehavioral effects of oral scutellarin treatment in a novel experimental model of chronic glaucoma. Methods : Ten adult C57BL/6J mice (Group 1) were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice (Group 2) received a unilateral intracameral injection of phosphate-buffered saline only. Another eight mice (Group 3) with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin from 1 week before to 2 weeks after hydrogel injection. Tonometry, optical coherence tomography, and optokinetic visuobehavioral testing were performed longitudinally to monitor the IOP, total retinal thickness, visual acuity, and contrast threshold of bilateral eyes in all three groups. Results : Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant IOP difference between scutellarin treatment and untreated groups (Figure site uses cookies. By continuing to use our website, you are agreeing to 1). With scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes (Figure 2). No significant difference in retinal thickness or optokinetic measures was found in the non-injected eyes over time or between all groups. Conclusions : Oral scutellarin treatment appeared to preserve retinal structure and visual function in experimental glaucoma induced by chronic IOP elevation. Scutellarin may be a possible candidate as a novel neurotherapeutic agent for glaucoma treatment

Purpose : Prevalence and severity of glaucoma varies between ethnicities. It has been previously shown that ocular vessel density (VD) varies among healthy subjects of different ethnicities. To further elucidate the potential role of VD in glaucoma we examined ocular VD in Caucasian, African American (AA), and Latin at similar stages of glaucoma severity. Methods : 150 glaucoma eyes of which 46 eyes (30 subjects) were Caucasian, 71 eyes (43 subjects) African American, and 33 eyes (19 subjects) Latin were included in the analysis. Comorbidities known to affect the systemic or local micro-or macro-vasculature and medications that are known to modify vessel diameter were excluded. Disease severity distribution was similar across ethnicity groups. All eyes had comprehensive ophthalmic examination, Cirrus HD-OCT (Zeiss, Dublin, CA) and OCT angiography (OCTA; Angioplex, Zeiss) qualified scans of the macula and optic nerve head regions (200x200 OCT cube scans and 3x3mm / 6x6mm OCTA scans). VD as provided by the device's native software in the inner vascular plexus was used for the analysis. Statistical analysis was performed using mixed-effects models accounting for ethnicity, age, axial length, visual field mean deviation (MD), OCT signal strength (SS), disc area and intra-subject correlation. Tukeyadjusted p-values for pairwise ethnicity comparisons were obtained.Results : No significant difference was detected in age and MD among ethnicities (Table 1). Caucasian subjects had the longest AL and thinnest RNFL, and Latin subjects had the largest disc area and cup-to-disc ratio (CDR; Table 1). No significant differences were detected among ethnicities in ONH VD in any of the scan types and regions. In the macula, Caucasians had significantly higher VD in the center of both scan sizes in comparison with both AA and Latin (Table 2). Caucasian eyes also had significantly higher VD in the full 3x3 scan in comparison with AA eyes. There were no significant differences in the rest of the macular VD measurements among the 3 groups. Conclusions : Macular VD in glaucoma subjects varies among ethnicities and might play a role in the varying disease behavior among ethnicities. Differences in foveal avascular zone size might explain our findings but further investigation is warranted

Purpose : Schlemm canal (SC) is characterized by high local variations in morphology. Previously, we reported characteristics of SC using SC area measurements by optical coherence tomography (OCT) in healthy eyes. Herein, we examine the interobserver variability of SC height, width, and area in glaucomatous and healthy eyes. Methods : The anterior segment of six eyes from three subjects (1 female, 2 male) were imaged using OCT (Cirrus HD-OCT, Zeiss, Dublin, California, USA). A 4x4mm volumetric image of the limbus (depth of 2mm) was acquired with the Anterior Segment Cube scan protocol, comprised of 128 horizontal B-scans composed of 512 A-scans. SC was positioned to the side of the image to maximize visualization of aqueous humor vessel crossings. Scans were processed to maximize visualization of SC; image volumes were averaged (3x3x3 kernel) and contrast was enhanced with the local histogram algorithm using Fiji (version 2.10/1.53c). A cross-sectional B-scan and the two B-scans +/-5 frames were identified as three reference frames, based on best visualized SC location (Fig. 1). Three independent observers performed manual segmentation to measure SC width, height, and cross-sectional area for these three reference frames per volume. Width was defined as the longest measure of SC and height as perpendicular to the line used for width measurement. The observers performed these measurements on 15 volumes for a total of 45 analyzed frames each. The coefficient of variation was calculated based on standard deviations estimated using hierarchical multi-level random-effects models. Interobserver variability was quantified with a two-way ANOVA to calculate the intraclass correlation coefficient (ICC). Results : Participants had a mean age of 72.0 +/- 7.47 years (range: 66 to 82) and consisted of one healthy subject and two with primary open angle glaucoma. Measurement means and variation are presented in Table 1. The ICCs for interobserver variability are excellent for width measurements and low to moderate for height and area (Table 2) Conclusions : Excellent ICC for interobserver variability of SC width suggests it is suitable for use in clinical trials

Purpose : Rhesus macaques are a common animal model in ophthalmology because of the high similarity of their eyes and visual pathway to human. The characterization of optic nerve head (ONH) and peripapillary region in monkeys reported so far mostly involved a manual process which is laborious and subjected to operator errors. It is also usually generated from a cohort of similar age group. In this cross-sectional observational study, we deploy automated and manual segmentations to evaluate the OCT retinal nerve fiber layer (RNFL) thickness, ONH and lamina cribrosa (LC) microstructure parameters in a cohort of free roaming macaques. Methods : In-vivo ONH spectral-domain OCT scans (Leica, Chicago, IL) were obtained by a single experienced operator after excluding eyes with any retinal pathologies. The margins of the optic disc were drawn manually and the resultant scans were analyzed using an automated segmentation software of our own design. The LC microstructure parameters were obtained through a previously described segmentation algorithm. The other parameters of ONH, namely the cup-to-disc (C/D) ratio and minimum rim width (MRW) were assessed manually. Wilcoxon rank sum test was used to test the association of LC parameters, C/D ratio and MRW with age, while the rest of the parameters were analyzed using mixed effects model accounting for age, sex and intra-subject correlation. Results : 29 eyes from 19 monkeys (11 females, 8 males) with age ranging from 4.2 to 23.8 years were analyzed. Males were overall bigger and significantly heavier than females in our cohort (Table 1). Superior RNFL was thicker in male and is the only RNFL parameter that was associated with age or sex in this healthy cohort. No significant association was detected for any of the ONH parameters with age or sex. LC was more visible and thicker in male with higher beam to pore ratio and connective tissue fraction than in female. Conclusions : The characterization of normal macaque eyes from a cohort of free roaming animals is useful as a standard reference to assess pathological changes in future experimental studies

Purpose : Mutations in optineurin (OPTN) are associated with familial normal tension glaucoma and other neurodegenerative diseases. It remains unclear how OPTN loss or mutation alters visual function during aging. Here, we used transgenic mouse models and in vivo assessments to test the hypothesis that OPTN dysfunction contributes to progressive visual impairment through a toxic gain of function mechanism. Methods : Mice with C57BL/6 background were used (Fig 1): wildtype (WT; n=19), homozygous OPTN knock-out (mOPTN-KO; n=13), hemizygous mouse E50K OPTN knock-in (mE50K-het; n=8), homozygous mouse E50K OPTN knock-in (mE50K homoz; n=10), and human E50K OPTN bacterial artificial chromosome overexpression (hE50K BAC; n=6) (PMID: 31076632, 25818176). Intraocular pressure (IOP), total retinal thickness (TRT), visual acuity (VA), and contrast sensitivity (CS) were measured at 6, 12, and 18 months of age in the same mice using the TonoLab rebound tonometer, Bioptigen spectral-domain optical te uses cookies. By continuing to use our website, you are agreeing to coherence tomography imaging, and OptoMotry optokinetic virtual reality system respectively. Left and right eye data were averaged and analyzed using ANOVAs followed by posthoc tests between genotype and age groups, as well as linear regressions for VA versus contrast threshold (CT). Results : Our longitudinal study of the same mice during the aging process showed that IOP remained normal between 10-15 mmHg (Fig 2A). Small to no difference in TRT over time or compared to WT was observed (Fig 2B). mE50K-homoz, mE50K-het, and hE50K BAC mice exhibited greater age-dependent decline in VA and CT than WT or mOPTN-KO mice (Fig 2C, 2D, 2E). In contrast, mOPTN-KO mice showed preservation of VA and CT over time compared to WT. Consistently, mice with one copy of E50K OPTN (mE50K het) experienced less deterioration of VA and CT compared to mice with two copies (mE50K homoz) or mild overexpression (hE50K BAC). Conclusions : Depsite limited IOP and TRT changes between age and genotype groups, E50K OPTN was associated with differential age-dependent visual impairment (greater for CS than VA). Surprisingly, OPTN deficiency preserved visual function such that CS in knockout mice was better than WT mice. Our results suggest visual loss associated with E50K OPTN is due to a toxic gain of function mechanism, and that suppression of OPTN might constitute a therapeutic strategy for glaucomatous neurodegeneration