Faculty Bibliography

Purpose: The shape of the lamina cribrosa (LC) is an important determinant of IOPinduced mechanical stress. Our goals were to analyze monkey LC shapes under normal and elevated IOPs and compare our data to published studies of human LC shape. We measured shape index (SI) and curvedness (C), two measures of intrinsic lamina shape that are independent of external structures. Methods: Optic nerve heads of 7 eyes (6 monkeys) were imaged with SD-OCT while IOP was modulated through cannulas and set at 4 levels: low (5-8 mmHg), baseline (15 mmHg), high (30 mmHg) and very high (40-50 mmHg). Custom code was used to reconstruct anterior LC (ALC) surfaces from manual markings (Tran et al, ARVO 2016) and quantify SI and C (Koenderink, Image and Vis Comp, 1992; Thakku, IOVS, 2015). ALC curvatures K were measured every 1degree as the inverse radius of a circular arc fit, and the SI and C of a surface calculated from the maximum and minimum Ks (Fig 1i). Within each eye, changes of SI and C were compared with baseline and fitted with linear regressions, using eye and IOP as predictors. Results: At baseline IOPs, SI (-0.81+/-0.08, mean +/- SD) was more similar across eyes and monkeys than C (-33+/-12 10 mum ) (Fig 1ii). Neither IOP nor eye were correlated with changes in SI (Fig 2i). IOP was positively correlated with changes in C (beta=1.4x10, p=0.015) (Fig 2ii). Conclusions: At baseline IOP, monkey ALCs had a trough-like shape, without the characteristic central ridge that makes human ALCs saddle rut shaped (Fig 1iii). As IOP increased, monkey ALCs became curvier, without much change in its shape. This is different from human ALCs in which IOP increases cause a decrease in SI from a saddle rut to a trough (Fig 2iii). The fact that there are differences between monkey and human LCs does not mean that the monkey model is not the best model to study LC biomechanics, however, there are differences that we must be aware of. The implications on the susceptibility to glaucoma remain to be determined

Purpose: Task performance is affected by glaucomatous visual field loss. People often use a compensatory strategy singly or in combination to manage the effects of disease to perform daily life tasks. Yet, they may still have difficulty performing daily life tasks. This analysis of cross-sectional data explored the relationship between glaucoma severity and difficulty performing daily life tasks. Methods: We recruited community-dwelling adults aged 50 years and older with glaucoma, no other ocular comorbidities, who underwent full ophthalmic evaluation. We measured glaucoma severity (visual field mean deviation [MD]) and task difficulty (Assessment of Life Habits [LIFE-H]). LIFE-H assesses performance of daily life tasks, in particular task difficulty and use of compensatory strategy. Correlation analyses and logistic regression were conducted to evaluate the association between MD and task difficulty. Results: Subjects (n=87) on average were aged 60 years (range 50-89) and had early stage glaucoma (MD better-seeing eye [Median (Q1, Q3)],-2.45 dB [-4.28,-0.54]). Subjects reported difficulty performing daily life tasks even when they used a compensatory strategy: 48% reported difficulty when using an assistive device/adaptation, 89% reported difficulty when also receiving human assistance, 83% reported difficulty when using both an assistive device/adaptation and human assistance. MD had a negative relationship with task difficulty (Figure; Spearman rho=-0.37, p<0.01). For each 1 dB of worsening MD the odds of reporting difficulty performing daily life tasks increased 0.15 (OR=1.15, p<0.01; age-adjusted). Similar results were obtained with the worse-seeing eye. Conclusions: Our results indicate that task difficulty is related to glaucoma severity. As glaucoma progresses, clinicians need to be aware of its effect on performance of daily life tasks, suggesting consult with vision rehabilitation as disease deteriorates

Purpose: We aim to assess retinal structural integrity, anterograde transport of the visual system and retinal function with optical coherence tomography (OCT), manganese (Mn)-enhanced MRI (MEMRI) and electroretinography (ERG) in our recently established whole eye transplantation (WET) rat model. Methods: Syngeneic orthotopic WET were performed to the right eyes of 9 Lewis rats (Fig.1-A) The donor flaps consisted of tissue anterior to the optic chiasm, a section of temporal bone and skin of the eyelid and external ear. A similar region of tissue was removed in the recipient with the exception of the optic nerve (ON), which was cut at the base of the globe. ON coaptations, anastomoses of carotid arteries and external jugular veins were performed between donors and recipients. OCT was performed at week 1 after WET (n=7). MEMRI was performed at week 3 to evaluate anterograde Mn transport along the visual pathway after binocular intravitreal Mn injections. ERG was performed at week 7 in 2 separate animals to evaluate retinal function. Results: OCT revealed visualization of retinal layers in 5 of the 7 transplanted eyes examined (Fig.1-B), whereas the other 2 eyes had corneal opacities that prevented visualization. MEMRI showed that after intravitreal Mn injections to both eyes, Mn transported anterogradely from the left, untreated eye to the right visual brain centers (Fig.2). Mn enhancement was also observed in the right, transplanted donor eye and intraorbital ON when compared to the eye and visual system prior to Mn injections. No apparent difference in Mn enhancement was observed between left naive and right transplanted intraorbital ON. No apparent Mn enhancement was observed in the right recipient prechiasmatic ON, left lateral geniculate nucleus or left superior colliculus. In ERG, the transplanted eyes showed a-and b-waves in response to light stimulation. Conclusions: OCT imaging revealed the existence of retinal layers after WET. MEMRI data suggested the presence of anterograde Mn transport from the donor eye to the optic nerve up to the site of transection. ERG data suggested some responses to light stimuli in the photoreceptors of transplanted eyes. The ocular viability seen after WET allows the potential for future therapeutic strategies for neuroprotection, ON regeneration and vision restoration

Purpose: To evaluate the ability of OCT optic nerve head (ONH) and macular parameters to detect disease progression in eyes with advanced glaucoma, including those reaching the practical minimal possible thickness measurements (floor effect). Methods: Subjects with advanced glaucoma with >= 4 visits, at least 5 months apart, with Swedish interactive thresholding algorithm 24-2 perimetry (SITA standard; Humphrey Field Analyzer; Zeiss) and spectral-domain OCT (Cirrus HD-OCT; Zeiss) were enrolled. Advanced glaucoma was defined as OCT average circumpapillary retinal nerve fiber layer (cRNFL) <=60um. The OCT measurements that were analyzed were average cRNFL, macular ganglion cell inner plexiform layer thickness (GCIPL), vertical C/D ratio and average C/D ratio, rim area and cup volume. The rate of change of each parameter was computed using a linear mixed effect model (LME) accounting for baseline age, gender and signal strength. Results: Forty-nine eyes (41 subjects) qualified for the study. The average age at baseline was 67 years (range 44-87) and the mean follow-up duration was 40.1 months. At baseline, subjects presented with visual field mean deviation (MD) of-11.38+/- 6.06dB and cRNFL of 55.20+/-3.60 mum. The rate of change for MD over the course of follow-up, while accounting for age at baseline and gender only, was statistically significant (-0.452 dB/yr (p=0.01)). In the same follow-up period, cRNFL rate of change was not significant (0.047 um/yr, p=0.743), while OCT parameters demonstrated a significant rate of change: GCIPL=-0.504 mum/yr (p<0.001); cup volume=0.006 mm³/yr (pO.001); rim area=-0.012 mm²/yr (p<0.001); vertical C/D ratio=0.006/yr (p<0.001); average C/D ratio=0.005/yr (p<0.001). Age, gender and signal strength were not significant in any of the models. Conclusions: Macula and ONH parameters might be useful in following subjects with advanced glaucoma reaching the floor effect of cRNFL measurements

Purpose: Imaging the lamina cribrosa (LC) has gained importance in the understanding and assessment of glaucoma. However, its clinical utility is limited because typical optical coherence tomography (OCT) images of the LC are of poor quality which precludes performing reliable micro-structural analysis. The purpose of this study was to assess an image enhancement technique involving the averaging of multiple OCT volumes. Methods: Repetitive OCT volumes (up to 6 volumes scanned on the same day) from 10 healthy eyes (10 subjects) were acquired using Cirrus HD-OCT (Zeiss, Dublin, CA; software version 7.0.3.19; Optic Disc 200x200 scan pattern). All volumes had signal strength of 7 or above. 3D OCT volumes were first registered to each other using the Elastix software, then super-sampled to 800x800x1024 using 3D bi-cubic interpolation. Signal to noise ratio (SNR) and contrast to noise ratio (CNR) were calculated to quantify the image quality of the visible LC. SNR and CNR were then compared between multiple-volume-averaged images and corresponding single volume images using the Wilcoxon test. Results: Image quality of the visible LC showed notable improvement with multiple volume averaging (Figure 1-6). SNR showed statistically significant improvement from the baseline image quality after 3 or more volumes were averaged (P=0.01), while CNR showed significant improvement from baseline after 2 or more volumes were averaged (P=0.0005) (Figure A, B). Conclusions: The presented image enhancement technique successfully improved image quality of the visible LC. This technique can be applied to any existing OCT images as long as multiple volumes (minimum of 3 volumes) are available on the same eye from the same session in order to improve image quality

Purpose: Guided progression analysis (GPA) is a commonly used glaucoma progression detection method based on optical coherence tomography (OCT) that measures retinal nerve fiber layer (RNFL) thickness obtained with Cirrus HD-OCT. Recently, GPA based on ganglion cell inner plexiform layer (GCIPL) was introduced. The purpose of this study was to assess the agreement in progression detection between GPA using RNFL and GCIPL measurements. Methods: 118 open angle glaucoma eyes (78 subjects), 50 glaucoma suspects eyes (28 subjects), and 4 healthy eyes (2 subjects) that had comprehensive ophthalmic examination and greater than or equal to 5 visits with qualified OCT scans of the macula and optic nerve head regions were enrolled. GPA was used in all eyes with matching dates for baseline and final visits for RNFL and GCIPL analysis. Considering that trend analyses for both regions was previously reported, we focused on the event analysis where "probable event" of progression was defined as the first test showing progression and "likely event" as the one that immediately followed the probable event also showing progression. Stuart-Maxwell test was used for assessing agreement in the categorical analysis of progression. Results: Mean subject age was 68.5 +/- 10.2 years and median baseline visual field mean deviation was -1.5dB ([Q1, Q3]; -4.32, -0.13). The majority of the eyes did not progress, but progression agreement between average RNFL and GCIPL and for superior RNFL and GCIPL showed statistically significant differences (P=0.017 and P<0.001, respectively; Table 1). No difference was detected in agreement for progression between inferior RNFL and GCIPL (P=0.389). Conclusions: Superior and inferior RNFL and GCIPL GPAs showed limited agreement in detecting progression. Further investigation is required to identify the factors affecting this disparity

Purpose: Evaluation of the effect of prelaminar tissue thickness on visualization of the lamina cribrosa (LC) using optical coherence tomography (OCT). Methods: The optic nerve head (ONH) region was scanned using OCT. The quality of visible LC microstructure was assessed subjectively using a grading system and objectively by analyzing the signal intensity of each scan's superpixel components. Manual delineations were made separately and in 3-dimensions quantifying prelaminar tissue thickness, analyzable regions of LC microstructure, and regions with a visible anterior LC (ALC) boundary. A linear mixed effect model quantified the association between tissue thickness and LC visualization. Results: A total of 17 healthy, 27 glaucoma suspect, and 47 glaucomatous eyes were included. Scans with thicker average prelaminar tissue measurements received worse grading scores (P = 0.007), and superpixels with low signal intensity were associated significantly with regions beneath thick prelaminar tissue (P < 0.05). The average prelaminar tissue thickness in regions of scans where the LC was analyzable (214 mum) was significantly thinner than in regions where the LC was not analyzable (569 mum; P < 0.001). Healthy eyes had significantly thicker average prelaminar tissue measurements than glaucoma or glaucoma suspect eyes (both P < 0.001), and glaucoma suspect eyes had significantly thicker average prelaminar tissue measurements than glaucoma eyes (P = 0.008). Significantly more of the ALC boundary was visible in glaucoma eyes (63% of ONH) than in healthy eyes (41%; P = 0.005). Conclusions: Thick prelaminar tissue was associated with impaired visualization of the LC. Healthy subjects generally had thicker prelaminar tissue, which potentially could create a selection bias against healthy eyes when comparing LC structures.

Since the introduction of commercial optical coherence tomography (OCT) systems, the ophthalmic imaging modality has rapidly expanded and it has since changed the paradigm of visualization of the retina and revolutionized the management and diagnosis of neuro-retinal diseases, including glaucoma. OCT remains a dynamic and evolving imaging modality, growing from time-domain OCT to the improved spectral-domain OCT, adapting novel image analysis and processing methods, and onto the newer swept-source OCT and the implementation of adaptive optics (AO) into OCT. The incorporation of AO into ophthalmic imaging modalities has enhanced OCT by improving image resolution and quality, particularly in the posterior segment of the eye. Although OCT previously captured in-vivo cross-sectional images with unparalleled high resolution in the axial direction, monochromatic aberrations of the eye limit transverse or lateral resolution to about 15-20 mum and reduce overall image quality. In pairing AO technology with OCT, it is now possible to obtain diffraction-limited resolution images of the optic nerve head and retina in three-dimensions, increasing resolution down to a theoretical 3 mum3. It is now possible to visualize discrete structures within the posterior eye, such as photoreceptors, retinal nerve fiber layer bundles, the lamina cribrosa, and other structures relevant to glaucoma. Despite its limitations and barriers to widespread commercialization, the expanding role of AO in OCT is propelling this technology into clinical trials and onto becoming an invaluable modality in the clinician's arsenal.