Identification and Characterization of Imaging Technique Errors and Artifacts Using Anterior-Segment OCT for Irido-Corneal Angle Evaluations in Glaucoma.

PURPOSE: Anterior-segment OCT (AS-OCT) platforms provide noninvasive and quantifiable evaluations of anterior chamber angle (ACA) anatomy. Although these ACA measurements have been validated with high repeatability and reproducibility, there is a paucity of data previously published regarding the technique errors and artifacts (TEA) that may occur during imaging of the ACA. The purpose of this study was to report on the types and frequency of imaging TEA that are seen in ACA evaluation of a large cohort of patients with open-angle glaucoma. DESIGN: Retrospective, cross-sectional design. PARTICIPANTS: Images were obtained with AS-OCT from 5082 eyes of 2541 patients with glaucoma and were reviewed at the Doheny Image Reading Center (DIRC). METHODS: Images had been captured using AS-OCT devices from 4 different manufacturers (Zeiss Cirrus [Oberkochen, Germany], Heidelberg Spectralis [Heidelberg, Germany], Optovue RTVue [Fremont, CA], or Zeiss Visante). All images were analyzed by 2 independent and certified DIRC image readers for angle opening distance under Schwalbe's line (SL-AOD), and then re-reviewed by a DIRC-certified principal investigator to adjudicate nonconsensus measurements. Images were defined to have TEA when image readers were unable to confidently measure the SL-AOD. MAIN OUTCOME MEASURES: Type and frequency of TEA in the AS-OCT image. RESULTS: Of 5082 eyes reviewed, 208 images (4.09%) were found to have TEA that restricted proper visualization of irido-corneal angle structures and measurements of SL-AOD. The most common TEA was that the image readers were unable to identify Schwalbe's line (74% of TEA images). Other common TEA included poor visualization of the anterior iris surface (15%), misaligned scan location (11%), irregular corneal irregularities (5%), and illumination-related pupillary abnormalities (4%). CONCLUSIONS: This large-scale study presents the types and frequency of TEA found in AS-OCT-derived angle images. More than 95% of the images reviewed were usable for the quantification of irido-corneal angle measurements. Knowing the common types of TEA may help in enhancing the training of both human image readers and in the design of automated algorithms to improve image acquisition and image interpretation parameters. This will become especially useful as AS-OCT becomes more widely used in clinical practice for anterior chamber assessment.

Relationship between the Presence of a Cilioretinal Artery and Subretinal Fluid in Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the relationship between presence of a cilioretinal artery (CRA) and the extent of subretinal fluid (SRF) in eyes with treatment-naïve neovascular age-related macular degeneration (nAMD). Eyes with nAMD have varying amounts of SRF, and factors affecting exudation volume are not well established. We hypothesize that presence of CRA may affect the extent of SRF by affecting the hemodynamics of blood flow supplying the choroidal neovascular membrane. DESIGN: Retrospective case-control study. PARTICIPANTS: Two hundred twelve patients with treatment-naïve nAMD in at least 1 eye from anonymized datasets available at the Doheny Image Reading Center. METHODS: Color fundus photographs and fluorescein angiograms of the study eyes were reviewed to identify those with a CRA (cases) and those without (controls). Spectral-domain OCT data were evaluated by 2 masked graders to identify presence and volume of SRF. We identified subtypes of CNV and evaluated other OCT features that could affect SRF, such as presence of subretinal hyperreflective material (SHRM), cystoid macular edema (CME), and pigment epithelial detachment (PED). Nonparametric Mann-Whitney U test and univariate and multivariate analyses were performed to identify significant differences between cases and controls and to evaluate the relationship between these factors and SRF volume. MAIN OUTCOME MEASURES: Presence and volume of SRF, presence of CME, PED types, and CNV types. RESULTS: We identified 44 cases and 168 controls. Mean SRF volume was significantly lower in cases than controls (0.72±0.9 mm3 vs. 1.60±2.36 mm3; P = 0.03). Univariate regression analysis showed a weakly significant correlation between presence of CRA and SRF volume (r = -0.15; P = 0.03) and OCT parameters, including SHRM (r = 0.16; P = 0.023), CME (r = -0.20; P = 0.004), and type 2 CNV (r = 0.16; P = 0.02). Multivariate analysis demonstrated that the presence of a CRA (r = -0.17; P = 0.02) was correlated independently with the presence of SRF. CONCLUSIONS: Presence of a CRA was correlated negatively with the volume of SRF in eyes with nAMD. These findings may draw insights into the potential hemodynamic effect of the CRA, which warrants further investigation.

Measurement and Reproducibility of Preserved Ellipsoid Zone Area and Preserved Retinal Pigment Epithelium Area in Eyes With Choroideremia.

PURPOSE: To identify valid and reproducible methods for quantifying anatomic outcome measures for eyes with choroideremia (CHM) in clinical trials. DESIGN: Reliability analysis study. METHODS: In this multicenter study, patients with confirmed genetic diagnosis of CHM were enrolled. All cases underwent spectral-domain optical coherence tomography (SDOCT) and fundus autofluorescence (FAF) imaging. Two graders independently delineated boundaries of preserved autofluorescence (PAF) and preserved ellipsoid zone (EZ) on FAF and OCT images, respectively. The results of the 2 independent gradings of both FAF and OCT images were compared to assess the reproducibility of the grading methods. RESULTS: A total of 148 eyes from 75 cases were included. In 21% of eyes PAF and in 43% of eyes preserved EZ had extended beyond the image capture area. After exclusion of these eyes and low-quality images, 114 FAF and 77 OCT images were graded. The mean PAF areas from 2 independent gradings were 3.720 ± 3.340 mm2 and 3.692 ± 3.253 mm2, respectively. Intraclass correlation coefficient (ICC) for these gradings was 0.996. The mean preserved EZ areas from 2 independent gradings were 2.746 ± 2.319 mm2 and 2.858 ± 2.446 mm2, respectively. ICC for these gradings was 0.991. CONCLUSIONS: Quantifying preserved retinal pigment epithelium and EZ areas on FAF and OCT images, respectively, in CHM patients is highly reproducible. These variables would be potential anatomic outcome measures for CHM clinical trials and could be studied and tracked longitudinally in choroideremia.

Advanced imaging for glaucoma study: design, baseline characteristics, and inter-site comparison.

PURPOSE: To report the baseline characteristics of the participants in the Advanced Imaging for Glaucoma Study. To compare the participating sites for variations among subjects and the performance of imaging instruments. DESIGN: Multicenter longitudinal observational cohort study. METHODS: A total of 788 participants (1329 eyes) were enrolled from 3 academic referral centers. There were 145 participants (289 eyes) in the normal group, 394 participants (663 eyes) in the glaucoma suspect/preperimetric glaucoma group, and 249 participants (377 eyes) in the perimetric glaucoma group. Participants underwent a full clinical examination, standard automated perimetry, and imaging with time-domain and Fourier-domain optical coherence tomography (OCT), scanning laser polarimetry, and confocal scanning laser ophthalmoscopy. The baseline average, population standard deviation, and repeatability of imaging-derived anatomic variables were reported for each technology and center. RESULTS: Compared to the normal participants, glaucoma suspect/preperimetric glaucoma and perimetric glaucoma groups had significantly reduced anatomic measurements. Repeatability of nerve fiber layer thickness was best for Fourier-domain OCT (overall coefficient of variation <2%), followed by time-domain OCT (coefficient of variation 2%-2.9%), scanning laser polarimetry (coefficient of variation 2.6%-4.5%), and confocal scanning laser ophthalmoscopy rim area (coefficient of variation 4.2%-7.6%). A mixed-effects model showed that the differences between sites was less than 25 percent of the variation within groups and less than the differences between the normal and glaucoma suspect/preperimetric glaucoma group. CONCLUSIONS: Site-to-site variation was smaller than both the variation within groups and the changes attributable to glaucoma. Therefore pooling of participants between sites is appropriate.

Euodenine A: a small-molecule agonist of human TLR4.

A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.

Sources of structural autofluorescence in the human trabecular meshwork.

PURPOSE: In situ 2-photon excitation fluorescence (TPEF) of the human trabecular meshwork (TM) reveals beams of heterogeneous autofluorescence (AF) comprising high intensity fluorescent fibers (AF-high) on a background of lower intensity fluorescence (AF-low). To determine the sources of this AF heterogeneity, we imaged human TM to characterize AF, second harmonic generation (SHG) for collagen, and eosin-labeled fluorescence identifying elastin. METHODS: Corneoscleral rims retained after corneal transplantation were incubated with and without eosin, and imaged by TPEF. TPEF was collected through multiphoton bandpass filters to obtain AF, SHG (collagen bandwidth), and eosin-labeled fluorescence images. For qualitative comparisons, near-simultaneous image acquisition pairs of AF-SHG (+/-eosin coincubation), AF-eosin, and SHG-eosin were captured. For quantitative comparisons, multiple regions of interest (ROI) were defined in separate TM beam regions within the uveal and corneoscleral meshwork for image acquisition pairs of AF-SHG (without eosin coincubation) and SHG-eosin. We defined 18 ROI within each acquisition pair as the basis for Manders colocalization analysis. Perfect colocalization was defined as a Manders coefficient (Mcoeff) of 1. RESULTS: Qualitatively and quantitatively, AF-low colocalized with SHG (Mcoeff=1), but not SHG signal-voids. AF-high colocalized with SHG signal-voids (Mcoeff=1), but not the SHG signal. Like AF-high, eosin-labeled fluorescence qualitatively and quantitatively colocalized (Mcoeff=1) with SHG signal-voids, but not the SHG signal. CONCLUSIONS: Heterogeneous AF in human TM is comprised of high intensity signal originating from elastin fibers in beam cores and lower intensity signal originating from collagen. These findings are relevant to interpreting structural extracellular matrix signals in AF images of the TM.

Regional correlation among ganglion cell complex, nerve fiber layer, and visual field loss in glaucoma.

PURPOSE: To analyze the relationship among macular ganglion cell complex (GCC) thickness, peripapillary nerve fiber layer (NFL) thickness, and visual field (VF) defects in patients with glaucoma. METHODS: A Fourier-domain optical coherence tomography (FD-OCT) system was used to map the macula and peripapillary regions of the retina in 56 eyes of 38 patients with perimetric glaucoma. The macular GCC and peripapillary NFL thicknesses were mapped and standard automated perimetry (SAP) was performed. Loss of GCC and NFL were correlated with the VF map on both a point-by-point and regional basis. RESULTS: Correlation between GCC thickness and peripapillary NFL thickness produced a detailed correspondence map that demonstrates the arcuate course of the NFL in the macula. Corresponding regions within the GCC, NFL, and VF maps demonstrate significant correlation, once parafoveal retinal ganglion cell (RGC) displacement is taken into account. CONCLUSIONS: There are significant point-specific and regional correlations between GCC loss, NFL loss, and deficits on SAP. Using these different data sources together may improve our understanding of glaucomatous damage and aid in the management of patients with glaucoma.