Faculty Bibliography

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 : 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 : To investigate the least variable sampling location for OCT retinal nerve fiber layer (RNFL) thickness measurements on rhesus macaque monkeys, for determining the preferred sampling location. Methods : In vivo three-dimensional spectral-domain OCT scans (Leica, Chicago, IL) were obtained as raster scan data (400x400x1024) in a 5x5x1.6 mm region (human equivalent, not the actual size in the monkey eye) centered on the optic nerve head (ONH) of 33 healthy adult rhesus macaques (19 males, 14 females; ages 3.0-10.7 years). The ONH scans of 48 eyes were analyzed using OCT segmentation software of our own design to calculate point-by-point RNFL thickness measurements. Mean RNFL thickness was computed on consecutive concentric circles within the scan window, centered on the geometric ONH center and starting at the optic disc margin (between 64-119 circles). The least variable RNFL measurement area was identified in the vicinity of the RNFL peak within the 2 mum deviation. Results : The least variable RNFL was observed in between 98.88+/-11.82 and 114.4+/-11.32 pixels from the ONH center with the peak RNFL at 106.42+/-11.55 pixels (Figure 1). Note that the number of available eyes in each sampling location varied as detailed in Figure 2. For comparison, the radius of the OCT scan circle conventionally used in humans is 1.7 mm, or 136 pixels, from the center of the ONH. Conclusions : In order to obtain less variable circumpapillary RNFL thickness measurements on rhesus macaque monkey eyes, it is recommended to use a sampling circle with a radius of approximately 106 pixels from the ONH center, which is smaller than the human equivalent

Purpose : Falls risk increases with glaucoma. Gait impairments occur in people with glaucoma; however, they do not fully explain why greater visual field loss results in higher fall rates (Mihailovic 2020). Harmonic ratios, which are derived based on the frequency analysis of trunk acceleration signals, quantify step-to-step gait symmetry and have been associated with falls risk in older adults (Bellanca 2013). Harmonic ratios have not been examined in glaucoma. This pilot study tested the hypothesis that gait symmetry will be reduced with worse visual field loss in glaucoma, particularly under sensory challenging conditions and increased attention demands. Methods : Ten adults with glaucoma (6F/4M, 67+/-8 years), instrumented with motion capture markers (Vicon Motion Systems Ltd, UK) and accelerometers (Delsys Inc., MA), were asked to walk in 8 conditions with varying floor (hard floor, carpet), light (well-lit, dim) and concurrent information processing (IP) task conditions (no task, auditory IP choice reaction time task). Glaucoma severity was determined using the visual field mean deviation (VF MD) assessed by automated Humphrey perimetry (Zeiss, CA). The VF MD measured in the better/worse eye and averaged across the 10 participants was equal to -2.9+/-3.8 / -7.5+/-6.7 dB, respectively. The analyses used mixed linear models with the fixed effects including VF MD either in the better eye or worse eye, floor/light condition, IP condition and the first order interaction of these factors. Subject was added as a random effect. The dependent gait measure was the anteroposterior (AP) harmonic ratio (Bellanca 2013). Statistical significance was set at 0.05. Results : Visual field MD in the better eye was associated with the AP harmonic ratio (F(1,8)=11.9, p=0.009), i.e. step-to-step gait symmetry in the anteroposterior direction was reduced with worse visual field loss in the better eye. In addition, the main effect of floor/light condition was associated with the AP harmonic ratio (F(3,58)=8.4, p<0.0001). Post-hoc analyses found this effect was driven by a change in floor condition. All other effects included in the analyses did not reach statistical significance (p>0.1). Conclusions : Gait symmetry is reduced in glaucoma and thus may be an important metric. Further research is needed to determine if reduced gait symmetry is associated with increased falls risk in this population

Purpose/UNASSIGNED:The purpose was to establish the position of the fovea centralis to the optic nerve via en-face, near-infrared spectral domain optical coherence tomography (NIR-OCT) in healthy patients. This may shed light on physiological variability and be used for studying subtle cases of foveal ectopia in macular pathology and after retinal detachment. Methods/UNASSIGNED:SD-OCT data of 890 healthy eyes were retrospectively analyzed. Exclusion criteria included axial myopia causing tilting of the optic disc, peripapillary atrophy >1/3 the width of the disc, macular images excluding greater than half of the optic disc, and patients unable to maintain vertical head positioning. Two independent reviewers measured the horizontal and vertical distance from the fovea to the optic disc center and optic disc diameter via cross-sectional and en-face scanning laser ophthalmoloscopy OCT imaging. Results/UNASSIGNED:890 eyes were included in the study. The right and left eyes differed in the horizontal distance from the fovea to the disc center (4359 vs. 4248 µm, P < 0.001) and vertical distance from the fovea to the disc center (464 µm vs. 647, P < 0.001). This corresponded to a smaller angle between the right and left eyes (6.07° vs. 8.67°, P < 0.001). Older age was associated with a larger horizontal (P = 0.008) and vertical distance (0.025). These differences persisted after correcting for axial length in the 487 patients with axial-length data. Conclusions/UNASSIGNED:This study compares the position of the fovea centralis among individuals without macular pathology on a micron level basis. The significant variability between right and left eyes indicates that contralateral eye evaluation cannot be reliably used. Rather, true foveal ectopia requires assessments of preoperative and postoperative NIR-OCT scans. This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia. Translational Relevance/UNASSIGNED:This finding is relevant to retinal detachment cases and evaluation of subtle foveal ectopia.

Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.

OBJECTIVE:Familial Dysautonomia (FD) disease, lacks a useful biomarker for clinical monitoring. In this longitudinal study we characterized the structural changes in the macula, peripapillary and the optic nerve head (ONH) regions in subjects with FD. METHODS:Data was consecutively collected from subjects attending the FD clinic between 2012 and 2019. All subjects were imaged with spectral-domain Optical Coherence Tomography (OCT). Global and sectoral measurements of mean retinal nerve fiber layer (RNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness, and ONH parameters of rim area, average cup-to-disc (C:D) ratio, and cup volume were used for the analysis. The best fit models (linear, quadratic and broken stick linear model) were used to describe the longitudinal change in each of the parameters. RESULTS:91 subjects (149 eyes) with FD of ages 5-56 years were included in the analysis. The rate of change for average RNFL and average GCIPL thicknesses were significant before reaching a plateau at the age of 26.2 for RNFL and 24.8 for GCIPL (- 0.861 µm/year (95% CI - 1.026, - 0.693) and - 0.553 µm/year (95% CI - 0.645, - 0.461), respectively). Significant linear rate of progression was noted for all ONH parameters, except for a subset of subjects (24%), with no cupping that did not show progression in any of the ONH parameters. CONCLUSIONS:The rapidly declining RNFL and GCIPL can explain the progressive visual impairment previously reported in these subjects. Among all structural parameters, ONH parameters might be most suitable for longitudinal follow-up, in eyes with a measurable cup.

PURPOSE/OBJECTIVE:To evaluate the accuracy at which visual field global indices could be estimated from OCT scans of the retina using deep neural networks and to quantify the contributions to the estimates by the macula (MAC) and the optic nerve head (ONH). DESIGN/METHODS:Observational cohort study. PARTICIPANTS/METHODS:A total of 10 370 eyes from 109 healthy patients, 697 glaucoma suspects, and 872 patients with glaucoma over multiple visits (median = 3). METHODS:Three-dimensional convolutional neural networks were trained to estimate global visual field indices derived from automated Humphrey perimetry (SITA 24-2) tests (Zeiss, Dublin, CA), using OCT scans centered on MAC, ONH, or both (MAC + ONH) as inputs. MAIN OUTCOME MEASURES/METHODS:Spearman's rank correlation coefficients, Pearson's correlation coefficient, and absolute errors calculated for 2 indices: visual field index (VFI) and mean deviation (MD). RESULTS:The MAC + ONH achieved 0.76 Spearman's correlation coefficient and 0.87 Pearson's correlation for VFI and MD. Median absolute error was 2.7 for VFI and 1.57 decibels (dB) for MD. Separate MAC or ONH estimates were significantly less correlated and less accurate. Accuracy was dependent on the OCT signal strength and the stage of glaucoma severity. CONCLUSIONS:The accuracy of global visual field indices estimate is improved by integrating information from MAC and ONH in advanced glaucoma, suggesting that structural changes of the 2 regions have different time courses in the disease severity spectrum.