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: Caloric restriction (CR) has been shown in animal models to increase longevity and delay the effects of aging. This study investigates the effect of CR on ocular tissues in a cohort of human subjects adopting a particular CR lifestyle (CRWay). Methods: Age matched healthy controls and CRWay members with no general or ocular co-morbidities underwent a full ophthalmic examination including visual field (VF) and optical coherence tomography (OCT) (Cirrus HD-OCT) testing. Duration of time in the CRWay, body mass index (BMI), axial length, central corneal thickness, VF mean deviation (MD) and OCT measured retinal nerve fiber layer (RNFL) thickness, cup to disc (C/D) ratio, and ganglion cell inner plexiform layer (GCIPL) thickness were analyzed. Multivariate linear regressions were used to estimate RNFL and GCIPL thicknesses using the above variables. Results: Nine CRWay subjects (18 eyes) were compared to a population of 23 age-matched controls (46 eyes). The average age of all subjects was 60.8+/-10.4 years, and the duration of time in the CRWay ranged from 2-36 years. The average BMI was 20.7+/-1.6 for the CR participants and 28.3+/-5.2 for the control group. GCIPL thickness was negatively associated with BMI for the CRWay group. Multivariate analyses showed that C/D ratio, BMI, participation in the CR lifestyle, and the interaction terms between these variables were significant in the model for predicting RNFL thickness and GCIPL thickness (all p-values<0.03). Conclusions: A chronic CR lifestyle shows a significant effect on ocular structures, deserving further investigation in a larger cohort and investigation into the mechanisms of action

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: 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

Although it is well documented that abnormal levels of either intraocular (IOP) or intracranial pressure (ICP) can lead to potentially blinding conditions, such as glaucoma and papilledema, little is known about how the pressures actually affect the eye. Even less is known about potential interplay between their effects, namely how the level of one pressure might alter the effects of the other. Our goal was to measure in-vivo the pressure-induced stretch and compression of the lamina cribrosa due to acute changes of IOP and ICP. The lamina cribrosa is a structure within the optic nerve head, in the back of the eye. It is important because it is in the lamina cribrosa that the pressure-induced deformations are believed to initiate damage to neural tissues leading to blindness. An eye of a rhesus macaque monkey was imaged in-vivo with optical coherence tomography while IOP and ICP were controlled through cannulas in the anterior chamber and lateral ventricle, respectively. The image volumes were analyzed with a newly developed digital image correlation technique. The effects of both pressures were highly localized, nonlinear and non-monotonic, with strong interactions. Pressure variations from the baseline normal levels caused substantial stretch and compression of the neural tissues in the posterior pole, sometimes exceeding 20%. Chronic exposure to such high levels of biomechanical insult would likely lead to neural tissue damage and loss of vision. Our results demonstrate the power of digital image correlation technique based on non-invasive imaging technologies to help understand how pressures induce biomechanical insults and lead to vision problems.

There is increasing clinical evidence that the eye is not only affected by intraocular pressure (IOP), but also by intracranial pressure (ICP). Both pressures meet at the optic nerve head of the eye, specifically the lamina cribrosa (LC). The LC is a collagenous meshwork through which all retinal ganglion cell axons pass on their way to the brain. Distortion of the LC causes a biological cascade leading to neuropathy and impaired vision in situations such as glaucoma and idiopathic intracranial hypertension. While the effect of IOP on the LC has been studied extensively, the coupled effects of IOP and ICP on the LC remain poorly understood. We investigated in-vivo the effects of IOP and ICP, controlled via cannulation of the eye and lateral ventricle in the brain, on the LC microstructure of anesthetized rhesus monkeys eyes using the Bioptigen spectral-domain optical coherence tomography (OCT) device (Research Triangle, NC). The animals were imaged with their head upright and the rest of their body lying prone on a surgical table. The LC was imaged at a variety of IOP/ICP combinations, and microstructural parameters, such as the thickness of the LC collagenous beams and diameter of the pores were analyzed. LC microstructure was confirmed by histology. We determined that LC microstructure deformed in response to both IOP and ICP changes, with significant interaction between the two. These findings emphasize the importance of considering both IOP and ICP when assessing optic nerve health.

The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral autoregulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and the oxygen supply might be unstable. Lassen's blood flow autoregulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact autoregulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to autoregulation impairment. Non-invasive methods for monitoring blood flow autoregulation are therefore needed. We propose to use Near infrared spectroscopy (NIRS) to fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We pe erformed experiments on non-human primates during exsanguination to demonstrate that the limits of blood flow autoregulation can be accessed with NIRS.

Ocular imaging has been heavily incorporated into glaucoma management and provides important information that aids in the detection of disease progression. Longitudinal studies have shown that the circumpapillary retinal nerve fiber layer is an important parameter for glaucoma progression detection, whereas other studies have demonstrated that macular parameters, such as the ganglion cell inner plexiform layer and optic nerve head parameters, also are useful for progression detection. The introduction of novel technologies with faster scan speeds, wider scanning fields, higher resolution, and improved tissue penetration has enabled the precise quantification of additional key ocular structures, such as the individual retinal layers, optic nerve head, choroid, and lamina cribrosa. Furthermore, extracting functional information from scans such as blood flow rate and oxygen consumption provides new perspectives on the disease and its progression. These novel methods promise improved detection of glaucoma progression and better insight into the mechanisms of progression that will lead to better targeted treatment options to prevent visual damage and blindness.