Faculty Bibliography

Purpose : To evaluate the extent of anatomical changes of the retinal ganglion cell axons and trans-neuronal changes in the optic radiation across glaucoma stages using noninvasive MRI and clinical ophthalmic assessments. Methods : This observational, cross-sectional study included 21 advanced glaucoma, 16 early glaucoma, and 13 healthy subjects who underwent spectral-domain OCT imaging of the eye, 3-Tesla anatomical MRI, diffusion tensor imaging (DTI) of the brain, and perimetry. Glaucoma staging criteria were based on recommendation by the American Glaucoma Society ICD-10 coding guidelines. Optic nerve and optic chiasm volumes were manually estimated from anatomical MR images. DTI-derived parametric values [fractional anisotropy (FA), mean diffusivity (DTI-MD), axial diffusivity (AD), and radial diffusivity (RD)] were extracted using manual regions-of-interests drawn on the optic radiation of each hemisphere. The anatomical MRI and DTI parameters were compared to clinical OCT parameters [peripapillary retinal-nerve-fiber-layer (pRNFL) thickness, macular ganglioncell- inner-plexiform layer (GCIPL) thickness, optic nerve head cup-to-disc ratio (C/D)], visual field mean deviation (VF-MD), and to each other using linear mixed-effects models. Each parameter was also compared across groups using one-way MANOVA and receiver operating characteristic (ROC) analyses. Results : From linear mixed effects models, optic nerve and optic chiasm volumes were associated positively with pRNFL thickness and VF-MD (p<0.05), but not GCIPL thickness or C/D. Optic chiasm volume was significantly associated with FA, DTI-MD, and RD, while optic nerve volume was negatively associated only with RD (p<0.05). Summary statistics in Figure 1 indicated significantly thinner pRNFL and higher C/D in early glaucoma than healthy control, whereas volumetric brain measurements, optic radiation DTI parameters (FA and RD), and VF-MD altered significantly between early and advanced glaucoma. ROC analyses in Figure 2 indicated differential abilities among MRI and clinical ophthalmic techniques to distinguish between glaucoma stages. Conclusions : Both volumetric and diffusional brain changes measured from anatomical MRI and DTI may be useful for examining glaucomatous damages along the visual pathway complementary to OCT and perimetry

Purpose : We previously described the two-dimensional continuous time hidden Markov model (2D CT-HMM) to model glaucoma progression using structural and functional measurements simultaneously. The purpose of this study was to validate the glaucoma progression prediction performance of a previously trained model on data collected from a different cohort. Methods : A 2D CT-HMM was trained using optical coherence tomography (OCT; Cirrus HD-OCT, Zeiss, Dublin, CA) mean circumpapillary retinal nerve fiber layer (cRNFL) thickness and visual field index (VFI; Humphrey Field Analyzer, Zeiss) obtained from 107 eyes of 107 subjects, including glaucoma and glaucoma suspect. Average observation period was 4.2 years (7.1 visits). Approximately 1 year of longitudinal data were collected from a separate cohort. 78 eyes of 39 subjects, glaucoma and glaucoma suspect, with an average of 2.2 +/- 0.4 visits were included. After matching the distribution of OCT and VF data on the training cohort, 19 eyes from 14 subjects were selected. The previously trained model was tested on these cases. One visit was used as an input to the model to predict the state at the next visit at least 6 months later, with 4 possible state changes (stable, OCT, VF, or OCT+VF progression). The percentage of correct prediction against the actual recorded state was reported as the prediction accuracy. Results : Baseline age of the test cohort was 58.4 +/- 13.9 years, VFI 93.6 +/- 8.3, mean cRNFL thickness 74.0 +/- 10.9mum. Figure 1 shows the trained model. The size of the circle (state) shows the number of subjects passing through the state. The grayscale of the state indicates the length of time spent there, increasing white to black. Lines indicate state changes, with the blue line being the most likely. This information is also shown in numerical form. The inset shows an example of model use. The calculated prediction accuracy of this pre-trained 2D CT-HMM on test data was 52.6%. Conclusions : Although the glaucoma progression prediction performance of the trained 2D CT-HMM was slightly lower than that previously reported, it is acceptable given the training and testing cohorts were different, and it exceeds the random chance of making a correct prediction, 25%. Furthermore, unlike conventional methods, this model requires only one visit as an input, which makes it a potentially useful tool in the clinical prediction of glaucoma progression. (Figure Presented)

Purpose: When assessing treatment effects in observational studies, the propensity score (PS) method is commonly used to reduce the selection bias of treatments. Weighting subjects by the inverse probability of treatment using the PS mimics treatment s ran e domization e Our y c o ntin as to g apply PS t r website, you are ag ation o g glaucoma treatment c cmeepdtication with rates of structural changes in a longitudinal cohort of glaucoma subjects.
Method(s): Glaucoma subjects treated with prostaglandin, beta blockers, and/or carbonic anhydrase inhibitors (CAIs) with > 2 visits with qualified OCT (Cirrus HD-OCT; Zeiss) were included. Subjects were on medication for at least 3 months prior to each OCT visit. Multinomial PS for baseline medication selection was estimated by baseline age, visual field (VF) mean deviation (MD), intraocular pressure and ethnicity. Rates of change for OCT's average circumpapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses were calculated per eye using linear regression. Their associations with baseline RNFL, GCIPL, baseline medication, post-baseline medication and medication duration were tested using linear regression with and without PS weighting.
Result(s): 207 eyes (117 subjects) were qualified with average age of 62.2+/-12.7 years and median MD of -3.6 dB (IQR -9.0, -1.4) at baseline, and a mean follow-up of 3.2+/-1.8 years. The average duration of treatment range from 1.3+/-1.8 to 2.4+/-2.5 years for CAIs and prostaglandin, respectively. At baseline, average RNFL and GCIPL were 71.5+/-14.4 mum and 65.9+/-13.5 mum. Throughout follow-up, mean rate of change for RNFL and GCIPL were -0.30+/-2.60 mum/year and 0.27+/-7.72 mum/year. Without PS weighting, no medication effect was shown to be associated with either rate of change. With PS weighting, however, the rate of change for RNFL was significantly associated with taking CAIs (-1.26 mum/year, p=0.029) and prostaglandin (-0.98 mum/year, p=0.044) and baseline RNFL (-0.05 mum/year, p=0.017). Longer use of the medications slowed RNFL decrease, although the effects were not statistically significant. No association was detected between treatment and rate of change for GCIPL.
Conclusion(s): PS can be useful to reduce treatment selection bias and facilitate more rigorous estimation of medication effects in observational glaucoma research

Purpose: It has been shown that Asians have a high prevalence of normal tension glaucoma, while Caucasians and African-Americans have predominantly high tension glaucoma. This study compared the lamina cribrosa (LC) microstructure of a cohort of Korean and American eyes in order to discern microstructure differences between the cohorts that could contribute to this phenomenon.
Method(s): The optic nerve head of 53 healthy eyes (42 subjects; 38 Korean eyes and 15 American eyes, consisting of a mixture of Caucasian and African-American eyes) was scanned 3 times during the same session with Cirrus HD-OCT (Zeiss, Dublin CA). These scans were registered and averaged to increase LC visibility using a method we have previously described. The area of the ONH featuring clearly visible LC was delineated, and scans were semi-automatically analyzed within the delineated area to segment the LC microstructure in 3D. The LC measurements of beam thickness, pore diameter, and beam/pore ratio were compared using a hierarchical linear model taking ethnicity and age into account.
Result(s): Baseline characteristics were similar between the cohorts (Table 1). Mean pore diameter was on average 3.78mum bigger in Asian subjects compared to non-Asian subjects (p<0.001), and beam/pore ratio was 0.33 units smaller in Asian subjects (p<0.001). No differences were detected in beam thickness.
Conclusion(s): The in vivo microstructure of the LC varies among different ethnicities. Further research is needed to determine the cause, effect and clinical relevance of these differences. (Table presented)

Purpose: The optic nerve and peripapillary sclera undergo mechanical stresses and strains due to tractional forces as the eyes move. In this study, gaze as a potential cause of lamina cribrosa (LC) deformation was explored in a well-controlled in-vivo animal model at normal and elevated intracranial pressure (ICP).
Method(s): An adult healthy macaque was anesthetized, and OCT (Leica Microsystems, Chicago, IL) scans of the optic nerve head (ONH) (3x3mm; 400x400x1024 pixels) were obtained. A baseline scan was acquired at normal ICP (9mmHg) with the eye at neutral position followed by adduction and abduction positions. ICP was raised to 25mmHg via a ventricular cannula, and scanning was repeated in all gaze settings and locations. All scans were acquired after a 10-minute pause to allow for dissipation of tissue viscoelastic changes. Scans were registered in 3D using our own algorithm and evaluated for macroand microstructure deformation. Lamina microstructure measurements were generated from shared regions among all scanning setting using our own 3D segmentation algorithm.
Result(s): At baseline and elevated ICPs, the IOPs were10 and 19mmHg, respectively. Gaze shifts from the neutral position were associated with a seesaw movement of the macrostructure - nasal elevation and temporal depression in adduction and the reverse effect in abduction (Fig. 1). This effect was more pronounced in elevated ICP condition. At both pressure settings, the ratio of beam thickness to pore diameter increased when gaze deviated from midline (Table 1). The changes seen from neutral to abduction were greater than those seen from neutral to adduction; both findings were more pronounced under elevated ICP.
Conclusion(s): We demonstrated that gaze can induce noticeable macrostructure deformation of the ONH region and a measurable effect on global LC microstructural parameters. Microstructure effects are more pronounced in abduction and in elevated ICP. The magnitude of gaze effect as well as the potential damage to the lamina and its associated axons should be studied further. (Figure presented)

Purpose: Most reported information regarding the in vivo prelaminar tissue is based on a limited number of sampling planes on OCT volumes. In this study we used whole volume data to compute a global mean prelaminar thickness and examined its association with structural and functional parameters in subjects with moderate to advanced glaucoma. Given the low reliability of OCT and visual field (VF) to detect progression in advanced subjects, this study focuses on this subset as it could benefit most from a novel structural parameter.
Method(s): Subjects with moderate to advanced glaucoma, as indicated by a baseline spectral-domain(SD) OCT's mean RNFL thickness <=70mum, were included. All subjects had a baseline prototype swept-source(SS) OCT, VF (Humphrey Field Analyzer, Zeiss), and at least one follow-up SD-OCT (Cirrus HD-OCT, Zeiss). SS-OCT raster scan of the optic nerve head (ONH) (3.5 mmx3.5mm;400x400x861sampling points) was performed. The prelaminar tissue was manually delineated in each SS-OCT cross-section and the mean distance between the vitreous/ONH interface and the anterior lamina surface was automatically computed by averaging the thickness in every sampling point within the ONH. A random mixed effects model was used for assessing the association between baseline prelaminar thickness and cross-sectional variables, and longitudinal changes in structural and functional parameters.
Result(s): 31 eyes from 27 subjects were available for analysis (mean follow-up=20 months). Baseline prelaminar thickness was positively associated with baseline RNFL (average, superior, inferior), GCIPL (average, superior, inferior), rim area, vertical cup to disc ratio (C/D ratio), VFI and MD (p<=0.02) and negatively associated with baseline average C/D ratio and cup volume (p<=0.002;Table). Longitudinal analysis demonstrated that thicker baseline prelaminar tissue was associated with faster rate of progression for average and inferior RNFL thickness and faster enlargement of average and vertical C/D ratio (p<=0.03).
Conclusion(s): Prelaminar tissue thickness is significantly associated with ONH, peripapillary, macular and VF parameters on cross-sectional analysis. On longitudinal analysis prelaminar thickness showed association with faster rate of RNFL progression. Thorough sampling of the prelaminar tissue thickness has the potential to serve as a biomarker for both disease status and risk of progression in subjects with glaucoma. (Table presented)

Purpose: Currently, lowering intraocular pressure (IOP) is the only clinically proven way to treat glaucoma. However, glaucomatous neurodegeneration may still continue after IOP is reduced. Recent studies suggest that citicoline may improve visual outcomes in glaucoma patients, yet its underlying mechanisms remain poorly understood. Here we examined the effects of IOP elevation on visuomotor response and brain functional connectivity (FC) with and without citicoline treatment.
Method(s): Eighty-two Long Evans rats were divided into 6 groups and received acute or chronic IOP elevation to the right eye. Acute IOP elevation was induced by anterior chamber perfusion for 60min at 15mmHg (sham, n=10), 40mmHg (mild, n=12) or 130mmHg (severe, n=12). Chronic IOP elevation was induced by intracameral injection of an optically clear crosslinking hydrogel. A subset of animals (treated, n=19) received daily oral citicoline treatment (500mg/kg) for 7 days prior to, and every 48 hours for 14 days after gel injection, while another 19 rats were not treated orally (untreated). Ten rats received intracameral injection of buffer solution as sham control. IOP and visual acuity (VA) were measured by tonometry and optokinetics, respectively, for 5 weeks. Restingstate FC MRI was acquired at 9.4 Tesla covering the visual brain nuclei at 5 weeks after IOP elevation induction.
Result(s): Hydrogel injection significantly increased IOP for 5 weeks, with no difference between citicoline-treated (25.8+/-0.4mmHg) and untreated (26.4+/-0.5mmHg) groups (p>0.05). Severe acute IOP elevation resulted in lower VA [0.21+/-0.03cycles/degree (c/d)] than mild acute IOP elevation (0.38+/-0.03c/d) at week 5 (p<0.05), whereas VA of the citicoline-treated chronic group (0.31+/-0.01c/d) was higher than the untreated group (0.26+/-0.01c/d) (p<0.05). Larger magnitude of acute IOP elevation caused larger FC differences in subcortical visual nuclei (Fig. 1). In the chronic IOP elevation groups, untreated animals showed significantly decreased cortico-collicular, cortico-geniculate and subcortical FC, while citicoline treatment appeared to preserve or improve such FC (Fig. 2).
Conclusion(s): Increasing magnitude and duration of IOP elevation caused differential effects on visuomotor behavior and functional brain integrity, whereas citicoline ameliorated the effects. These findings merit further investigation into treating glaucoma beyond lowering IOP. (Figure presented)

Purpose : Glaucoma affects task performance, a measure of ability in the context of performing daily tasks. Task factors affected by glaucoma are not well characterized for practical ophthalmic application. This study identifies domains of task performance associated with structure-function measures in order to characterize task factors relevant in the context of glaucoma. Methods : We recruited adults aged 50 years and older with glaucoma, with no other ocular comorbidities, who underwent ophthalmic evaluation. Eleven domains of task performance were analyzed (Table) using the standardized Assessment of Life Habits questionnaire to measure 1) ability to perform tasks (accomplishment, scale 0-10) and 2) satisfaction with task performance (satisfaction, scale 1-5). Better eye visual field mean deviation (MD) and OCT retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) average thickness were analyzed. Multivariable regression analyses determined the association between task performance and MD, RNFL, and GCIPL, adjusting for age, race, glaucoma and depressive symptoms. Depressive symptoms were in the models due to their known association with vision loss. Results : 77 subjects of average age 68 +/- 9.2 years and baseline MD of -3.7 +/- 6.3 dB, RNFL of 76.1 +/- 13.3 mum and GCIPL of 69.8 +/- 10.7 mum were enrolled. Overall task performance scores were high (accomplishment 9.3 +/- 0.6, satisfaction 4.5 +/- 0.5). For accomplishment, MD, RNFL, and GCIPL were significant indicators for overall task performance scores (p < 0.001) and for >=6 domains (p <= 0.028, Table). For satisfaction, RNFL was a significant indicator for overall task performance scores (p = 0.037). Unlike accomplishment, satisfaction was less associated with structure-function (3 domains across measures). Depressive symptoms were significantly associated with task performance (p <= 0.05) in all domains except communication. Conclusions : Task performance affected by glaucoma is underrecognized in ophthalmic practice. Awareness of task performance accomplishment (ability) may be relevant in glaucoma more so than patients' satisfaction. Satisfaction is a measure of patients' perception and their reports often overestimate actual ability. Therefore, measuring accomplishment and its association with structure-function measures may guide future evaluation of those tasks most affected by glaucoma in order to enable timely treatment for task performance limitations

Purpose: Macular ganglion cell-inner plexiform layer (GCIPL) measurement with OCT has been suggested as an alternative for detecting progression in advanced stages of glaucoma. In this study we evaluated if conventional optic nerve head (ONH) and visual field (VF) parameters could be used to detect progression in eyes with advanced structural damage, in which the GCIPL approaches the practical minimal measurable level (floor effect).
Method(s): Subjects with advanced structural glaucoma (average circumpapillary retinal nerve fiber layer (cRNFL) thickness <=60mum) with >= 4 visits with qualified perimetry (Humphrey Field Analyzer; Zeiss) and spectral-domain OCT (Cirrus HD-OCT; Zeiss) were enrolled. Subjects were divided into Change or No change groups based on their GCIPL findings on macular guided progression analysis (GPA). No change was defined as: no change >2mum in average, superior or inferior GCIPL between the first and last visits, no statistically significant rate of change, and no cluster marking change in deviation maps in any visits. Structural (cRNFL, GCIPL and ONH) and functional (VF mean deviation (MD) and visual field index (VFI)) parameters were analyzed using a hierarchical linear model adjusting for eye correlation within subjects. Covariates included were age, ethnicity, signal strength, inclusion in No change group, follow-up duration and its interaction with the No change group.
Result(s): 44 eyes (37 subjects) qualified for the study with 22 eyes (50%) in each group. The average age at baseline was 67.0+/-11.4 years and mean follow-up was 4.1+/-1.8 years. The Change group had significantly thicker average, superior and inferior GCIPLs compared to the No change group at baseline (Table 1). Longitudinal analysis showed significant rates of change for most parameters in the Change group (Table 2). In the No change group, no significant thinning of the cRNFL was detected whereas VF and ONH parameters (Cup/Disc ratios and cup volume) showed significant change.
Conclusion(s): Eyes with advanced glaucomatous structural damage approaching the presumable GCIPL floor effect on OCT demonstrated changes in ONH and VF parameters even when no further RNFL thinning was detected. Novel parameters for evaluating ONH structure may be useful in the follow-up of advanced glaucoma. (Table presented)