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Author(s): Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H; Butkiewicz, Mariusz; Sullivan, David A; Weinreb, Robert N; Aschard, Hugues; Allingham, R Rand; Ashley-Koch, Allison; Lee, Richard K; Moroi, Sayoko E; Brilliant, Murray H; Wollstein, Gadi; Schuman, Joel S; Fingert, John H; Budenz, Donald L; Realini, Tony; Gaasterland, Terry; Scott, William K; Singh, Kuldev; Sit, Arthur J; Igo, Robert P; Song, Yeunjoo E; Hark, Lisa; Ritch, Robert; Rhee, Douglas J; Vollrath, Douglas; Zack, Donald J; Medeiros, Felipe; Vajaranant, Thasarat S; Chasman, Daniel I; Christen, William G; Pericak-Vance, Margaret A; Liu, Yutao; Kraft, Peter; Richards, Julia E; Rosner, Bernard A; Hauser, Michael A; Craig, Jamie E; Burdon, Kathryn P; Hewitt, Alex W; Mackey, David A; Haines, Jonathan L; MacGregor, Stuart; Wiggs, Janey L; Pasquale, Louis R; Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium | Abstract: Purpose: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: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: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:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Optical coherence tomography (OCT) has become the cornerstone technology for clinical ocular imaging in the past few years. The technology is still rapidly evolving with newly developed applications. This manuscript reviews recent innovative OCT applications for glaucoma diagnosis and management.The improvements made in the technology have resulted in increased scanning speed, axial and transverse resolution, and more effective use of the OCT technology as a component of multimodal imaging tools. At the same time, the parallel evolution in novel algorithms makes it possible to efficiently analyze the increased volume of acquired data.The innovative iterations of OCT technology have the potential to further improve the performance of the technology in evaluating ocular structural and functional characteristics and longitudinal changes in glaucoma.

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets., Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

There is increasing clinical evidence that the eye is not only affected by intraocular pressure (IOP), but also by intracranial pressure (ICP). Both pressures meet at the optic nerve head of the eye, specifically the lamina cribrosa (LC). The LC is a collagenous meshwork through which all retinal ganglion cell axons pass on their way to the brain. Distortion of the LC causes a biological cascade leading to neuropathy and impaired vision in situations such as glaucoma and idiopathic intracranial hypertension. While the effect of IOP on the LC has been studied extensively, the coupled effects of IOP and ICP on the LC remain poorly understood. We investigated in-vivo the effects of IOP and ICP, controlled via cannulation of the eye and lateral ventricle in the brain, on the LC microstructure of anesthetized rhesus monkeys eyes using the Bioptigen spectral-domain optical coherence tomography (OCT) device (Research Triangle, NC). The animals were imaged with their head upright and the rest of their body lying prone on a surgical table. The LC was imaged at a variety of IOP/ICP combinations, and microstructural parameters, such as the thickness of the LC collagenous beams and diameter of the pores were analyzed. LC microstructure was confirmed by histology. We determined that LC microstructure deformed in response to both IOP and ICP changes, with significant interaction between the two. These findings emphasize the importance of considering both IOP and ICP when assessing optic nerve health.

PURPOSE: Previously we introduced a state based two-dimensional continuous time hidden Markov model (2D CT-HMM) to model the pattern of glaucoma detected changes using structural and functional information simultaneously. The purpose of this study was to evaluate the glaucoma detected change prediction performance of the model in a real clinical setting using a retrospective longitudinal dataset. DESIGN: A longitudinal retrospective study SUBJECTS: One hundred thirty-four eyes from 134 subjects diagnosed as glaucoma or glaucoma suspect (average follow-up period 4.4 ± 1.2 years, average number of visits 7.1 ± 1.8 visits). METHODS: A 2D CT-HMM model was trained using optical coherence tomography (OCT; Cirrus HD-OCT, Zeiss, Dublin, CA) average circumpapillary retinal nerve fiber layer (cRNFL) thickness and visual field index (VFI) or mean deviation (MD) (Humphrey Field Analyzer, Zeiss, Dublin, CA). The model was trained using a subset of the data (107 out of 134 eyes, 80%) including all visits except for the last visit, which was used to test the prediction performance (training set). Additionally, the remaining 27 eyes were used for secondary performance testing as an independent group (validation set). The 2D CT-HMM predicts one out of 4 possible detected state changes based on one input state. MAIN OUTCOME MEASURES: Prediction accuracy was assessed as the percentage of correct prediction against the actual patients’ recorded state. In addition, deviations of the predicted long-term detected change paths from the actual detected change paths were measured. RESULTS: Baseline age was 61.9 ± 11.4 years (mean ± standard deviation), VFI was 90.7 ± 17.4, MD was −3.50 ± 6.04 dB, and cRNFL thickness was 74.9 ± 12.2 µm. The accuracy of glaucoma detected change prediction using the training set was comparable to the validation set (57.0% and 68.0%, respectively). Prediction deviation from the actual detected change path showed stability throughout patient follow-up. CONCLUSIONS: The 2D CT-HMM demonstrated promising glaucoma detected change prediction performance in a simulated clinical setting using an independent cohort. The 2D CT-HMM allows information from just one visit to predict at least 5 subsequent visits with similar performance.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p&nbsp

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.

To evaluate whether pointwise regression analysis of serial measures of retinal sensitivity can predict future visual field (VF) loss.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.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 ∼ 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.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.

IMPORTANCE: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. OBJECTIVE: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. MAIN OUTCOMES AND MEASURES: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. RESULTS: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10(−66)). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = −0.36; 95% CI, −0.56 to −0.16; P = 4.0 × 10(−4)). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10(−4)). CONCLUSIONS AND RELEVANCE: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

The lamina cribrosa (LC) is a sieve-like structure in the sclera where retinal ganglion cell axons exit from the eye. The LC has been known to play a critical role in the pathogenesis of glaucoma. With the advent of imaging technologies, such as enhanced depth imaging, spectral-domain optical coherence tomography (OCT) enables us to unveil the LC in vivo features. The application of adaptive optics technology and a compensatory image-processing algorithm has further improved the visualization of the beams and pores and neural pathways of the LC and the scleral insertion sites. Monitoring the changes of these structures in relation to acute and chronic elevation of intraocular pressure would be germane to decipher the relationship between the stress and strain response of the LC and optic nerve damage and improve our understanding of glaucoma pathophysiology. While the impact of investigating the integrity of LC is substantive, considerable challenges remain for imaging the LC. Nevertheless, with the rapid development of the OCT technology, it is expected that some of these limitations can be overcome and the potentials of LC imaging will be unraveled.

Advances in imaging have made it increasingly common to study soft tissues without first embedding them in plastic or paraffin and without using labels or stains. The process, however, usually still involves fixation and cryosectioning, which could deform the tissues. Our goal was to quantify the morphological changes of ocular tissues caused by formalin fixation and cryosectioning. From each of 6 porcine eyes, 4 regions were obtained: cornea, equatorial and posterior sclera, and posterior pole containing the optic nerve head. Samples were imaged using visible light microscopy fresh, 1-minute and 24-hours post-fixation, and post-cryosectioning. Effects were assessed by 14 parameters representing sample size and shape. Overall, formalin fixation and sectioning caused only minimal changes to the ocular tissues, with average percentage parameter differences of 0.1%, 1%, and 1.2% between fresh and post-fixing by 1 minute, 24 hours, and post-cryosectioning, respectively. Parameter changes were not directional, and were only weakly dependent on the duration of fixation and the region of the eye. These results demonstrate that formalin fixation and cryosectioning are good choices for studying ocular tissue morphology and structure, as they do not cause the large tissue shrinkage or distortions typically associated with other, more complicated, techniques.

Purpose: Evaluation of the effect of prelaminar tissue thickness on visualization of the lamina cribrosa (LC) using optical coherence tomography (OCT). Methods: The optic nerve head (ONH) region was scanned using OCT. The quality of visible LC microstructure was assessed subjectively using a grading system and objectively by analyzing the signal intensity of each scan's superpixel components. Manual delineations were made separately and in 3-dimensions quantifying prelaminar tissue thickness, analyzable regions of LC microstructure, and regions with a visible anterior LC (ALC) boundary. A linear mixed effect model quantified the association between tissue thickness and LC visualization. Results: A total of 17 healthy, 27 glaucoma suspect, and 47 glaucomatous eyes were included. Scans with thicker average prelaminar tissue measurements received worse grading scores (P = 0.007), and superpixels with low signal intensity were associated significantly with regions beneath thick prelaminar tissue (P < 0.05). The average prelaminar tissue thickness in regions of scans where the LC was analyzable (214 μm) was significantly thinner than in regions where the LC was not analyzable (569 μm; P < 0.001). Healthy eyes had significantly thicker average prelaminar tissue measurements than glaucoma or glaucoma suspect eyes (both P < 0.001), and glaucoma suspect eyes had significantly thicker average prelaminar tissue measurements than glaucoma eyes (P = 0.008). Significantly more of the ALC boundary was visible in glaucoma eyes (63% of ONH) than in healthy eyes (41%; P = 0.005). Conclusions: Thick prelaminar tissue was associated with impaired visualization of the LC. Healthy subjects generally had thicker prelaminar tissue, which potentially could create a selection bias against healthy eyes when comparing LC structures., United States. National Institutes of Health (R01-EY013178), United States. National Institutes of Health (R01-EY025011), United States. National Institutes of Health (R01-EY011289), United States. National Institutes of Health (P30-EY008098), United States. National Institutes of Health (T32-EY017271)

The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral autoregulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and the oxygen supply might be unstable. Lassen's blood flow autoregulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact autoregulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to autoregulation impairment. Non-invasive methods for monitoring blood flow autoregulation are therefore needed. We propose to use Near infrared spectroscopy (NIRS) to fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We pe erformed experiments on non-human primates during exsanguination to demonstrate that the limits of blood flow autoregulation can be accessed with NIRS.

Although it is well documented that abnormal levels of either intraocular (IOP) or intracranial pressure (ICP) can lead to potentially blinding conditions, such as glaucoma and papilledema, little is known about how the pressures actually affect the eye. Even less is known about potential interplay between their effects, namely how the level of one pressure might alter the effects of the other. Our goal was to measure in-vivo the pressure-induced stretch and compression of the lamina cribrosa due to acute changes of IOP and ICP. The lamina cribrosa is a structure within the optic nerve head, in the back of the eye. It is important because it is in the lamina cribrosa that the pressure-induced deformations are believed to initiate damage to neural tissues leading to blindness. An eye of a rhesus macaque monkey was imaged in-vivo with optical coherence tomography while IOP and ICP were controlled through cannulas in the anterior chamber and lateral ventricle, respectively. The image volumes were analyzed with a newly developed digital image correlation technique. The effects of both pressures were highly localized, nonlinear and non-monotonic, with strong interactions. Pressure variations from the baseline normal levels caused substantial stretch and compression of the neural tissues in the posterior pole, sometimes exceeding 20%. Chronic exposure to such high levels of biomechanical insult would likely lead to neural tissue damage and loss of vision. Our results demonstrate the power of digital image correlation technique based on non-invasive imaging technologies to help understand how pressures induce biomechanical insults and lead to vision problems.

Human visual performance has been observed to show superiority in localized regions of the visual field across many classes of stimuli. However, the underlying neural mechanisms remain unclear. This study aims to determine whether the visual information processing in the human brain is dependent on the location of stimuli in the visual field and the corresponding neuroarchitecture using blood-oxygenation-level-dependent functional MRI (fMRI) and diffusion kurtosis MRI, respectively, in 15 healthy individuals at 3 T. In fMRI, visual stimulation to the lower hemifield showed stronger brain responses and larger brain activation volumes than the upper hemifield, indicative of the differential sensitivity of the human brain across the visual field. In diffusion kurtosis MRI, the brain regions mapping to the lower visual field showed higher mean kurtosis, but not fractional anisotropy or mean diffusivity compared with the upper visual field. These results suggested the different distributions of microstructural organization across visual field brain representations. There was also a strong positive relationship between diffusion kurtosis and fMRI responses in the lower field brain representations. In summary, this study suggested the structural and functional brain involvements in the asymmetry of visual field responses in humans, and is important to the neurophysiological and psychological understanding of human visual information processing.

The microstructural organization and composition of the corneoscleral shell (CSS) determine the biomechanical behavior of the eye, and are important in diseases such as glaucoma and myopia. However, limited techniques can assess these properties globally, non-invasively and quantitatively. In this study, we hypothesized that multi-modal magnetic resonance imaging (MRI) can reveal the effects of biomechanical or biochemical modulation on CSS. Upon intraocular pressure (IOP) elevation, CSS appeared hyperintense in both freshly prepared ovine eyes and living rat eyes using T2-weighted MRI. Quantitatively, transverse relaxation time (T2) of CSS increased non-linearly with IOP at 0–40 mmHg and remained longer than unloaded tissues after being unpressurized. IOP loading also increased fractional anisotropy of CSS in diffusion tensor MRI without apparent change in magnetization transfer MRI, suggestive of straightening of microstructural fibers without modification of macromolecular contents. Lastly, treatments with increasing glyceraldehyde (mimicking crosslinking conditions) and chondroitinase-ABC concentrations (mimicking glycosaminoglycan depletion) decreased diffusivities and increased magnetization transfer in cornea, whereas glyceraldehyde also increased magnetization transfer in sclera. In summary, we demonstrated the changing profiles of MRI contrast mechanisms resulting from biomechanical or biochemical modulation of the eye non-invasively. Multi-modal MRI may help evaluate the pathophysiological mechanisms in CSS and the efficacy of corneoscleral treatments.

Since the introduction of commercial optical coherence tomography (OCT) systems, the ophthalmic imaging modality has rapidly expanded and it has since changed the paradigm of visualization of the retina and revolutionized the management and diagnosis of neuro-retinal diseases, including glaucoma. OCT remains a dynamic and evolving imaging modality, growing from time-domain OCT to the improved spectral-domain OCT, adapting novel image analysis and processing methods, and onto the newer swept-source OCT and the implementation of adaptive optics (AO) into OCT. The incorporation of AO into ophthalmic imaging modalities has enhanced OCT by improving image resolution and quality, particularly in the posterior segment of the eye. Although OCT previously captured in-vivo cross-sectional images with unparalleled high resolution in the axial direction, monochromatic aberrations of the eye limit transverse or lateral resolution to about 15-20 μm and reduce overall image quality. In pairing AO technology with OCT, it is now possible to obtain diffraction-limited resolution images of the optic nerve head and retina in three-dimensions, increasing resolution down to a theoretical 3 μm3. It is now possible to visualize discrete structures within the posterior eye, such as photoreceptors, retinal nerve fiber layer bundles, the lamina cribrosa, and other structures relevant to glaucoma. Despite its limitations and barriers to widespread commercialization, the expanding role of AO in OCT is propelling this technology into clinical trials and onto becoming an invaluable modality in the clinician's arsenal.

Glaucoma is the second leading cause of blindness worldwide and its pathogenesis remains unclear. In this study, we measured the structure, metabolism and function of the visual system by optical coherence tomography and multi-modal magnetic resonance imaging in healthy subjects and glaucoma patients with different degrees of vision loss. We found that inner retinal layer thinning, optic nerve cupping and reduced visual cortex activity occurred before patients showed visual field impairment. The primary visual cortex also exhibited more severe functional deficits than higher-order visual brain areas in glaucoma. Within the visual cortex, choline metabolism was perturbed along with increasing disease severity in the eye, optic radiation and visual field. In summary, this study showed evidence that glaucoma deterioration is already present in the eye and the brain before substantial vision loss can be detected clinically using current testing methods. In addition, cortical cholinergic abnormalities are involved during trans-neuronal degeneration and can be detected non-invasively in glaucoma. The current results can be of impact for identifying early glaucoma mechanisms, detecting and monitoring pathophysiological events and eye-brain-behavior relationships, and guiding vision preservation strategies in the visual system, which may help reduce the burden of this irreversible but preventable neurodegenerative disease.

Aim To evaluate the utility of gold nanorods (AuNRs) as a contrast agent for ocular optical coherence tomography (OCT). Methods Mice were intravitreally injected with sterile AuNRs coated with either poly(strenesulfate) (PSS-AuNRs) or anti-CD90.2 antibodies (Ab-AuNRs), and imaged using OCT. After 24 h, eyes were processed for transmission electron microscopy or rendered into single cell suspensions for flow cytometric analysis to determine absolute numbers of CD45 + leukocytes and subsets (T cells, myeloid cells, macrophages, neutrophils). Generalised estimation equations were used to compare cell counts between groups. Results PSS-AuNRs and Ab-AuNRs were visualised in the vitreous 30 min and 24 h post-injection with OCT. At 24 h, a statistically significant increase in leukocytes, comprised primarily of neutrophils, was observed in eyes that received either AuNR in comparison to eyes that received saline. The accumulation of leukocytes was equal in eyes given PSS-AuNR or Ab-AuNR. Endotoxin-resistant C3H/HeJ mice also showed ocular inflammation after injection with AuNRs, indicating that the inflammatory response was not due to lipopolysaccharide contamination of AuNRs. Conclusions Although AuNRs can be visualised in the eye using OCT, they can induce ocular inflammation, which limits their use as a contrast agent.

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.

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.

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.

To evaluate the effects of age and race on optic disc, retinal nerve fiber layer (RNFL), and macular measurements with spectral-domain optical coherence tomography (SD OCT).Cross-sectional observational study.Three hundred fifty adult subjects without ocular disease.Data from SD OCT imaging of the optic nerve head, peripapillary RNFL, and macula of 632 eyes from 350 subjects without ocular disease were imaged with SD OCT. Multivariate models were used to determine the effect of age and race on quantitative measurements of optic disc, RNFL, and macula.Optic nerve, RNFL, and macular measurements with SD OCT across racial strata and age.For optic nerve parameters, participants of European descent had significantly smaller optic disc area than other groups (P0.0001), and Indian participants had significantly smaller rim area than other groups (P0.0001). Indian and Hispanic participants had thicker global RNFL measurements than other groups (P0.0001). Participants of African descent were associated with thinner inner retinal thickness in the macula (P0.0001). Age was associated with several parameters, with rim area reducing by 0.005 mm(2)/year, RNFL thickness reducing by 0.18 μm/year, and inner retinal thickness reducing by 0.1 μm/year (P0.0001 for all age associations).Optic nerve, RNFL, and macular measurements with SD OCT all varied across racial groups and with age. These differences are important in defining the range of normal variation in differing populations and should be considered in the use of these instruments in the detection of optic nerve and macular disease across these population groups.Proprietary or commercial disclosure may be found after the references.

Aims To determine the retinal nerve fibre layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss. Methods In a prospective cross-sectional study, 72 healthy and 40 glaucoma subjects (one eye per subject) recruited from an academic institution had VF examinations and spectral domain optical coherence tomography (SD-OCT) optic disc cube scans (Humphrey field analyser and Cirrus HD-OCT, respectively). Comparison of global mean and sectoral RNFL thicknesses with VF threshold values showed a plateau of threshold values at high RNFL thicknesses and a sharp decrease at lower RNFL thicknesses. A ‘broken stick’ statistical model was fitted to global and sectoral data to estimate the RNFL thickness ‘tipping point’ where the VF threshold values become associated with the structural measurements. The slope for the association between structure and function was computed for data above and below the tipping point. Results The mean RNFL thickness threshold for VF loss was 75.3 mm (95% CI: 68.9 to 81.8), reflecting a 17.3% RNFL thickness loss from age-matched normative value. Above the tipping point, the slope for RNFL thickness and threshold value was 0.03 dB/mm (CI: � 0.02 to 0.08) and below the tipping point, it was 0.28 dB/mm (CI: 0.18 to 0.38); the difference between the slopes was statistically significant (p

Optical coherence tomography (OCT) images of the retina are a powerful tool for diagnosing and monitoring eye disease. However, they are plagued by speckle noise, which reduces image quality and reliability of assessment. This paper introduces a novel speckle reduction method inspired by the recent successes of deep learning in medical imaging. We present two versions of the network to reflect the needs and preferences of different end-users. Specifically, we train a convolution neural network to denoise cross-sections from OCT volumes of healthy eyes using either (1) mean-squared error, or (2) a generative adversarial network (GAN) with Wasserstein distance and perceptual similarity. We then interrogate the success of both methods with extensive quantitative and qualitative metrics on cross-sections from both healthy and glaucomatous eyes. The results show that the former approach provides state-of-the-art improvement in quantitative metrics such as PSNR and SSIM, and aids layer segmentation. However, the latter approach, which puts more weight on visual perception, outperformed for qualitative comparisons based on accuracy, clarity, and personal preference. Overall, our results demonstrate the effectiveness and efficiency of a deep learning approach to denoising OCT images, while maintaining subtle details in the images.

Purpose To determine if inner retinal layer reflectivity in eyes with acute central retinal vein occlusion (CRVO) correlates with visual acuity at 12 months. Methods Macular optical coherence tomography (OCT) scans were obtained from 22 eyes of 22 patients with acute CRVO. Optical intensity ratios (OIRs), defined as the mean OCT reflectivity of the inner retinal layers normalized to the mean reflectivity of the RPE, were measured from the presenting and 1-month OCT image by both manual measurements of grayscale B-scans and custom algorithmic measurement of raw OCT volume data. OIRs were assessed for association with final visual outcome. Cohort subgroup division for analysis was determined statistically. Results Eyes with poorer final visual acuity (≥20/70) at 1 year were more likely to have a higher ganglion cell layer OIR than eyes with better final visual acuity (

PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Purpose: To evaluate, within ocular imaging scans of acceptable quality as determined by manufacturers’ guidelines, the effects of image quality on glaucoma discrimination capabilities. Methods: One hundred and four healthy and 75 glaucomatous eyes from the Advanced Imaging in Glaucoma Study (AIGS) were imaged with GDx-VCC, HRT II, and StratusOCT. Quality score (QS≥8), pixel standard deviation (SD≤50), and signal strength (SS≥5) were used as quality parameter cutoffs, respectively. GDx nerve fiber indicator (NFI), and HRT Moorfields regression analysis (MRA) classifications and OCT mean retinal nerve fiber layer (RNFL) thickness were used as the discriminatory parameters. Logistic regression models were used to model the dichotomous clinical classification (healthy vs. glaucoma) as a function of image quality parameters and discriminatory parameters. Results: Quality parameter covariates were statistically non¬-significant for GDx and HRT but had an inverse effect on OCT in predicting disease (higher SS had lower probability of glaucoma). Age was a significant covariate for GDx and HRT, but not OCT, while ethnicity and interaction between the image quality and the institute where scans were acquired were significant covariates in the OCT models. Conclusion: Within scans considered to be acceptable based on the manufacturers’ recommended limits, scan quality does not affect the discriminating ability of global discriminatory parameters of GDx, HRT but have an effect on OCT measurements.

Background:Glaucoma is a group of diseases characterised by retinal ganglion cell dysfunction and death. Detection of glaucoma and its progression are based on identification of abnormalities or changes in the optic nerve head (ONH) or the retinal nerve fibre layer (RNFL), either functional or structural. This review will focus on the identification of structural abnormalities in the RNFL associated with glaucoma.Discussion:A variety of new techniques have been created and developed to move beyond photography, which generally requires subjective interpretation, to quantitative retinal imaging to measure RNFL loss. Scanning laser polarimetry uses polarised light to measure the RNFL birefringence to estimate tissue thickness. Optical coherence tomography (OCT) uses low-coherence light to create high-resolution tomographic images of the retina from backscattered light in order to measure the tissue thickness of the retinal layers and intraretinal structures. Segmentation algorithms are used to measure the thickness of the retinal nerve fibre layer directly from the OCT images. In addition to these clinically available technologies, new techniques are in the research stages. Polarisation-sensitive OCT has been developed that combines the strengths of scanning laser polarimetry with those of OCT. Ultra-fast techniques for OCT have been created for research devices. The continued utilisation of imaging devices into the clinic is refining glaucoma assessment. In the past 20 years glaucoma has gone from a disease diagnosed and followed using highly subjective techniques to one measured quantitatively and increasingly objectively.

MRI has long been applied to clinical medical and neurological cases for the structural assessment of tissues as well as their physiological and functional needs and processes. These uses are at a variety of developmental stages in ophthalmology, from common use of clinical structural assessment for neuro-ophthalmology and evaluation of space-occupying lesions to the beginning stages of experimentally measuring functional activation of specific layers within the retina and measurement of physiological oxygen responses. New MRI methodologies, such as the use of orbital coils and Gd-DTPA image enhancement, have been researched, developed, and validated in the eye, opening new possibilities for this technology to enter the clinic. This review aims to summarize the clinical ophthalmological uses of MRI, focusing on the current use of the technology and future applications.

Aims: The purpose of this study was to compare the day-to-day reproducibility of optical coherence tomography (OCT; StratusOCT, Carl Zeiss Meditec, Dublin, CA) measurements of retinal nerve-fibre layer (RNFL) measurements at time points 1 year apart. Methods: One eye in each of 11 healthy subjects was examined using the StratusOCT fast RNFL scan protocol. Three fast RNFL scans with signal strength ⩾7 were obtained on each of 3 days within a month. This protocol was repeated after 12 months. A linear mixed effects model fitted to the nested data was used to compute the variance components. Results: The square root of the variance component that was attributed to the differences between subjects was 7.17 μm in 2005 and 7.28 μm in 2006. The square roots of the variance component due to differences between days within a single subject were 1.95 μm and 1.50 μm, respectively, and for within day within a single subject were 2.51 μm and 2.55 μm, respectively. There were no statistically significant differences for any variance component between the two testing occasions. Conclusions: Measurement error variance remains similar from year to year. Day and scan variance component values obtained in a cohort study may be safely applied for prediction of long-term reproducibility.

To compare stereometric parameters and classification results from the Heidelberg Retina Tomograph version 2 (HRT2); HRT3; and HRT3 Glaucoma Probability Score (GPS), an automated method of obtaining optic nerve head analysis without the need for manual definition of disc margin.Retrospective cross-sectional study.Five hundred four eyes from 281 consecutive subjects (glaucoma, glaucoma suspect, and healthy) evaluated in a glaucoma clinic.All participants had HRT2 scanning of the optic nerve head. Inclusion criteria were scans with good centration and focus, even illumination, an overall quality score by HRT3 of acceptable or better, and standard deviation50 mum. A Bland-Altman analysis was used for the comparison of HRT2 and HRT3. From these results, calibration equations were determined to permit conversion of the measurements between devices. The agreement between HRT2 and HRT3 Moorfields regression analysis (MRA) and HRT3 GPS classification methods was measured using kappa statistics.Heidelberg Retina Tomograph version 2 and HRT3 stereometric parameters, MRA, and global GPS.There was a statistically significant difference between HRT2 and HRT3 global disc area, rim area, cup area, rim volume, cup volume, height variation contour, and retinal nerve fiber layer cross-sectional area stereometric parameters. All of those parameters were smaller using HRT3, due to a manufacturer-reported horizontal scaling error of 4% in HRT2 that was corrected in HRT3. kappas for agreement were 0.60 between classifications (within normal limits, borderline, and outside normal limits) of MRA by HRT2 and HRT3 and 0.47 between HRT3 MRA and GPS.The HRT3 generally provided smaller stereometric disc measurements than HRT2. There was no clear conversion between HRT3 and GPS parameters, as the 2 methods for measuring the stereometric parameters differ.

International audience; Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

Optical coherence tomography (OCT) has become the cornerstone technology in clinical and research imaging in the past two decades. OCT performs in vivo, real-time, noncontact scanning and provides cross-sectional and volumetric images with a resolution approaching that of histology. The technology is used in various medical disciplines, but it is still most profoundly used in the field of ophthalmology where it was initially applied. OCT is continuously evolving with newly developed applications.

Author(s): Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas; Dismuke, W Michael; Cai, Jingwen; Drewry, Michelle; Brilliant, Murray H; Budenz, Donald L; Christen, William G; Chasman, Daniel I; Fingert, John H; Gaasterland, Douglas; Gaasterland, Terry; Gordon, Mae O; Igo, Robert P; Kang, Jae H; Kass, Michael A; Kraft, Peter; Lee, Richard K; Lichter, Paul; Moroi, Sayoko E; Realini, Anthony; Richards, Julia E; Ritch, Robert; Schuman, Joel S; Scott, William K; Singh, Kuldev; Sit, Arthur J; Song, Yeunjoo E; Vollrath, Douglas; Weinreb, Robert; Medeiros, Felipe; Wollstein, Gadi; Zack, Donald J; Zhang, Kang; Pericak-Vance, Margaret A; Gonzalez, Pedro; Stamer, W Daniel; Kuchtey, John; Kuchtey, Rachel W; Allingham, R Rand; Hauser, Michael A; Pasquale, Louis R; Haines, Jonathan L; Wiggs, Janey L | Abstract: PurposeNoncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG).MethodsUsing the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls.ResultsOnly rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment.ConclusionsOur integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

The Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA) is the predominant time-domain OCT in clinical use at the time of this writing. A variety of scan patterns (radial or circular) can be acquired with this device to image the area of interest. The “Fast Optic Disc” pattern is used to analyze the optic nerve head. The “Fast Optic Disc” pattern consists of six evenly spaced radial lines centered on the ONH (see Fig. 5.4a). Each of the six lines is made of 128 A-scans (vertically scanned sampling points), crossing an area of 4.0 mm in length, and the total scan time is 1.92 s.

Purpose To compare the ability of the Heidelberg retina tomograph version 3 (HRT 3) and HRT version 2 (HRT 2) to discriminate between healthy and glaucomatous eyes. Design Retrospective cross-sectional study. Participants Seventy-one eyes of 71 healthy volunteers and 50 eyes of 50 glaucoma patients were studied. The average visual field mean deviation of the glaucoma group was −6.03±5.78 dB. Intervention All participants had comprehensive ocular examinations, perimetry, and HRT scanning within 6 months. HRT 2 data were analyzed using HRT 3 software without modifying the disc margin. Main Outcome Measures Discrimination capabilities between healthy and glaucomatous eyes were determined by areas under the receiver operating characteristics (AROCs) curves. Comparisons between corresponding AROCs obtained by HRT 2 and HRT 3 analyses were performed using the nonparametric DeLong method. Agreement between classifications as defined by the different analysis methods was quantified by κ analysis. Results The individual stereometric parameters with the best discrimination were linear cup/disc ratio (AROC = 0.897; 95% confidence interval [CI], 0.836–0.958) for standard HRT 3 analysis and horizontal retinal nerve fiber layer curvature (0.905) for HRT 3 glaucoma probability score (GPS) analysis. Areas under the receiver operating characteristics for discrimination between glaucomatous and healthy eyes of the overall classification by HRT 2 Moorfields regression analysis (MRA), HRT 3 MRA, and GPS were 0.927 (95% CI, 0.877–0.977), 0.934 (0.888–0.980), and 0.880 (0.812–0.948), respectively. The difference between the 3 AROCs was not significant ( P = 0.44). The agreement between HRT 2 and HRT 3 overall MRA classification was good (κ = 0.70; CI, 0.59–0.80) with HRT 3 tending to report more abnormalities than HRT 2 analysis. The agreement between overall HRT 3 MRA and overall GPS was κ = 0.58 (CI, 0.45–0.70). Conclusions The glaucoma discriminating ability of the new HRT 3 software is similar to that of the previous generation HRT 2. The GPS analysis showed promising results in differentiating between healthy and glaucomatous eyes without the need for subjective operator input.

To compare visual field (VF) defects found by Swedish interactive thresholding Algorithm (SITA) perimetry and Matrix perimetry, a new VF device that utilizes frequency doubling technology in a 24-2 test pattern.Prospective cross-sectional study.Fifty eyes from 50 subjects with SITA field defects were recruited for an observational study.Swedish Interactive Threshold Algorithm and Matrix VF testing were performed on patients from a glaucoma practice. To evaluate the learning effect on the performance of the VF, we tested subsets of each group who had previous experience with standard automated perimetry (SAP).Test duration, mean threshold, mean deviation (MD), pattern standard deviation (PSD), glaucoma hemifield test, and number of abnormal points on the pattern deviation plot were evaluated for each device.Test duration was significantly shorter for Matrix (SITA, 357.0+/-85.6 seconds; Matrix, 319.5+/-16.5 seconds; P = 0.0002, paired t-test). Thirty-six percent of eyes with SITA VF defects showed a normal Matrix field. In 30 of 32 eyes (94%) where both devices showed VF defects, the defects were congruent. Mean threshold value was significantly lower with Matrix compared to SITA (P0.0001, paired t-test), as was MD (-5.34+/-5.42 dB, -4.14+/-5.29 dB, respectively; P = 0.03, paired t-test). There was no significant difference in PSD between the 2 devices (P = 0.78, paired t-test). Matrix delineated significantly smaller (P = 0.005, Wilcoxon's test) and deeper (P0.001, Wilcoxon's test) defects than those found with SITA. Similar results were observed in the subgroups with prior SAP experience.The Matrix examination did not detect 36% of abnormal SITA fields. Matrix field defects were smaller and deeper than those appearing in SITA perimetry.

Purpose: Matrix perimetry is a new iteration of frequency doubling technology (FDT) using a smaller target size in the standard achromatic perimetry presentation pattern. This study compared Matrix and Swedish interactive thresholding algorithm (SITA) perimetry performance in detecting glaucoma diagnosed by structural assessment. Design: Prospective cross-sectional study. Methods: Seventy-six eyes of 76 consecutive healthy subjects, glaucoma suspects and glaucoma patients were included. All patients underwent optic nerve head (ONH) photography, SITA and Matrix perimetry and optical coherence tomography (OCT; Stratus OCT) within a six month interval. Glaucoma diagnosis was established by either glaucomatous optic neuropathy or OCT retinal nerve fiber layer (RNFL) thickness. Mean deviation (MD), pattern standard deviation (PSD), glaucoma hemifield test (GHT) and cluster of abnormal testing locations were recorded from Matrix and SITA. Results: Similar correlations were observed with Matrix and SITA MD and PSD with either cup-to-disc ratio or OCT mean RNFL. The area under the receiver operating characteristic (AROC) curves of MD and PSD for discriminating between healthy and glaucomatous eyes ranged from 0.69 to 0.81 for Matrix and from 0.75 to 0.77 for SITA. There were no statistically significant differences among any corresponding Matrix and SITA AROCs. Conclusions: Matrix and SITA perimetry had similar capabilities for distinguishing between healthy and glaucomatous eyes regardless of whether the diagnosis was established by ONH or OCT RNFL assessment.

Purpose: To investigate how the lamina cribrosa (LC) microstructure changes with distance from the central retinal vessel trunk (CRVT), and to determine how this change differs in glaucoma. Methods: One hundred nineteen eyes (40 healthy, 29 glaucoma suspect, and 50 glaucoma) of 105 subjects were imaged using swept-source optical coherence tomography (OCT). The CRVT was manually delineated at the level of the anterior LC surface. A line was fit to the distribution of LC microstructural parameters and distance from CRVT to measure the gradient (change in LC microstructure per distance from the CRVT) and intercept (LC microstructure near the CRVT). A linear mixed-effects model was used to determine the effect of diagnosis on the gradient and intercept of the LC microstructure with distance from the CRVT. A Kolmogorov-Smirnov test was applied to determine the difference in distribution between the diagnostic categories. Results: The percent of visible LC in all scans was 26 ± 7%. Beam thickness and pore diameter decreased with distance from the CRVT. Glaucoma eyes had a larger decrease in beam thickness (−1.132 ± 0.503 μm, P = 0.028) and pore diameter (−0.913 ± 0.259 μm, P = 0.001) compared with healthy controls per 100 μm from the CRVT. Glaucoma eyes showed increased variability in both beam thickness and pore diameter relative to the distance from the CRVT compared with healthy eyes (P < 0.05). Conclusions: These findings results demonstrate the importance of considering the anatomical location of CRVT in the assessment of the LC, as there is a relationship between the distance from the CRVT and the LC microstructure, which differs between healthy and glaucoma eyes., Research to Prevent Blindness, Inc. (United States), Eye and Ear Foundation (Pittsburgh, Pa.), National Institutes of Health (U.S.) (NIH grant R01-EY013178), National Institutes of Health (U.S.) (NIH grant R01-EY025011), National Institutes of Health (U.S.) (NIH grant R01- EY011289), National Institutes of Health (U.S.) (NIH grant P30-EY008098), National Institutes of Health (U.S.) (NIH grant T32-EY017271)

The mechanical characteristics of the trabecular meshwork (TM) are linked to outflow resistance and intraocular pressure (IOP) regulation. The rationale behind this technique is the direct observation of the mechanical response of the TM to acute IOP elevation. Prior to scanning, IOP is measured at baseline and during IOP elevation. The limbus is scanned by spectral-domain optical coherence tomography at baseline and during IOP elevation (ophthalmodynamometer (ODM) applied at 30 g force). Scans are processed to enhance visualization of the aqueous humor outflow pathway using ImageJ. Vascular landmarks are used to identify corresponding locations in baseline and IOP elevation scan volumes. Schlemm canal (SC) cross-sectional area (SC-CSA) and SC length from anterior to posterior along its long axis are measured manually at 10 locations within a 1 mm segment of SC. Mean inner to outer wall distance (short axis length) is calculated as the area of SC divided by its long axis length. To examine the contribution of adjacent tissues to the effect IOP elevations, measurements are repeated without and with smooth muscle relaxation with instillation of tropicamide. TM migration into SC is resisted by TM stiffness, but is enhanced by the support of its attachment to adjacent smooth muscle within the ciliary body. This technique is the first to measure the living human TM response to pressure elevation in situ under physiological conditions within the human eye.

PURPOSE Developing a novel image enhancement method so that nonframe-averaged optical coherence tomography (OCT) images become comparable to active eye-tracking frame-averaged OCT images. METHODS Twenty-one eyes of 21 healthy volunteers were scanned with noneye-tracking nonframe-averaged OCT device and active eye-tracking frame-averaged OCT device. Virtual averaging was applied to nonframe-averaged images with voxel resampling and adding amplitude deviation with 15-time repetitions. Signal-to-noise (SNR), contrast-to-noise ratios (CNR), and the distance between the end of visible nasal retinal nerve fiber layer (RNFL) and the foveola were assessed to evaluate the image enhancement effect and retinal layer visibility. Retinal thicknesses before and after processing were also measured. RESULTS All virtual-averaged nonframe-averaged images showed notable improvement and clear resemblance to active eye-tracking frame-averaged images. Signal-to-noise and CNR were significantly improved (SNR: 30.5 vs. 47.6 dB, CNR: 4.4 vs. 6.4 dB, original versus processed, P < 0.0001, paired t-test). The distance between the end of visible nasal RNFL and the foveola was significantly different before (681.4 vs. 446.5 μm, Cirrus versus Spectralis, P < 0.0001) but not after processing (442.9 vs. 446.5 μm, P = 0.76). Sectoral macular total retinal and circumpapillary RNFL thicknesses showed systematic differences between Cirrus and Spectralis that became not significant after processing. CONCLUSION The virtual averaging method successfully improved nontracking nonframe-averaged OCT image quality and made the images comparable to active eye-tracking frame-averaged OCT images. TRANSLATIONAL RELEVANCE Virtual averaging may enable detailed retinal structure studies on images acquired using a mixture of nonframe-averaged and frame-averaged OCT devices without concerning about systematic differences in both qualitative and quantitative aspects.

Excitotoxicity has been linked to the pathogenesis of several ocular diseases and injuries such as retinal ischemia,1–5 traumatic injury,6,7 glaucoma,8–11 and diabetic retinopathy.12,13 In the retina, the retinal ganglion cells preferentially express N-methyl-D-aspartate (NMDA)-type glutamate receptors and are believed to play a major role in glutamate excitotoxic retinal injury.14,15 While the cell bodies in the retina are commonly regarded as the primary site of insult, recent studies have suggested the early involvement of white matter degeneration in the posterior visual pathway after glutamate excitotoxicity in the eye.16–19 Nevertheless, because of limited noninvasive techniques available for assessing the visual pathways, the spatiotemporal patterns of neurodegenerative events in the visual system and their relationships with excitotoxic retinal injury in the eye are not fully elucidated. This in part hinders the development of effective strategies for disease monitoring and treatment. Magnetic resonance imaging (MRI) allows noninvasive, longitudinal, and multiparametric assessments of the visual system without depth limitation.20–25 Although there were existing MR reports assessing the effects of NMDA-induced excitotoxicity in developing and adult brain tissues,26,27 most of the neuropathy models employed did not differentiate clearly the locations of the primary site of insult or the initial events in white matter degeneration. In addition, the early MRI studies assessing visual system injury28,29 mainly used the conventional anatomical T2-weighted imaging or diffusion weighted imaging techniques at low magnetic field strengths with relatively limited sensitivity and specificity to characterize the underlying pathophysiological events. In this study, we employed the advanced MR techniques, namely diffusion tensor MRI (DTI) and manganese-enhanced MRI (MEMRI) at a high magnetic field strength, in combination with spectral-domain optical coherence tomography (OCT), with an aim to develop an in vivo model system for characterizing the spatiotemporal patterns of white matter integrity changes in the visual system and their relations to retinal integrity after glutamate excitotoxicity in the eye. Diffusion tensor MRI has been recently shown to reveal white matter integrity in normal, developing and diseased visual systems in rodent models under high magnetic field strengths.30–35 In particular, the measurements of water diffusion parallel and perpendicular to the nerve fibers have been suggested to be sensitive to axonal and myelin integrity respectively.31,36 Since intravitreal injection of NMDA has been commonly used as an experimental model to induce glutamate excitotoxic retinal ganglion cell death,37,38 in this study, we quantified the spatiotemporal DTI profiles in the rodent visual system with a 9.4 Tesla MRI scanner after NMDA-induced excitotoxic retinal injury. In addition, DTI results were compared with OCT measurement of the thickness of the retina and MEMRI of the anterograde transport along the visual pathway, in order to determine the eye–brain relationships and to correlate between structural and physiological characteristics in the injured visual system. As the retinal ganglion cells and the sites of toxic insult after intravitreal NMDA injection in the eye are physically isolated from the axons beyond the eye in the brain's visual system, our MRI and OCT studies in this NMDA model of retinal injury are well suited for providing information about the effects of excitotoxic perikaryal injury on white matter integrity changes in both ocular diseases and other neuropathies. Our cross-sectional and longitudinal results from these in vivo multidisciplinary ophthalmic imaging techniques may allow better monitoring of the disease progression in the visual system, and provide a platform for assessing treatment effects on both the eye and the visual pathway in future studies.

Purpose To determine the effect of corneal drying on the outcome of optical coherence tomography (OCT). Design Cohort study. Participants Seventeen normal participants (mean age, 39±12 years). Methods Subjects underwent a series of peripapillary circular StratusOCT scans (version 3.0; Carl Zeiss Meditec, Inc., Dublin, CA) in a randomly selected eye. Baseline scan sets were acquired, and thereafter, blinking was prevented by taping the eyelid. Eyelid taping was immediately followed by 6 to 8 serial scan sets, each separated by 20 seconds. After removing the eyelid tape, 3 additional scans were acquired at 1, 2, and 4 minutes of blinking freely. Main Outcome Measures The analyzed outcome measures were scan quality as defined by signal-to-noise ratio (SNR) and signal strength (SS) provided by the built-in OCT software and mean nerve fiber layer (NFL) thickness. Results Significant reductions in SNR, SS, and NFL were noted at each scanning point in the drying phase (for each, P t test) except for NFL thickness measurements acquired at 140 and 160 seconds. The reduction in NFL thickness exceeded the 95% confidence limit of the reported reproducibility error of StratusOCT after 15 seconds of corneal drying. After 1 and 2 minutes of blinking freely, there was still a significant reduction in NFL thickness compared with the baseline value, which was no longer evident at the 4-minute scan. Conclusions Corneal dryness affects OCT scan quality and measured NFL thickness after a short exposure time. It is recommended to instruct those who are scanned to blink frequently or to instill artificial tears.

Objective Optical coherence tomography (OCT) has been shown to be a valuable tool in glaucoma assessment. We investigated a new ultrahigh-resolution OCT (UHR-OCT) imaging system in glaucoma patients and compared the findings with those obtained by conventional-resolution OCT. Design Retrospective comparative case series. Participants A normal subject and 4 glaucoma patients representing various stages of glaucomatous damage. Testing All participants were scanned with StratusOCT (axial resolution of ∼10 μm) and UHR-OCT (axial resolution of ∼3 μm) at the same visit. Main outcome measure Comparison of OCT findings detected with StratusOCT and UHR-OCT. Results Ultrahigh-resolution OCT provides a detailed cross-sectional view of the scanned retinal area that allows differentiation between retinal layers. These UHR images were markedly better than those obtained by the conventional-resolution OCT. Conclusions Ultrahigh-resolution OCT provides high-resolution images of the ocular posterior segment, which improves the ability to detect retinal abnormalities due to glaucoma.

Purpose To investigate the structure-function relationship between optical coherence tomography (OCT) macular retinal and peripapillary nerve fiber layer (NFL) thickness and automated visual field (VF) findings. Design Cross-sectional observational study. Methods Retrospective institutional study where 150 consecutive eyes (101 subjects) from a glaucoma service were included. All the participants had full ophthalmic evaluation, VF testing and prototype OCT scanning at the same visit. Orthogonal OCT macular analysis was obtained to maximize the sampling of the area of interest. Pearson age-adjusted correlation was determined between macular retinal thickness and peripapillary NFL thickness. Area under the receiver operator characteristics (AROC) curves for the association between macular retinal thickness and peripapillary NFL thickness and VF findings were calculated in a subgroup of eyes without VF defect and eyes with VF defect confined to one hemifield. Results The correlation between macular retinal and peripapillary NFL measurements ranged between r = .27 to .54 for quadrants, .44 to .55 for hemiretina, and .52 for the overall mean. Areas under the receiver operator characteristics for macular thickness were higher in areas corresponding to the VF defect location than the noncorresponding locations. Areas under the receiver operator characteristics for peripapillary NFL thickness were higher than for the macular retinal thickness. Including both macular retinal thickness and peripapillary NFL thickness measurements in the logistic regression model yielded AROCs (range: .69 − .77) similar to those found for the peripapillary NFL alone. Conclusion Macular retinal thickness, as measured by OCT, was capable of detecting glaucomatous damage and corresponded with peripapillary NFL thickness; however, peripapillary NFL thickness had higher sensitivity and specificity for the detection of VF abnormalities.

Purpose To compare computer-assisted planimetry using the Discam system (Marcher Enterprises Ltd., Hereford, UK), confocal scanning laser ophthalmoscopy (CSLO), and stereoscopic disc photography with respect to optic nerve head (ONH) measurements and glaucoma status.