Faculty Bibliography

Optical coherence tomography (OCT) is an interferometry-based imaging modality that generates high-resolution cross-sectional images of the retina. Circumpapillary retinal nerve fibre layer (cpRNFL) and optic disc assessments are the mainstay of glaucomatous structural measurements. However, because these measurements are not always available or precise, it would be useful to have another reliable indicator. The macula has been suggested as an alternative scanning location for glaucoma diagnosis. Using time-domain (TD) OCT, macular measurements have been shown to provide good glaucoma diagnostic capabilities. Performance of cpRNFL measurement was generally superior to macular assessment. However, macular measurement showed better glaucoma diagnostic performance and progression detection capability in some specific cases, which suggests that these two measurements may be combined to produce a better diagnostic strategy. With the adoption of spectral-domain OCT, which allows a higher image resolution than TD-OCT, segmentation of inner macular layers becomes possible. The role of macular measurements for detection of glaucoma progression is still under investigation. Improvement of image quality would allow better visualisation, development of various scanning modes would optimise macular measurements, and further refining of the analytical algorithm would provide more accurate segmentation. With these achievements, macular measurement can be an important surrogate for glaucomatous structural assessment.

PURPOSE: The objective of this study is to assess whether baseline optic nerve head (ONH) topography and retinal nerve fiber layer thickness (RNFLT) are predictive of glaucomatous visual-field progression in glaucoma suspect (GS) and glaucomatous eyes, and to calculate the level of risk associated with each of these parameters. METHODS: Participants with >/=28 months of follow-up were recruited from the longitudinal Advanced Imaging for Glaucoma Study. All eyes underwent standard automated perimetry (SAP), confocal scanning laser ophthalmoscopy (CSLO), time-domain optical coherence tomography (TDOCT), and scanning laser polarimetry using enhanced corneal compensation (SLPECC) every 6 months. Visual-field progression was assessed using pointwise linear-regression analysis of SAP sensitivity values (progressor) and defined as significant sensitivity loss of >1 dB/year at >/=2 adjacent test locations in the same hemifield at P<0.01. Cox proportional hazard ratios (HR) were calculated to determine the predictive ability of baseline ONH and RNFL parameters for SAP progression using univariate and multivariate models. RESULTS: Seventy-three eyes of 73 patients (43 GS and 30 glaucoma, mean age 63.2+/-9.5 years) were enrolled (mean follow-up 51.5+/-11.3 months). Four of 43 GS (9.3%) and 6 of 30 (20%) glaucomatous eyes demonstrated progression. Mean time to progression was 50.8+/-11.4 months. Using multivariate models, abnormal CSLO temporal-inferior Moorfields classification (HR=3.76, 95% confidence interval (CI): 1.02-6.80, P=0.04), SLPECC inferior RNFLT (per -1 mum, HR=1.38, 95% CI: 1.02-2.2, P=0.02), and TDOCT inferior RNFLT (per -1 mum, HR=1.11, 95% CI: 1.04-1.2, P=0.001) had significant HRs for SAP progression. CONCLUSION: Abnormal baseline ONH topography and reduced inferior RNFL are predictive of SAP progression in GS and glaucomatous eyes.

AIMS: To evaluate the glaucoma discriminating ability of macular retinal layers as measured by spectral domain optical coherence tomography (SD-OCT). METHODS: Healthy, glaucoma suspect and glaucomatous subjects had a comprehensive ocular examination, visual field testing and SD-OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA) in the macular and optic nerve head regions. OCT macular scans were segmented into macular nerve fibre layer (mNFL), ganglion cell layer with inner plexiform layer (GCIP), ganglion cell complex (GCC) (composed of mNFL and GCIP), outer retinal complex and total retina. Glaucoma discriminating ability was assessed using the area under the receiver operator characteristic curve (AUC) for all macular parameters and mean circumpapillary retinal nerve fibre layer (cpRNFL). RESULTS: Analysis was performed on 51 healthy, 49 glaucoma suspect and 63 glaucomatous eyes. The median visual field MD was -2.21 dB (IQR: -6.92 to -0.35) for the glaucoma group, -0.32 dB (IQR: -1.22 to 0.73) for the suspect group and -0.18 dB (IQR: -0.92 to 0.71) for the healthy group. Highest age adjusted AUCs were found for average GCC and GCIP (AUC=0.901 and 0.900, respectively) and their sectoral measurements: infero-temporal (0.922 and 0.913), inferior (0.904 and 0.912) and supero-temporal (0.910 and 0.897). These values were similar to the discriminating ability of the mean cpRNFL (AUC=0.913). Comparison of these AUCs did not yield any statistically significant difference (all p>0.05). CONCLUSIONS: SD-OCT GCIP and GCC measurements showed similar glaucoma diagnostic ability and were comparable with that of cpRNFL.

PURPOSE: To describe morphometric details of the human aqueous humor (AH) outflow microvasculature visualized with 360-degree virtual castings during active AH outflow in cadaver eyes and to compare these structures with corrosion casting studies. METHODS: The conventional AH outflow pathways of donor eyes (n = 7) and eyes in vivo (n = 3) were imaged with spectral-domain optical coherence tomography (SD-OCT) and wide-bandwidth superluminescent diode array during active AH outflow. Digital image contrast was adjusted to isolate AH microvasculature, and images were viewed in a 3D viewer. Additional eyes (n = 3) were perfused with mock AH containing fluorescent tracer microspheres to compare microvasculature patterns. RESULTS: Observations revealed components of the conventional outflow pathway from Schlemm's canal (SC) to the superficial intrascleral venous plexus (ISVP). The superficial ISVP in both our study and corrosion casts were composed of interconnected venules (10-50 mum) forming a hexagonal meshwork. Larger radial arcades (50-100 mum) drained the region nearest SC and converged with larger tortuous vessels (>100 mum). A 360-degree virtual casting closely approximated corrosion casting studies. Tracer studies corroborated our findings. Tracer decorated several larger vessels (50-100 mum) extending posteriorly from the limbus in both raw and contrast-enhanced fluorescence images. Smaller tracer-labeled vessels (30-40 mum) were seen branching between larger vessels and exhibited a similar hexagonal network pattern. CONCLUSIONS: SD-OCT is capable of detailed morphometric analysis of the conventional outflow pathway in vivo or ex vivo with details comparable to corrosion casting techniques.

BACKGROUND AND OBJECTIVE: To evaluate the ability of structural assessment to predict glaucomatous visual field progression. PATIENTS AND METHODS: A total of 119 healthy eyes with suspected glaucoma and glaucomatous eyes with 5 or more optic nerve stereophotographs, optical coherence tomography (OCT), and confocal scanning laser ophthalmoscopy (CSLO) all acquired within 6 months of each other were enrolled. Odds ratios to predict progression were determined by generalized estimating equation models. RESULTS: Median follow-up was 4.0 years (range: 1.5 to 5.7 years). Fifteen eyes progressed by glaucoma progression analysis, 20 by visual field index, and 10 by both. Baseline parameters from stereophotographs (vertical cup-to-disc ratio and Disc Damage Likelihood Scale), OCT (global, superior quadrant, and inferior quadrant retinal nerve fiber layer thickness), and CSLO (cup shape measure and mean cup depth) were significant predictors of progression. Comparing the single best parameter from all models, only the OCT superior quadrant RNFL predicted progression. CONCLUSION: Baseline stereophotographs, OCT, and CSLO measurements may be clinically useful to predict glaucomatous visual field progression.

PURPOSE: We sought to visualize the aqueous outflow system in 3 dimensions (3D) in living human eyes, and to investigate the use of commercially available spectral-domain optical coherence tomographic (SD-OCT) systems for this purpose. DESIGN: Prospective, observational study. PARTICIPANTS: One randomly determined eye in each of 6 normal healthy subjects was included. TESTING: We performed 3D SD-OCT imaging of the aqueous humor outflow structures with 2 devices: The Cirrus HD-OCT and the Bioptigen SDOIS. MAIN OUTCOME MEASURES: We created 3D virtual castings of Schlemm's canal (SC) and more distal outflow structures from scan data from each device. RESULTS: Virtual casting of the SC provided visualization of more aqueous vessels branching from SC than could be located by interrogating the 2-dimensional (2D) image stack. Similarly, virtual casting of distal structures allowed visualization of large and small aqueous outflow channel networks that could not be appreciated with conventional 2D visualization. CONCLUSIONS: The outflow pathways from SC to the superficial vasculature can be identified and tracked in living human eyes using commercially available SD-OCT.

PURPOSE: To determine the relationship between retinal nerve fiber layer (RNFL) thickness, optic disc size, and image magnification. METHODS: The cohort consisted of 196 normal eyes of 101 participants in the Advanced Imaging for Glaucoma Study (AIGS), a multicenter, prospective, longitudinal study to develop advanced imaging technologies for glaucoma diagnosis. Scanning laser tomography was used to measure disc size. Optical coherence tomography (OCT) was used to perform circumpapillary RNFL thickness measurements using the standard fixed 3.46-mm nominal scan diameter. A theoretical model of magnification effects was developed to relate RNFL thickness (overall average) with axial length and magnification. RESULTS: Multivariate regression showed no significant correlation between RNFL thickness and optic disc area (95% confidence interval [CI] = -0.9 to 4.1 mum/mm(2), P = 0.21). Linear regression showed that RNFL thickness depended significantly on axial length (slope = -3.1 mum/mm, 95% CI = -4.9 to -1.3, P = 0.001) and age (slope = -0.3 mum/y, 95% CI = -0.5 to -0.2, P = 0.0002). The slope values agreed closely with the values predicted by the magnification model. CONCLUSIONS: There is no significant association between RNFL thickness and optic disc area. Previous publications that showed such an association may have been biased by the effect of axial length on fundus image magnification and, therefore, both measured RNFL thickness and apparent disc area. The true diameter of the circumpapillary OCT scan is larger for a longer eye (more myopic eye), leading to a thinner RNFL measurement. Adjustment of measured RNFL thickness by axial length, in addition to age, may lead to a tighter normative range and improve the detection of RNFL thinning due to glaucoma.

PURPOSE: To investigate the effects of central corneal thickness (CCT)-associated variants on primary open-angle glaucoma (POAG) risk using single nucleotide polymorphisms (SNP) data from the Glaucoma Genes and Environment (GLAUGEN) and National Eye Institute (NEI) Glaucoma Human Genetics Collaboration (NEIGHBOR) consortia. METHODS: A replication analysis of previously reported CCT SNPs was performed in a CCT dataset (n = 1117) and these SNPs were then tested for association with POAG using a larger POAG dataset (n = 6470). Then a CCT genome-wide association study (GWAS) was performed. Top SNPs from this analysis were selected and tested for association with POAG. cDNA libraries from fetal and adult brain and ocular tissue samples were generated and used for candidate gene expression analysis. RESULTS: Association with one of 20 previously published CCT SNPs was replicated: rs12447690, near the ZNF469 gene (P = 0.001; beta = -5.08 mum/allele). None of these SNPs were significantly associated with POAG. In the CCT GWAS, no SNPs reached genome-wide significance. After testing 50 candidate SNPs for association with POAG, one SNP was identified, rs7481514 within the neurotrimin (NTM) gene, that was significantly associated with POAG in a low-tension subset (P = 0.00099; Odds Ratio [OR] = 1.28). Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP = rs1428758; P = 0.018; OR = 0.84). NTM and CNTNAP4 were shown to be expressed in ocular tissues. CONCLUSIONS: The results suggest previously reported CCT loci are not significantly associated with POAG susceptibility. By performing a quantitative analysis of CCT and a subsequent analysis of POAG, SNPs in two cell adhesion molecules, NTM and CNTNAP4, were identified and may increase POAG susceptibility in a subset of cases.