Faculty Bibliography

In 400BC, Hippocrates wrote the first record of glaucoma. Since then, increasingly objective diagnostic techniques have enabled earlier detection of glaucoma and its progression, providing greater certainty in decision-making and early medical and surgical intervention.

The lamina cribrosa is a primary site of damage in glaucoma. While mechanical distortion is hypothesized to cause reduction of axoplasmic flow, little is known about how the pores, which contains the retinal ganglion cell axons, traverse the lamina cribrosa. We investigated lamina cribrosa pore paths in vivo to quantify differences in tortuosity of pore paths between healthy and glaucomatous eyes. We imaged 16 healthy, 23 glaucoma suspect and 48 glaucomatous eyes from 70 subjects using a swept source optical coherence tomography system. The lamina cribrosa pores were automatically segmented using a previously described segmentation algorithm. Individual pore paths were automatically tracked through the depth of the lamina cribrosa using custom software. Pore path convergence to the optic nerve center and tortuosity was quantified for each eye. We found that lamina cribrosa pore pathways traverse the lamina cribrosa closer to the optic nerve center along the depth of the lamina cribrosa regardless of disease severity or diagnostic category. In addition, pores of glaucoma eyes take a more tortuous path through the lamina cribrosa compared to those of healthy eyes, suggesting a potential mechanism for reduction of axoplasmic flow in glaucoma.

Purpose/UNASSIGNED:To introduce an experimental approach for direct comparison of the primate optic nerve head (ONH) before and after death by exsanguination. Method/UNASSIGNED:The ONHs of four eyes from three monkeys were imaged with spectral-domain optical coherence tomography (OCT) before and after exsanguination under controlled IOP. ONH structures, including the Bruch membrane (BM), BM opening, inner limiting membrane (ILM), and anterior lamina cribrosa (ALC) were delineated on 18 virtual radial sections per OCT scan. Thirteen parameters were analyzed: scleral canal at BM opening (area, planarity, and aspect ratio), ILM depth, BM depth; ALC (depth, shape index, and curvedness), and ALC visibility (globally, superior, inferior, nasal, and temporal quadrants). Results/UNASSIGNED:All four ALC quadrants had a statistically significant improvement in visibility after exsanguination (overall P < 0.001). ALC visibility increased by 35% globally and by 36%, 37%, 14%, and 4% in the superior, inferior, nasal, and temporal quadrants, respectively. ALC increased 4.1%, 1.9%, and 0.1% in curvedness, shape index, and depth, respectively. Scleral canals increased 7.2%, 25.2%, and 1.1% in area, planarity, and aspect ratio, respectively. ILM and BM depths averaged -7.5% and -55.2% decreases in depth, respectively. Most, but not all, changes were beyond the repeatability range. Conclusions/UNASSIGNED:Exsanguination allows for improved lamina characterization, especially in regions typically blocked by shadowing in OCT. The results also demonstrate changes in ONH morphology due to the loss of blood pressure. Future research will be needed to determine whether there are differences in ONH biomechanics before and after exsanguination and what those differences would imply.

Although elevated intraocular pressure (IOP) and age are major risk factors for glaucoma, their effects on glaucoma pathogenesis remain unclear. This study examined the onset and progression of glaucomatous changes to ocular anatomy and physiology, structural and physiological brain integrity, and visuomotor behavior in the DBA/2J mice via non-invasive tonometry, multi-parametric magnetic resonance imaging (MRI) and optokinetic assessments from 5 to 12 months of age. Using T2-weighted MRI, diffusion tensor MRI, and manganese-enhanced MRI, increasing IOP elevation at 9 and 12 months old coincided with anterior chamber deepening, altered fractional anisotropy and radial diffusivity of the optic nerve and optic tract, as well as reduced anterograde manganese transport along the visual pathway respectively in the DBA/2J mice. Vitreous body elongation and visuomotor function deterioration were observed until 9 months old, whereas axial diffusivity only decreased at 12 months old in diffusion tensor MRI. Under the same experimental settings, C57BL/6J mice only showed modest age-related changes. Taken together, these results indicate that the anterior and posterior visual pathways of the DBA/2J mice exhibit differential susceptibility to glaucomatous neurodegeneration observable by in vivo multi-modal examinations.

BACKGROUND/AIMS:The objective of this study is to evaluate the accuracy and speed of trainees and experienced glaucoma specialists using the MatchedFlicker software against the manual examination of stereoscopic disc photographs for detecting glaucomatous optic disc change. METHODS:Three experienced glaucoma specialists, two resident ophthalmologists and one glaucoma fellow from multiple institutions independently evaluated the same 140 image pairs from 100 glaucomatous/ocular hypertensive eyes using a handheld stereo viewer and the MatchedFlicker programme. Fifty had progression to glaucoma as determined by the Ocular Hypertension Treatment Study (OHTS) Optic Disc Reading Group and endpoint committee, and 50 more were negative controls for progression with photos taken a few minutes apart. Twenty photo pairs from each of the two groups were duplicated for reviewer variability analysis. The initial viewing method was randomised and then alternated for each group of 70 image pairs. Reviewer accuracy and evaluation time for each method were measured. RESULTS:Evaluators averaged 8.6 s faster per image pair (26%) with the MatchedFlicker programme than with the stereo viewer (p=0.0007). Evaluators correctly identified more image pairs when using the MatchedFlicker software over the stereo viewer (p=0.0003). There was no significant difference between the expert and trainee group in speed or overall accuracy for either method. Experts were significantly more consistent than trainees with the duplicate image pairs (p=0.029). Trainees appeared more reluctant to designate eyes as showing glaucoma progression than experts. CONCLUSIONS:Both expert glaucoma specialists and ophthalmologists in various stages of training had greater accuracy and speed with the MatchedFlicker programme than with a handheld stereoscopic viewer.

Purpose/UNASSIGNED:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods/UNASSIGNED:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results/UNASSIGNED:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions/UNASSIGNED:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

The choroid is vascular tissue located underneath the retina and supplies oxygen to the outer retina; any damage to this tissue can be a precursor to retinal diseases. This paper presents an automated method of choroidal segmentation from Enhanced Depth Imaging Optical Coherence Tomography (EDI-OCT) images. The Dijkstra shortest path algorithm is used to segment the choroid-sclera interface (CSI), the outermost border of the choroid. A novel intensity-normalisation technique that is based on the depth of the choroid is used to equalise the intensity of all non-vessel pixels in the choroid region. The outer boundary of choroidal vessel and CSI are determined approximately and incorporated to the edge weight of the CSI segmentation to choose optimal edge weights. This method is tested on 190 B-scans of 10 subjects against choroid thickness (CTh) results produced manually by two graders. For comparison, results obtained by two state-of-the-art automated methods and our proposed method are compared against the manual grading, and our proposed method performed the best. The mean root-mean-square error (RMSE) for finding the CSI boundary by our method is 7.71±6.29 pixels, which is significantly lower than the RMSE for the two other state-of-the-art methods (36.17±11.97 pixels and 44.19±19.51 pixels). The correlation coefficient for our method is 0.76, and 0.51 and 0.66 for the other two state-of-the-art methods. The interclass correlation coefficients are 0.72, 0.43 and 0.56 respectively. Our method is highly accurate, robust, reliable and consistent. This identification can enable to quantify the biomarkers of the choroidin large scale study for assessing, monitoring disease progression as well as early detection of retinal diseases. Identification of the boundary can help to determine the loss or change of choroid, which can be used as features for the automatic determination of the stages of retinal diseases.

Ocular imaging has been heavily incorporated into glaucoma management and provides important information that aids in the detection of disease progression. Longitudinal studies have shown that the circumpapillary retinal nerve fiber layer is an important parameter for glaucoma progression detection, whereas other studies have demonstrated that macular parameters, such as the ganglion cell inner plexiform layer and optic nerve head parameters, also are useful for progression detection. The introduction of novel technologies with faster scan speeds, wider scanning fields, higher resolution, and improved tissue penetration has enabled the precise quantification of additional key ocular structures, such as the individual retinal layers, optic nerve head, choroid, and lamina cribrosa. Furthermore, extracting functional information from scans such as blood flow rate and oxygen consumption provides new perspectives on the disease and its progression. These novel methods promise improved detection of glaucoma progression and better insight into the mechanisms of progression that will lead to better targeted treatment options to prevent visual damage and blindness.

PURPOSE: To compare longitudinal glaucoma progression detection using optical coherence tomography (OCT) and visual field (VF). DESIGN: Validity assessment METHOD: We analyzed subjects with more than 5 follow-up visits (every 6 months) in the multi-center Advanced Imaging for Glaucoma Study. Fourier-domain optical coherence tomography (OCT) was used to map the thickness of the peripapillary retinal nerve fiber layer (NFL) and ganglion cell complex (GCC). OCT-based progression detection was defined as a significant negative trend for either NFL or GCC. VF progression was reached if either the event or trend analysis reached significance. RESULT: The analysis included 417 glaucoma suspect/pre-perimetric glaucoma (GS/PPG) eyes and 377 perimetric glaucoma (PG) eyes. In the GS/PPG group, progression was detect in 38.9% of eyes by OCT, significantly more (P<0.001) than the detection rate of 18.7% by VF. In severity-stratified analysis of PG eyes, OCT had significantly higher detection rate in early PG (49.7% vs. 32.0%, p=0.02), but not significantly different in moderate and advanced PG. The rate of NFL thinning declined dramatically in advanced PG, but GCC thinning rate remained relatively steady and allowed good progression detection even in advanced disease. The rate of false positive progression detection in permutated series was over 10% for VF trend analysis in both GS/PPG and PG group, while under 7% for both GCC and NFL. CONCLUSION: OCT is a more sensitive than VF for the detection of progression in early glaucoma. While the value of NFL declines in advanced glaucoma, GCC appears to be a useful progression detector from early to advanced stages.