Faculty Bibliography

Variability in illumination, signal quality, tilt and the amount of motion pose challenges for post-processing based 3D-OCT motion correction algorithms. We present an advanced 3D-OCT motion correction algorithm using image registration and orthogonal raster scan patterns aimed at addressing these challenges. An intensity similarity measure using the pseudo Huber norm and a regularization scheme based on a pseudo L0.5 norm are introduced. A two-stage registration approach was developed. In the first stage, only axial motion and axial tilt are coarsely corrected. This result is then used as the starting point for a second stage full optimization. In preprocessing, a bias field estimation based approach to correct illumination differences in the input volumes is employed. Quantitative evaluation was performed using a large set of data acquired from 73 healthy and glaucomatous eyes using SD-OCT systems. OCT volumes of both the optic nerve head and the macula region acquired with three independent orthogonal volume pairs for each location were used to assess reproducibility. The advanced motion correction algorithm using the techniques presented in this paper was compared to a basic algorithm corresponding to an earlier version and to performing no motion correction. Errors in segmentation-based measures such as layer positions, retinal and nerve fiber thickness, as well as the blood vessel pattern were evaluated. The quantitative results consistently show that reproducibility is improved considerably by using the advanced algorithm, which also significantly outperforms the basic algorithm. The mean of the mean absolute retinal thickness difference over all data was 9.9 um without motion correction, 7.1 um using the basic algorithm and 5.0 um using the advanced algorithm. Similarly, the blood vessel likelihood map error is reduced to 69% of the uncorrected error for the basic and to 47% of the uncorrected error for the advanced algorithm. These results demonstrate that our advanced motion correction algorithm has the potential to improve the reliability of quantitative measurements derived from 3D-OCT data substantially.

Treatment of glaucoma by intraocular pressure (IOP) reduction is typically accomplished through the administration of eye drops, the difficult and frequent nature of which contributes to extremely low adherence rates. Poor adherence to topical treatment regimens in glaucoma patients can lead to irreversible vision loss and increased treatment costs. Currently there are no approved treatments for glaucoma that address the inherent inefficiencies in drug delivery and patient adherence. Brimonidine tartrate (BT), a common glaucoma medication, requires dosing every 8-12 h, with up to 97% of patients not taking it as prescribed. This study provides proof-of-principle testing of a controlled release BT formulation. BT was encapsulated in poly(lactic-co-glycolic) acid microspheres and drug release was quantified using UV-Vis spectroscopy. For in vivo studies, rabbits were randomized to receive a single subconjunctival injection of blank (no drug) or BT-loaded microspheres or twice daily topical 0.2% BT drops. The microspheres released an average of 2.1 +/- 0.37 mug BT/mg microspheres/day in vitro. In vivo, the percent decrease in IOP from baseline was significantly greater in the treated eye for both topical drug and drug-loaded microspheres versus blank microspheres throughout the 4-week study, with no evidence of migration or foreign body response. IOP measurements in the contralateral, untreated eyes also suggested a highly localized effect from the experimental treatment. A treatment designed using the release systems described in this study would represent a vast improvement over the current clinical standard of 56-84 topical doses over 28 days.

PURPOSE: To compare three methods of Schlemm's canal (SC) cross-sectional area (CSA) measurement. METHODS: Ten eyes (10 healthy volunteers) were imaged three times using spectral-domain optical coherence tomography (Cirrus HD-OCT, Zeiss, Dublin, California, USA). Aqueous outflow vascular structures and SC collector channel ostia were used as landmarks to identify a reference location within the limbus. SC CSA was assessed within a 1 mm segment (+/-15 frames of the reference, 31 frames in all) by three techniques. (1) Using a random number table, SC CSA in five random frames from the set of 31 surrounding the reference were measured and averaged. (2) The most easily visualised SC location (subjective) was measured, and (3) SC CSA was measured in all 31 consecutive B-scans, and averaged. (comprehensive average, gold standard). Subjective and random CSAs were compared with the comprehensive by general estimating equation modelling, and structural equation modelling quantified agreement. RESULTS: The average from five random locations (4175+/-1045 microm(2)) was not significantly different than that obtained from the gold standard comprehensive assessment (4064+/-1308 microm(2), p=0.6537). Subjectively located SC CSA (7614+/-2162 microm(2)) was significantly larger than the comprehensive gold standard SC CSA (p<0.0001). The average of five random frames produced significantly less bias than did subjective location, yielding a calibration line crossing the 'no-bias' line. DISCUSSION: Subjectively located SC CSA measurements produce high estimates of SC CSA. SC assessed by measuring five random locations estimate CSA was similar to the gold standard estimate.

PURPOSE: To evaluate whether pointwise regression analysis of serial measures of retinal sensitivity can predict future visual field (VF) loss. METHODS: Medical records of 158 patients with glaucomatous eyes with at least 6 years follow-up and 10 reliable VF exams were retrospectively analyzed. The entire follow-up period was divided into two, roughly corresponding to the first (early period) and second (late period) half of follow-up. Retinal sensitivity data obtained from the Swedish interactive threshold algorithm standard or full-threshold VF tests were analyzed, and linear and first-order exponential regression analyses of retinal sensitivity against time were performed to obtain the slope of regression analysis in each VF test location. Paired t tests were used to compare the slopes of the early and late period in each regression analysis. RESULTS: When assessed by linear regression analysis, inferior nasal location showed highest rate of change (-0.52 dB/year) in early period. Late period showed generally faster rate of progression compared to early period. Superior arcuate and superior and inferior nasal locations showed that early and late slopes did not show significant difference (p value, 0.19 approximately 0.49). Central and edged locations showed significant difference between the two slopes (p value < 0.05). First-order exponential regression analysis showed similar result. DISCUSSION: Superior arcuate and superior and inferior nasal areas in VF had a consistent rate of change of retinal sensitivity, indicating that these locations may have the higher capability for prediction of future deterioration. These results suggest that location should be considered when predicting glaucomatous VF progression.

Optical coherence tomography (OCT) is a commonly used imaging modality in the evaluation of glaucomatous damage. The commercially available spectral domain (SD)-OCT offers benefits in glaucoma assessment over the earlier generation of time domain-OCT due to increased axial resolution, faster scanning speeds and has been reported to have improved reproducibility but similar diagnostic accuracy. The capabilities of SD-OCT are rapidly advancing with 3D imaging, reproducible registration, and advanced segmentation algorithms of macular and optic nerve head regions. A review of the evidence to date suggests that retinal nerve fibre layer remains the dominant parameter for glaucoma diagnosis and detection of progression while initial studies of macular and optic nerve head parameters have shown promising results. SD-OCT still currently lacks the diagnostic performance for glaucoma screening.

Optic nerve head (ONH) tissue properties and biomechanics remain mostly unmeasurable in the experiment. We hypothesized that these can be estimated numerically from ocular parameters measurable in vivo with optical coherence tomography (OCT). Using parametric models representing human ONHs we simulated acute intraocular pressure (IOP) increases (10 mmHg). Statistical models were fit to predict, from OCT-measurable parameters, 15 outputs, including ONH tissue properties, stresses, and deformations. The calculations were repeated adding parameters that have recently been proposed as potentially measurable with OCT. We evaluated the sensitivity of the predictions to variations in the experimental parameters. Excellent fits were obtained to predict all outputs from the experimental parameters, with cross-validated R2s between 0.957 and 0.998. Incorporating the potentially measurable parameters improved fits significantly. Predictions of tissue stiffness were accurate to within 0.66 MPa for the sclera and 0.24 MPa for the lamina cribrosa. Predictions of strains and stresses were accurate to within 0.62% and 4.9 kPa, respectively. Estimates of ONH biomechanics and tissue properties can be obtained quickly from OCT measurements using an applet that we make freely available. These estimates may improve understanding of the eye sensitivity to IOP and assessment of patient risk for development or progression of glaucoma.

AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P>/=0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Because glaucomatous damage is irreversible early detection of structural changes in the optic nerve head and retinal nerve fiber layer is imperative for timely diagnosis of glaucoma and monitoring of its progression. Significant improvements in ocular imaging have been made in recent years. Imaging techniques such as optical coherence tomography, scanning laser polarimetry and confocal scanning laser ophthalmoscopy rely on different properties of light to provide objective structural assessment of the optic nerve head, retinal nerve fiber layer and macula. In this review, we discuss the capabilities of these imaging modalities pertinent for diagnosis of glaucoma and detection of progressive glaucomatous damage and provide a review of the current knowledge on the clinical performance of these technologies.