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1.  Evaluating Objective and Subjective Quantitative Parameters at the Initial Visit to Predict Future Glaucomatous Visual Field Progression 
To evaluate the ability of structural assessment to predict glaucomatous visual field progression.
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.
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.
Baseline stereophotographs, OCT, and CSLO measurements may be clinically useful to predict glaucomatous visual field progression.
PMCID: PMC3444548  PMID: 22658308
2.  Visualization of the Conventional Outflow Pathway in the Living Human Eye 
Ophthalmology  2012;119(8):1563-1568.
The purpose of this study was to visualize the aqueous outflow system in three dimensions (3D) in living human eyes, and to investigate the use of commercially available Spectral-domain optical coherence tomographic (SD-OCT) systems for this purpose.
This was a prospective observational study.
Participants and/or Controls
One randomly determined eye in each of six normal healthy subjects was included.
3D SD-OCT imaging of the aqueous humor outflow structures was performed with two devices: Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin CA) and Bioptigen SDOIS (Bioptigen, Inc., Research Triangle, NC).
Main Outcome Measures
3D virtual castings of Schlemm’s canal (SC) and more distal outflow structures created from scan data from each device.
Virtual casting of SC provided visualization of more aqueous vessels branching from SC than could be located by interrogating the 2D image stack. Similarly, virtual casting of distal structures allowed visualization of large and small aqueous outflow channel networks that could not be appreciated with the conventional 2D visualization.
The outflow pathways from SC to the superficial vasculature can be identified and tracked in living human eyes using commercially available SD-OCT.
PMCID: PMC3411861  PMID: 22683063
3.  Glaucoma Discrimination of Segmented Cirrus Spectral Domain Optical Coherence Tomography (SD-OCT) Macular Scans 
The British journal of ophthalmology  2012;96(11):1420-1425.
To evaluate the glaucoma discriminating ability of macular retinal layers as measured by spectral-domain optical coherence tomography (SD-OCT).
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, CA) in the macular and optic nerve head regions. OCT macular scans were segmented into macular nerve fiber layer (mNFL), ganglion cell layer with inner plexiform layer (GCIP), ganglion cell complex (GCC) (composed of mNFL and GCIP), outer retinal complex (ORC) and total retina (TR). Glaucoma discriminating ability was assessed using the area under the receiver operator characteristic curve (AUC) for all macular parameters and mean circumpapillary (cp) RNFL. Glaucoma suspects and glaucoma subjects were grouped together for the calculation of AUCs.
Analysis was performed on 51 healthy, 49 glaucoma suspect and 63 glaucomatous eyes. The median visual field MD was −2.21dB (interquartile range (IQR): −6.92 to −0.35) for the glaucoma group, −0.32dB (IQR: −1.22 to 0.73) for the suspect group and −0.18dB (IQR: −0.92 to 0.71) for the healthy group. Highest age adjusted AUCs for discriminating between healthy and glaucomatous eyes 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). Similar discrimination performance but with slight reduction in AUCs was achieved for comparison between healthy and the combination of glaucoma and glaucoma suspect eyes.
SD-OCT GCIP and GCC measurements showed similar glaucoma diagnostic ability and was comparable with that of cpRNFL.
PMCID: PMC3721629  PMID: 22914498
4.  Detection of Glaucoma Progression by Population and Individual Derived Variability Criteria 
Ocular imaging devices provide quantitative structural information that might improve glaucoma progression detection. This study examined scanning laser polarimetry (SLP) population-derived versus individual-derived cut-off criteria for detecting progression.
Forty-eight healthy, glaucoma suspect and glaucoma subjects, providing 76 eyes were used. All subjects had reliable visual field (VF) and SLP scans acquired at the same visits from ≥ 4 visits. VF progression was defined by guided progression analysis (GPA) and by the VF index (VFI). SLP measurements were analyzed by fast mode (FM) GPA, compared to the population rate of progression, and extended mode (EM) GPA, compared to the individual variability. The agreement between progression detection methods was measured.
Poor agreement was observed between progression defined by VF and FM and EM. The difference in TSNIT average rate of change between VF defined progressors and non-progressors for both FM (p=0.010) and EM (p=0.015) was statistically significant.
There is poor agreement between VF and SLP progression regardless of the use of population derived or individual variability criteria. The best SLP progression detection method could not be ascertained, therefore, acquiring three SLP scans per visit is recommended.
PMCID: PMC3721630  PMID: 23203702
Scanning laser polarimetry; glaucoma progression
5.  Optical Coherence Tomography: Future Trends for Imaging in Glaucoma 
Optometry and Vision Science  2012;89(5):E554-E562.
Optical coherence tomography (OCT) captures a major role in clinical assessment in eye care. Innovative hardware and software improvements in the technology would further enhance its usefulness. In this review we present several promising initiatives currently in development or early phase of assessment that we expect to have a future impact on OCT.
PMCID: PMC3348373  PMID: 22488265
optical coherence tomography; OCT; image processing
6.  Variation in optical coherence tomography signal quality as an indicator of retinal nerve fibre layer segmentation error 
Commercial optical coherence tomography (OCT) systems use global signal quality indices to quantify scan quality. Signal quality can vary throughout a scan, contributing to local retinal nerve fibre layer segmentation errors (SegE). The purpose of this study was to develop an automated method, using local scan quality, to predict SegE.
Good-quality (global signal strength (SS)≥6; manufacturer specification) peripapillary circular OCT scans (fast retinal nerve fibre layer scan protocol; Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA) were obtained from 6 healthy, 19 glaucoma-suspect and 43 glaucoma subjects. Scans were grouped based on SegE. Quality index (QI) values were computed for each A-scan using software of our own design. Logistic mixed-effects regression modelling was applied to evaluate SS, global mean and SD of QI, and the probability of SegE.
The difference between local mean QI in SegE regions and No-SegE regions was −5.06 (95% CI −6.38 to 3.734) (p<0.001). Using global mean QI, QI SD and their interaction term resulted in the model of best fit (Akaike information criterion=191.8) for predicting SegE. Global mean QI≥20 or SS≥8 shows little chance for SegE. Once mean QI<20 or SS<8, the probability of SegE increases as QI SD increases.
When combined with a signal quality parameter, the variation of signal quality between A-scans provides significant information about the quality of an OCT scan and can be used as a predictor of segmentation error.
PMCID: PMC3375178  PMID: 21900227
7.  Three-Dimensional Spectral-Domain Optical Coherence Tomography Data Analysis for Glaucoma Detection 
PLoS ONE  2013;8(2):e55476.
To develop a new three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) data analysis method using a machine learning technique based on variable-size super pixel segmentation that efficiently utilizes full 3D dataset to improve the discrimination between early glaucomatous and healthy eyes.
192 eyes of 96 subjects (44 healthy, 59 glaucoma suspect and 89 glaucomatous eyes) were scanned with SD-OCT. Each SD-OCT cube dataset was first converted into 2D feature map based on retinal nerve fiber layer (RNFL) segmentation and then divided into various number of super pixels. Unlike the conventional super pixel having a fixed number of points, this newly developed variable-size super pixel is defined as a cluster of homogeneous adjacent pixels with variable size, shape and number. Features of super pixel map were extracted and used as inputs to machine classifier (LogitBoost adaptive boosting) to automatically identify diseased eyes. For discriminating performance assessment, area under the curve (AUC) of the receiver operating characteristics of the machine classifier outputs were compared with the conventional circumpapillary RNFL (cpRNFL) thickness measurements.
The super pixel analysis showed statistically significantly higher AUC than the cpRNFL (0.855 vs. 0.707, respectively, p = 0.031, Jackknife test) when glaucoma suspects were discriminated from healthy, while no significant difference was found when confirmed glaucoma eyes were discriminated from healthy eyes.
A novel 3D OCT analysis technique performed at least as well as the cpRNFL in glaucoma discrimination and even better at glaucoma suspect discrimination. This new method has the potential to improve early detection of glaucomatous damage.
PMCID: PMC3569462  PMID: 23408988
8.  Comparison of Retinal Nerve Fiber Layer Thickness Measurement Bias and Imprecision across Three Spectral-Domain Optical Coherence Tomography Devices 
We compared retinal nerve fiber layer (RNFL) bias and imprecision among three spectral-domain optical coherence tomographs (SD-OCT).
A total of 152 eyes of 83 subjects (96 healthy and 56 glaucomatous eyes) underwent peripapillary RNFL imaging using at least 2 of the following 3 SD-OCT devices on the same day: Cirrus HD-OCT (optic nerve head [ONH]) cube 200 × 200 protocol), RTVue-100 (ONH protocol [12 radial lines and 13 concentric circles]), and 3D OCT-1000 (3D Scan 256 × 256 protocol). Calibration equations, bias and imprecision of RNFL measurements were calculated using structural equation models.
The calibration equations for healthy and glaucoma RNFL thickness measurements among the 3 devices were: Cirrus = 2.136 + 0.831*RTVue; Cirrus = −15.521 + 1.056*3D OCT-1000; RTVue = −21.257 + 1.271*3D OCT-1000. Using Cirrus bias as an arbitrary reference, RTVue bias was 1.20 (95% CI 1.09–1.32, P < 0.05) times larger and 3D OCT-1000 was 0.95 (0.87–1.03, P > 0.05) times smaller. Relative to 3D OCT-1000, the RTVue bias was 1.27 (1.13–1.42, P < 0.05). RTVue imprecision (healthy eyes 7.83, 95% CI 6.43–9.58; glaucoma cases 5.71, 4.19–7.64) was statistically significantly higher than both Cirrus (healthy eyes 3.23, 2.11–4.31; glaucoma cases 3.53, 0.69–5.24) and 3D OCT-1000 (healthy eyes 4.07, 3.11–5.35; glaucoma cases 5.33, 3.77–7.67) in healthy eyes. The imprecision also was significantly higher for RTVue measurements in healthy compared to glaucomatous eyes. None of the other comparisons was statistically significant.
RTVue-100 showed higher imprecision (or higher measurement variability) than Cirrus HD-OCT and 3D OCT-1000 RNFL measurements. Three-dimensional cube scanning with post-hoc data sampling may be a factor reducing imprecision.
RTVue-100 showed worse imprecision (higher measurement variability) than Cirrus HD-OCT and 3D OCT-1000 retinal nerve fiber layer measurements. The results might be related to the use of raster scanning by the later devices, while RTVue uses a combination of radial and concentric scanning pattern.
PMCID: PMC3390182  PMID: 22538423
9.  3D Visualization of Aqueous Humor Outflow Structures In-Situ in Humans 
Experimental eye research  2011;93(3):308-315.
Aqueous humor (AH) exiting the eye via the trabecular meshwork and Schlemm's canal (SC) passes through the deep and intrascleral venous plexus (ISVP) or directly through aqueous veins. The purpose of this study was to visualize the human AH outflow system 360 degrees in three dimensions (3D) during active AH outflow in a virtual casting.
The conventional A Houtflow pathways of 7 donor eyes were imaged with a modified Bioptigen spectral-domain optical coherence tomography system (Bioptigen Inc, USA; SuperLum LTD, Ireland) at a perfusion pressure of 20 mmHg (N=3), and 10 mmHg (N=4). In all eyes, 36 scans (3 equally distributed in each clock hour), each covering a 2 × 3 × 2 mm volume (512 frames, each 512 × 1024 pixels), were obtained. All image data were black/white inverted, and the background subtracted (ImageJ 1.40g, Contrast was adjusted to isolate the ISVP.
SC, collector channels, the deep and ISVP, and episcleral veins were observed throughout the limbus. Aqueous veins could be observed extending into the episcleral veins. Individual scan ISVP castings were rendered and assembled in 3D space in Amira 4.1 (Visage Imaging Inc. USA). A 360-degree casting of the ISVP was obtained in all perfused eyes. The ISVP tended to be dense and overlapping in the superior and inferior quadrants, and thinner in the lateral quadrants.
The human AH outflow pathway can be imaged using SD-OCT. The more superficial structures of the AH outflow pathway present with sufficient contrast as to be optically isolated and cast in-situ 360 degrees in cadaver eye perfusion models. This approach may be useful as a model in future studies of human AH outflow.
PMCID: PMC3196779  PMID: 21514296
10.  Imaging of the retinal nerve fibre layer with spectral domain optical coherence tomography for glaucoma diagnosis 
Optical coherence tomography (OCT) techniques have been applied to develop a new generation of the technology, called spectral domain (SD) or Fourier domain (FD) OCT. The commercially available SD-OCT technology offers benefits over the conventional time domain (TD) OCT such as a scanning speed up to 200 times faster and higher axial resolution (3 to 6 μm). Overall, SD-OCT offers improved performance in terms of reproducibility. SD-OCT has a level of discriminating capability, between healthy and perimetric glaucoma eyes similar to that obtained with TD-OCT. Furthermore, the capabilities and features of SD-OCT are rapidly evolving, mainly due to three-dimensional imaging and image rendering. More sophisticated approaches for macular and optic disc assessment are expected to be employed in clinical practice. Analysis software should be further refined for interpretation of SD-OCT images in order to enhance the sensitivity and specificity of glaucoma diagnostics. Most importantly for SD-OCT is determination of its ability to diagnostic structural glaucomatous progression. Considering the recent launch time of the commercially available SD-OCT and slow progressing characteristic of glaucoma, we must wait for longitudinal SD-OCT data, with a long enough follow-up, to become available.
PMCID: PMC3421150  PMID: 21030413
11.  Clinical Use of OCT in Assessing Glaucoma Progression 
Detection of disease progression is an important and challenging component of glaucoma management. Optical coherence tomography (OCT) has proved to be valuable in the detection of glaucomatous damage. With its high resolution and proven measurement reproducibility, OCT has the potential to become an important tool for glaucoma progression detection. This manuscript presents the capabilities of the OCT technology pertinent for detection of progressive glaucomatous damage and provides a review of the current knowledge on the device’s clinical performance.
PMCID: PMC3407561  PMID: 21790113
12.  Retinal nerve fibre layer and visual function loss in glaucoma: the tipping point 
To determine the retinal nerve fibre layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss.
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.
The mean RNFL thickness threshold for VF loss was 75.3 μm (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/μm (CI: −0.02 to 0.08) and below the tipping point, it was 0.28 dB/μm (CI: 0.18 to 0.38); the difference between the slopes was statistically significant (p<0.001). A similar pattern was observed for quadrant and clock-hour analysis.
Substantial structural loss (~17%) appears to be necessary for functional loss to be detectable using the current testing methods.
PMCID: PMC3193885  PMID: 21478200
13.  Three Dimensional Optical Coherence Tomography Imaging: Advantages and Advances 
Three dimensional (3D) ophthalmic imaging using optical coherence tomography (OCT) has revolutionized assessment of the eye, the retina in particular. Recent technological improvements have made the acquisition of 3D-OCT datasets feasible. However, while volumetric data can improve disease diagnosis and follow-up, novel image analysis techniques are now necessary in order to process the dense 3D-OCT dataset. Fundamental software improvements include methods for correcting subject eye motion, segmenting structures or volumes of interest, extracting relevant data post hoc and signal averaging to improve delineation of retinal layers. In addition, innovative methods for image display, such as C-mode sectioning, provide a unique viewing perspective and may improve interpretation of OCT images of pathologic structures. While all of these methods are being developed, most remain in an immature state. This review describes the current status of 3D-OCT scanning and interpretation, and discusses the need for standardization of clinical protocols as well as the potential benefits of 3D-OCT scanning that could come when software methods for fully exploiting these rich data sets are available clinically. The implications of new image analysis approaches include improved reproducibility of measurements garnered from 3D-OCT, which may then help improve disease discrimination and progression detection. In addition, 3D-OCT offers the potential for preoperative surgical planning and intraoperative surgical guidance.
PMCID: PMC2962728  PMID: 20542136
14.  Optical Coherence Tomography: History, Current Status, and Laboratory Work 
Optical coherence tomography (OCT) imaging has become widespread in ophthalmology over the past 15 years, because of its ability to visualize ocular structures at high resolution. This article reviews the history of OCT imaging of the eye, its current status, and the laboratory work that is driving the future of the technology.
PMCID: PMC3088542  PMID: 21493951
15.  Identification and Assessment of Schlemm's Canal by Spectral-Domain Optical Coherence Tomography 
Schlemm's canal and the collector channels were imaged with spectral domain optical coherence tomography (SD-OCT). Doppler flow measurement was used to confirm the location and identity of these structures.
Measurements of human Schlemm's canal (SC) have been limited to histologic sections. The purpose of this study was to demonstrate noninvasive measurements of aqueous outflow (AO) structures in the human eye, examining regional variation in cross-sectional SC areas (on/off collector channel [CC] ostia [SC/CC] and nasal/temporal) in the eyes of living humans.
SC was imaged by spectral-domain optical coherence tomography with a 200-nm bandwidth light source. Both eyes of 21 healthy subjects and one glaucomatous eye of three subjects were imaged nasally and temporally. Contrast and magnification were adjusted to maximize visualization. Cross-sectional SC on and off SC/CC was traced three times by two independent masked observers using ImageJ (ImageJ 1.40g, Wayne Rasband, developer, National Institutes of Health, Bethesda, MD). The mean SC area was recorded. A linear mixed-effects model was used to analyze eye, nasal/temporal laterality, and SC area on or off SC/CC.
SC area was significantly larger on SC/CCs than off (12,890 vs. 7,391 μm2, P < 0.0001) and was significantly larger on the nasal side than on the temporal (10,983 vs. 8,308 μm2, P = 0.009). SC areas were significantly smaller in glaucoma patients than in normal subjects, whether pooled (P = 0.0073) or grouped by on (P = 0.0215) or off (P = 0.0114) SC/CC.
Aqueous outflow structures, including SC and CCs, can be noninvasively assessed in the human eye. These measurements will be useful in physiological studies of AO and will be clinically useful in the determination of the impact of glaucoma therapies on IOP as well as presurgical planning.
PMCID: PMC2910639  PMID: 20237244

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