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3D Microstructure of the Healthy Non-Human Primate Lamina Cribrosa by Optical Coherence Tomography Imaging

Sainulabdeen, Anoop; Glidai, Yoav; Wu, Mengfei; Liu, Mengling; Alexopoulos, Palaiologos; Ishikawa, Hiroshi; Schuman, Joel S; Wollstein, Gadi
Purpose/UNASSIGNED:The lamina cribrosa (LC) has an important role in the pathophysiology of ocular diseases. The purpose of this study is to characterize in vivo, noninvasively, and in 3D the structure of the LC in healthy non-human primates (NHPs). Methods/UNASSIGNED:Spectral-domain optical coherence tomography (OCT; Leica, Chicago, IL) scans of the optic nerve head (ONH) were obtained from healthy adult rhesus macaques monkeys. Using a previously reported semi-automated segmentation algorithm, microstructure measurements were assessed in central and peripheral regions of an equal area, in quadrants and depth-wise. Linear mixed-effects models were used to compare parameters among regions, adjusting for visibility, age, analyzable depth, graded scan quality, disc area, and the correlation between eyes. Spearmen's rank correlation coefficients were calculated for assessing the association between the lamina's parameters. Results/UNASSIGNED:Sixteen eyes of 10 animals (7 males and 3 females; 9 OD, 7 OS) were analyzed with a mean age of 10.5 ± 2.1 years. The mean analyzable depth was 175 ± 37 µm, with average LC visibility of 25.4 ± 13.0% and average disc area of 2.67 ± 0.45mm2. Within this volume, an average of 74.9 ± 39.0 pores per eye were analyzed. The central region showed statistically significantly thicker beams than the periphery. The quadrant-based analysis showed significant differences between the superior and inferior quadrants. The anterior LC had smaller beams and pores than both middle and posterior lamina. Conclusions/UNASSIGNED:Our study provides in vivo microstructure details of NHP's LC to be used as the foundation for future studies. We demonstrated mostly small but statistically significant regional variations in LC microstructure that should be considered when comparing LC measurements.
PMID: 35435922
ISSN: 2164-2591
CID: 5206252

In Vivo Sublayer Analysis of Human Retinal Inner Plexiform Layer Obtained by Visible-Light Optical Coherence Tomography

Ghassabi, Zeinab; Kuranov, Roman V; Schuman, Joel S; Zambrano, Ronald; Wu, Mengfei; Liu, Mengling; Tayebi, Behnam; Wang, Yuanbo; Rubinoff, Ian; Liu, Xiaorong; Wollstein, Gadi; Zhang, Hao F; Ishikawa, Hiroshi
Purpose/UNASSIGNED:Growing evidence suggests that dendrite retraction or degeneration in a subpopulation of the retinal ganglion cells (RGCs) may precede detectable soma abnormalities and RGC death in glaucoma. Visualization of the lamellar structure of the inner plexiform layer (IPL) could advance clinical management and fundamental understanding of glaucoma. We investigated whether visible-light optical coherence tomography (vis-OCT) could detect the difference in the IPL sublayer thicknesses between small cohorts of healthy and glaucomatous subjects. Method/UNASSIGNED:We imaged nine healthy and five glaucomatous subjects with vis-OCT. Four of the healthy subjects were scanned three times each in two separate visits, and five healthy and five glaucoma subjects were scanned three times during a single visit. IPL sublayers were manually segmented using averaged A-line profiles. Results/UNASSIGNED:The mean ages of glaucoma and healthy subjects are 59.6 ± 13.4 and 45.4 ± 14.4 years (P = 0.02.) The visual field mean deviations (MDs) are -26.4 to -7.7 dB in glaucoma patients and -1.6 to 1.1 dB in healthy subjects (P = 0.002). Median coefficients of variation (CVs) of intrasession repeatability for the entire IPL and three sublayers are 3.1%, 5.6%, 6.9%, and 5.6% in healthy subjects and 1.8%, 6.0%, 7.7%, and 6.2% in glaucoma patients, respectively. The mean IPL thicknesses are 36.2 ± 1.5 µm in glaucomatous and 40.1 ± 1.7 µm in healthy eyes (P = 0.003). Conclusions/UNASSIGNED:IPL sublayer analysis revealed that the middle sublayer could be responsible for the majority of IPL thinning in glaucoma. Vis-OCT quantified IPL sublayers with good repeatability in both glaucoma and healthy subjects.
PMID: 35024761
ISSN: 1552-5783
CID: 5118912

Interplay between intraocular and intracranial pressure effects on the optic nerve head in vivo

Zhu, Ziyi; Waxman, Susannah; Wang, Bo; Wallace, Jacob; Schmitt, Samantha E; Tyler-Kabara, Elizabeth; Ishikawa, Hiroshi; Schuman, Joel S; Smith, Matthew A; Wollstein, Gadi; Sigal, Ian A
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 0.17mm2 at baseline IOP, and contracted BMO area by 0.02 mm2 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 mm2 at baseline ICP, and contracted BMO area by 0.09 mm2 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.
PMID: 34736887
ISSN: 1096-0007
CID: 5038392

Sensory integration abilities for balance in glaucoma, a preliminary study

O'Connell, Caitlin; Redfern, Mark; Chan, Kevin C; Wollstein, Gadi; Conner, Ian P; Cham, Rakié
The goal of this study was to quantify the association between sensory integration abilities relevant for standing balance and disease stage in glaucoma. The disease stage was assessed using both functional (visual field deficit) and structural (retinal nerve fiber layer thickness) deficits in the better and worse eye. Balance was assessed using an adapted version of the well-established Sensory Organization Test (SOT). Eleven subjects diagnosed with mild to moderate glaucoma stood for 3 min in 6 sensory challenging postural conditions. Balance was assessed using sway magnitude and sway speed computed based on center-of-pressure data. Mixed linear regression analyses were used to investigate the associations between glaucoma severity and balance measures. Findings revealed that the visual field deficit severity in the better eye was associated with increased standing sway speed. This finding was confirmed in eyes open and closed conditions. Balance was not affected by the extent of the visual field deficit in the worse eye. Similarly, structural damage in either eye was not associated with the balance measures. In summary, this study found that postural control performance was associated with visual field deficit severity. The fact that this was found during eyes closed as well suggests that reduced postural control in glaucoma is not entirely attributed to impaired peripheral visual inputs. A larger study is needed to further investigate potential interactions between visual changes and central processing changes contributing to reduced balance function and increased incidence of falls in adults with glaucoma.
PMID: 34608185
ISSN: 2045-2322
CID: 5061842

Optical Coherence Tomography and Glaucoma

Geevarghese, Alexi; Wollstein, Gadi; Ishikawa, Hiroshi; Schuman, Joel S
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.
PMID: 34242054
ISSN: 2374-4650
CID: 5011472

Diffusion Tensor Imaging of Visual Pathway Abnormalities in Five Glaucoma Animal Models

Colbert, Max K; Ho, Leon C; van der Merwe, Yolandi; Yang, Xiaoling; McLellan, Gillian J; Hurley, Samuel A; Field, Aaron S; Yun, Hongmin; Du, Yiqin; Conner, Ian P; Parra, Carlos; Faiq, Muneeb A; Fingert, John H; Wollstein, Gadi; Schuman, Joel S; Chan, Kevin C
Purpose:To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI). Methods:Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract. Results:Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls. Conclusions:Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity.
PMID: 34410298
ISSN: 1552-5783
CID: 5010982

Uncertainty estimation for the feature agnostic glaucoma detection based on OCT volumes [Meeting Abstract]

Tahayori, B; Antony, B J; Schuman, J S; Wollstein, G; Ishikawa, H; Garnavi, R
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
ISSN: 1552-5783
CID: 4982392

Variability in schlemm canal anatomical measurements [Meeting Abstract]

Apatoff, M B L; Schuman, J S; Liu, M; Wollstein, G; Ishikawa, H; Wu, M; Zambrano, R; Ede, E; Achanta, P; Kagemann, L
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
ISSN: 1552-5783
CID: 4982312

Oral scutellarin treatment preserves retinal structure and visual function in glaucomatous neurodegeneration [Meeting Abstract]

Zhu, J; Sainulabdeen, A; Adi, V; Akers, K; Sims, J R; Yarsky, E; Yan, Y; Yu, Y; Ishikawa, H; Wollstein, G; Schuman, J S; Leung, C K -S; Wei, W; Chan, K
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
ISSN: 1552-5783
CID: 4982422

Longitudinal age effects of optineurin E50K mutation and deficiency on visual function [Meeting Abstract]

Adi, V; Sims, J; Forlenza, D; Liu, C; Song, H; Hamilton-Fletcher, G; Colwell, N; Faiq, M A; Ishikawa, H; Wollstein, G; Schuman, J S; Tseng, H; Chan, K
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
ISSN: 1552-5783
CID: 4982412