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

Purpose: To determine the role of CSFP and the CON in ONH biomechanics. Methods: We extended our previous numerical model of the ONH (IOVS. 2005; 46: 4189-4199) to include more detailed anatomy (Fig. 1). The model was parameterized on 28 factors representing tissue geometry, material properties, pressures (CSFP, IOP and central retinal artery blood pressure [BP]) and the CON (free or fully fixed). 8,350 unique models were generated to examine factor influences in two steps: a fractional factorial design of experiments (DOE) to identify the ten most influential factors, followed by a response surface methodology (RSM) to determine factor eflects precisely. Standard DOE and RSM techniques were used to determine the contributions of the factors and their interactions to the variances of 94 response measures. Results: CSFP was the sixth most influential factor (Fig. 2a). Particularly strong were its contributions to the variations in the lamina cribrosa (LC) stretch and the peripapillary sclera (PPS) rotation. In fact, CSFP influence on PPS rotation was more than twice that of IOP. The eflects of CSFP elevation were distinct from those of IOP (Fig. 2b). The CON had a large effect on the ONH response. Its influence on the LC displacement was 15 times more than that of IOP. The displacement and rotation of the PPS, as well as the rotation of the canal wall were also more sensitive to the CON than IOP. BP influence on the responses was 633 smaller than that of IOP. Conclusions: CSFP is an important factor in ONH biomechanics, with a stronger influence than the scleral thickness and the lamina radius. CSFP and IOP affect different aspects of ONH biomechanics, suggesting that translaminar pressure difference (IOP-CSFP) may be insuficient to predict glaucomatous optic nerve damage. The CON may drastically affect the geometric responses of the ONH and should be considered when conducting ex-vivo inflation testing

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: Glaucoma is the 2nd leading cause of irreversible blindness, and eye drop adherence rates are around 50%. Recent studies have shown that glaucoma patients have interest in using a free application to aid adherence. The purpose of this study is to investigate the demographics of patients interested in a behavioral economics based smartphone app developed by NYU Ophthalmology, Duke University, and Pattern Health, and measure their drop adherence, satisfaction and intraocular pressure during the study. Methods: After IRB-approved informed consent, patients with primary open angle glaucoma on at least two drops downloaded the app, and their glaucoma regimen was entered. Reminders were sent by push notifications and patients indicated adherence within the app. A virtual pet "Virgil the Turtle" was used to motivate adherence - the pet was happy with good adherence, but was despondent when users did not respond. Intraocular pressure was measured every 2-4 weeks. Post-study surveys are to be given at the study conclusion. Results: 5 of an expected 25 patients have entered the study. Mean age was 70.4 years (SD+13.2, range 57-85), 60% were Caucasian, and 3 were male. The most common reason for not enrolling was difficulty attending IOP checks. Of those refusing enrollment, average age was 70.9 (SD+13). 52% were male and 78% were Caucasian. In pre-study surveys, average expected experience using the app was 7.6 out of 10, SD +2.6 (range 4-10, 10 most positive). Average predicted drop adherence during the study was 9.2, SD +1.3, (range 7-10) vs pre-study, subjective adherence of 8, SD+ 1.6 (range 6-10). Patients rated their expected increase in compliance as a result of Virgil the turtle to be 5.6, SD +4.3 (range 1-10). The patient with the best adherence (100%), was noted to have the best IOP reduction, at 26%. The patient with the lowest adherence (39%) was noted to have the highest IOP increase, at 20%. Conclusions: Preliminary results suggest that a behavioral economics based smartphone app can enhance adherence, but Virgil the Turtle will play only a modest role. Comfort with the app was not dependent upon age. Better adherence as measured by the app was associated with improved IOP lowering. Future work aims to investigate alternate methods of motivation, and analyze long term adherence and IOP. Optimizing compliance can reduce costs and improve patient outcomes by avoiding expensive and invasive treatments