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Purpose A pilot study showed that prediction of individual Humphrey 24-2 visual field (HVF 24-2) sensitivity thresholds from optical coherence tomography (OCT) image analysis is possible. We evaluate performance of an improved approach as well as 3 other predictive algorithms on a new, fully independent set of glaucoma subjects. Methods Subjects underwent HVF 24-2 and 9-field OCT (Heidelberg Spectralis) testing. Nerve fiber (NFL), and ganglion cell and inner plexiform (GCL+IPL) layers were cosegmented and partitioned into 52 sectors matching HVF 24-2 test locations. The Wilcoxon rank sum test was applied to test correlation R, root mean square error (RMSE), and limits of agreement (LoA) between actual and predicted thresholds for four prediction models. The training data consisted of the 9-field OCT and HVF 24-2 thresholds of 111 glaucoma patients from our pilot study. Results We studied 112 subjects (112 eyes) with early, moderate, or advanced primary and secondary open angle glaucoma. Subjects with less than 9 scans (15/112) or insufficient quality segmentations (11/97) were excluded. Retinal ganglion cell axonal complex (RGC-AC) optimized had superior average R = 0.74 (95% confidence interval [CI], 0.67-0.76) and RMSE = 5.42 (95% CI, 5.1-5.7) dB, which was significantly better (P < 0.05/3) than the other three models: Naive (R = 0.49; 95% CI, 0.44-0.54; RMSE = 7.24 dB; 95% CI, 6.6-7.8 dB), Garway-Heath (R = 0.66; 95% CI, 0.60-0.68; RMSE = 6.07 dB; 95% CI, 5.7-6.5 dB), and Donut (R = 0.67; 95% CI, 0.61-0.69; RMSE = 6.08 dB, 95% CI, 5.8-6.4 dB). Conclusions The proposed RGC-AC optimized predictive algorithm based on 9-field OCT image analysis and the RGC-AC concept is superior to previous methods and its performance is close to the reproducibility of HVF 24-2.

Exfoliation syndrome (XFS) is a common age-related disorder primarily recognized by the pathologic accumulations of a fibrillar exfoliative material in the anterior chamber of the eye but also associated with several other ocular and systemic abnormalities.1–6 In many patients, accumulation of exfoliative material within the iridocorneal angle is accompanied by elevated intraocular pressure (IOP) and glaucoma. Indeed, XFS is the most commonly identified cause of secondary open-angle glaucoma.7 In parallel to the clinical significance of exfoliative material in the diagnosis of XFS, much of the experimental work on XFS syndrome has focused on studies of exfoliative material. Such studies have shown that exfoliative material consists of an irregular conglomeration of randomly cross-banded fibrils approximately 30 nm in diameter surrounded by an amorphous matrix of glycoconjugates.8 Exfoliative material also contains epitopes for a variety of proteins related to elastic microfibers, including fibrillin-1,9 elastin,10 latent TGF-β proteins,11 lysyl oxidase,4 and others.3,4 These results and other experimental work on XFS have led to a hypothesis that XFS is a disease of elastosis. According to this theory, insults such as increased oxidative stress and elevated levels of TGF-β1 likely trigger increased production of elastic microfibrils that are subsequently prone to aggregate and accumulate.4 After aggregation and accumulation of exfoliative material within the anterior chamber, aqueous humor outflow becomes impeded, ultimately resulting in increased IOP and glaucoma. A breakthrough in understanding XFS has been precipitated by genomewide association studies that have begun to unravel the genetic factors underlying XFS. XFS has long been appreciated to have strong hereditary contributions.12,13 Recently, the lysyl oxidase-like protein 1 gene (LOXL1) has been identified as the first known genetic risk factor contributing to XFS.14 Initially identified from a large genomewide association study among Scandinavian patients with glaucoma14 and subsequently replicated in additional populations,15–24 a strong association exists between XFS and two single nucleotide polymorphism (SNP) genetic markers resulting in nonsynonymous changes (rs1048661, R141L; rs3825942, G153D) in LOXL1. These LOXL1 SNPs are highly associated with XFS, and the high-risk alleles of these SNPs occur within most XFS patients. The high-risk haplotype of LOXL1 alleles has a 99% population attributable risk in Caucasian populations.14 However, the influence of LOXL1 in XFS may not be as straightforward as is seemingly indicated by these impressive statistics. A multifactorial risk for XFS is suggested by the extremely high occurrence of high-risk LOXL1 alleles among the general population. Within the original Scandinavian populations studied, the high-risk haplotype of LOXL1 alleles was also detected at a frequency of approximately 50% in the general population, with approximately 25% of the general population homozygous for the haplotype.14 Follow-up studies have also confirmed similar high-carrier frequencies.15–24 Thus, most people with high-risk LOXL1 alleles likely do not have XFS. This indicates that although LOXL1 is an important risk factor for XFS, additional factors must play a role in the pathogenesis of the condition. Here, we identify the Lyst gene as an additional gene potentially important to XFS. B6-Lystbg-J mice homozygous for the beige-J (bg-J) allele recapitulate multiple ocular features of human XFS. Our initial consideration of B6-Lystbg-J mice as a possible model of XFS was based on a resemblance of iris transillumination defects between these mice and human patients with XFS. In testing the anatomic basis for the Lyst-mediated transillumination defects, we found that the transillumination defects were caused by an unusual sawtooth-like morphology of the iris pigment epithelium and were accompanied by the presence of a material resembling human exfoliative material. Interestingly, the molecular basis of the beige mutation was discovered to be a 3-bp deletion. The mutation is predicted to delete a single isoleucine from the carboxyl terminus of the LYST protein within the WD40 domain, potentially disrupting a protein-protein interaction. This work represents one of the first descriptions of a mouse model potentially relevant to XFS and provides a genetic resource for continued study of this novel molecular pathway contributing to XFS.

PURPOSE. To search for and validate potential molecular pathogenic mechanisms in the trabecular meshwork (TM) responsible for the elevated intraocular pressure (IOP) associated with glaucoma. METHODS. Gene chip arrays were used to identify differential gene expression in glaucomatous TM tissues. Serum amyloid A (SAA) upregulation was subsequently confirmed with quantitative PCR (QPCR) and ELISA. The effect of SAA on gene expression of cultured human TM cells was tested with gene chip arrays and verified with ELISA, and its effect on IOP was evaluated in the human ocular perfusion organ culture. RESULTS. Microarray analysis showed that the expression of SAA2 was increased in TM tissues from donors with glaucoma. This finding was subsequently confirmed by QPCR. The SAA mRNA levels were increased in glaucoma TM tissues by more than 5-fold (P 0.05) and in cultured TM cells derived from donors with glaucoma by 25-fold (P 0.05) compared with controls. SAA protein levels in the TM of glaucoma patients were also significantly (P 0.05) elevated by 2.9-fold. Treatment of cultured human TM cells with recombinant SAA affected gene expression, including a 22-fold up-regulation of interleukin-8 (P 0.001). SAA increased IOP by approximately 40% (P 0.05) in the human ocular perfusion organ culture without any observable changes in the morphology of the tissues involved in aqueous outflow. CONCLUSIONS. These findings indicate that SAA, which is an acute-phase apolipoprotein that plays important roles in infection, inflammation, and tissue repair, may contribute to the pathogenic changes to the TM in glaucoma. (Invest Ophthalmol Vis Sci. 2008;49:1916‐1923) DOI:10.1167/iovs.07-1104

PURPOSE. Numerous genetic diseases and environmental stimuli affect optic nerve morphology. The purpose of this study was to identify the principal heritable components of visible optic nerve head structures in a population-based sample of twins. METHODS. Fifteen optic nerve specialists viewed stereoscopic optic nerve head photographs (Stereo Viewer-II; Pentax Corp., Tokyo, Japan) from 50 randomly selected monozygotic or dizygotic twin pairs. Before viewing, each expert was questioned about which optic nerve head traits they believed were inherited. After viewing a standardized teaching set, the experts indicated which twin pairs they thought were monozygotic. Participants were then questioned about how their decisions were reached. A rank-ordered Rasch analysis was used to determine the relative weighting and value applied to specific optic nerve head traits. RESULTS. The proportion of twin pairs for which zygosity was correctly identified ranged from 74% to 90% (median, 82%) across the panel. Experts who correctly identified the zygosity in more than 85% of cases placed most weighting on shape and size of the optic disc and cup, whereas experts with the lowest scores placed greater weighting on the optic nerve head vasculature in reaching their decisions. CONCLUSIONS. In determining the genetic components of the optic nerve head, the results of this study suggest that the shape and size of the optic disc and cup are more heritable and should receive a greater priority for quantification than should vascular features. (Invest Ophthalmol Vis Sci. 2007;48: 2469‐2475) DOI:10.1167/iovs.06-1470

To evaluate a novel automated segmentation algorithm for cup-to-disc segmentation from stereo color photographs of patients with glaucoma for the measurement of glaucoma progression.Stereo color photographs of the optic disc were obtained by using a fixed stereo-base fundus camera in 58 eyes of 58 patients with suspected or open-angle glaucoma. Manual planimetry was performed by three glaucoma faculty members to delineate a reference standard rim and cup segmentation of all stereo pairs and by three glaucoma fellows as well. Pixel feature classification was evaluated on the stereo pairs and corresponding reference standard, by using feature computation based on simulation of photoreceptor color opponency and visual cortex simple and complex cells. An optimal subset of 12 features was used to segment all pixels in all stereo pairs, and the percentage of pixels assigned the correct class and linear cup-to-disc ratio (LCDR) estimates of the glaucoma fellows and the algorithm were compared to the reference standard.The algorithm was able to assign cup, rim, and background correctly to 88% of all pixels. Correlations of the LCDR estimates of glaucoma fellows with those of the reference standard were 0.73 (95% CI, 0.58-0.83), 0.81 (95% CI, 0.70-0.89), and 0.86 (95% CI, 0.78-0.91), respectively, whereas the correlation of the algorithm with the reference standard was 0.93 (95% CI, 0.89-0.96; n = 58).The pixel feature classification algorithm allows objective segmentation of the optic disc from conventional color stereo photographs automatically without human input. The performance of the disc segmentation and LCDR calculation of the algorithm was comparable to that of glaucoma fellows in training and is promising for objective evaluation of optic disc cupping.