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1.  Spectral Domain Optical Coherence Tomography for Glaucoma (An AOS Thesis) 
Optical coherence tomography (OCT) is a rapidly evolving, robust technology that has profoundly changed the practice of ophthalmology. Spectral domain OCT (SD-OCT) increases axial resolution 2- to 3-fold and scan speed 60- to 110-fold vs time domain OCT (TD-OCT). SD-OCT enables novel scanning, denser sampling, and 3-dimensional imaging. This thesis tests my hypothesis that SD-OCT improves reproducibility, sensitivity, and specificity for glaucoma detection.
OCT progress is reviewed from invention onward, and future development is discussed. To test the hypothesis, TD-OCT and SD-OCT reproducibility and glaucoma discrimination are evaluated. Forty-one eyes of 21 subjects (SD-OCT) and 21 eyes of 21 subjects (TD-OCT) are studied to test retinal nerve fiber layer (RNFL) thickness measurement reproducibility. Forty eyes of 20 subjects (SD-OCT) and 21 eyes of 21 subjects (TD-OCT) are investigated to test macular parameter reproducibility. For both TD-OCT and SD-OCT, 83 eyes of 83 subjects are assessed to evaluate RNFL thickness and 74 eyes of 74 subjects to evaluate macular glaucoma discrimination.
Compared to conventional TD-OCT, SD-OCT had statistically significantly better reproducibility in most sectoral macular thickness and peripapillary RNFL sectoral measurements. There was no statistically significant difference in overall mean macular or RNFL reproducibility, or between TD-OCT and SD-OCT glaucoma discrimination. Surprisingly, TD-OCT macular RNFL thickness showed glaucoma discrimination superior to SD-OCT.
At its current development state, SD-OCT shows better reproducibility than TD-OCT, but glaucoma discrimination is similar for TD-OCT and SD-OCT. Technological improvements are likely to enhance SD-OCT reproducibility, sensitivity, specificity, and utility, but these will require additional development.
PMCID: PMC2646438  PMID: 19277249
2.  Three-dimensional Retinal Imaging with High-Speed Ultrahigh-Resolution Optical Coherence Tomography 
Ophthalmology  2005;112(10):1734-1746.
To demonstrate high-speed, ultrahigh-resolution, 3-dimensional optical coherence tomography (3D OCT) and new protocols for retinal imaging.
Ultrahigh-resolution OCT using broadband light sources achieves axial image resolutions of ~2 μm compared with standard 10-μm-resolution OCT current commercial instruments. High-speed OCT using spectral/Fourier domain detection enables dramatic increases in imaging speeds. Three-dimensional OCT retinal imaging is performed in normal human subjects using high-speed ultrahigh-resolution OCT. Three-dimensional OCT data of the macula and optic disc are acquired using a dense raster scan pattern. New processing and display methods for generating virtual OCT fundus images; cross-sectional OCT images with arbitrary orientations; quantitative maps of retinal, nerve fiber layer, and other intraretinal layer thicknesses; and optic nerve head topographic parameters are demonstrated.
Three-dimensional OCT imaging enables new imaging protocols that improve visualization and mapping of retinal microstructure. An OCT fundus image can be generated directly from the 3D OCT data, which enables precise and repeatable registration of cross-sectional OCT images and thickness maps with fundus features. Optical coherence tomography images with arbitrary orientations, such as circumpapillary scans, can be generated from 3D OCT data. Mapping of total retinal thickness and thicknesses of the nerve fiber layer, photoreceptor layer, and other intraretinal layers is demonstrated. Measurement of optic nerve head topography and disc parameters is also possible. Three-dimensional OCT enables measurements that are similar to those of standard instruments, including the StratusOCT, GDx, HRT, and RTA.
Three-dimensional OCT imaging can be performed using high-speed ultrahigh-resolution OCT. Three-dimensional OCT provides comprehensive visualization and mapping of retinal microstructures. The high data acquisition speeds enable high-density data sets with large numbers of transverse positions on the retina, which reduces the possibility of missing focal pathologies. In addition to providing image information such as OCT cross-sectional images, OCT fundus images, and 3D rendering, quantitative measurement and mapping of intraretinal layer thickness and topographic features of the optic disc are possible. We hope that 3D OCT imaging may help to elucidate the structural changes associated with retinal disease as well as improve early diagnosis and monitoring of disease progression and response to treatment.
PMCID: PMC1939719  PMID: 16140383
3.  Detection of Macular Ganglion Cell Loss in Glaucoma by Fourier-Domain Optical Coherence Tomography 
Ophthalmology  2009;116(12):2305-2314.e2.
To map ganglion cell complex thickness with high-speed Fourier-domain optical coherence tomography (FD-OCT) and compute novel macular parameters for glaucoma diagnosis.
Observational, cross-sectional study.
One hundred seventy-eight participants in the Advanced Imaging for Glaucoma Study, divided into three groups: 65 persons in the normal group (N), 78 in the perimetric glaucoma group (PG), and 52 in the pre-perimetric glaucoma group (PPG).
The RTVue FD-OCT system was used to map the macula over a 7×6 mm region. The macular OCT images were exported for automatic segmentation using software we developed. The program measured macular retinal (MR) thickness and ganglion cell complex (GCC) thickness. The GCC was defined as the combination of nerve fiber, ganglion cell, and inner plexiform layers. Pattern analysis was applied to the GCC map and the diagnostic power of pattern-based diagnostic parameters were investigated. Results were compared to time-domain (TD) Stratus OCT measurements of MR and circumpapillary nerve fiber layer (NFL) thickness.
Main Outcome Measures
Repeatability was assessed by intraclass correlation (ICC), pooled standard deviation, and coefficient of variation. Diagnostic power was assessed by the area under the receiver operator characteristic (AROC) curve. Measurements in the PG group were the primary measures of performance.
The FD-OCT measurements of MR and GCC averages had significantly better repeatability than TD-OCT measurements of MR and NFL averages. The FD-OCT GCC average had significantly (P=0.02) higher diagnostic power (AROC = 0.90) than MR (AROC = 0.85 for both FD-OCT & TD-OCT) in differentiating between PG and N. One GCC pattern parameter, global loss volume, had significantly higher AROC (0.92) than the overall average (P=0.01). The diagnostic powers of the best GCC parameters were statistically equal to TD-OCT NFL average.
The higher speed and resolution of FD-OCT improved the repeatability of macular imaging compared to standard TD-OCT. Ganglion cell mapping and pattern analysis improved diagnostic power. The improved diagnostic power of macular GCC imaging is on par with, and complementary to, peripapillary NFL imaging. Macular imaging with FD-OCT is a useful method for glaucoma diagnosis and has potential for tracking glaucoma progression.
PMCID: PMC2787911  PMID: 19744726
optical coherence tomography; glaucoma; imaging; image processing
4.  Comparison of StratusOCT and Cirrus HD-OCT Imaging in Macular Diseases 
The Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) device is a spectral-domain optical coherence tomography system that allows faster data acquisition than the previous generation StratusOCT (Carl Zeiss Meditec, Dublin, CA), which is a time-domain device. The authors compared images from both units to determine the clinical usefulness of spectral-domain optical coherence tomography technology in patients with macular diseases.
Six consecutive patients were imaged with both the Cirrus HD-OCT and the StratusOCT devices and the images were compared.
Cirrus HD-OCT images were typically more useful than StratusOCT images for assessing fine architectural details in macular pathology. The Cirrus HD-OCT software also facilitated a better understanding of three-dimensional data volumes.
Commercially available spectral-domain optical coherence tomography is a clinically useful tool for visualizing and understanding macular diseases and offers benefits not inherent in previous generation machines.
PMCID: PMC2917043  PMID: 19205492
5.  High-Definition and 3-dimensional Imaging of Macular Pathologies with High-speed Ultrahigh-Resolution Optical Coherence Tomography 
Ophthalmology  2006;113(11):2054.e1-2054.14.
To assess high-speed ultrahigh-resolution optical coherence tomography (OCT) image resolution, acquisition speed, image quality, and retinal coverage for the visualization of macular pathologies.
Retrospective cross-sectional study.
Five hundred eighty-eight eyes of 327 patients with various macular pathologies.
High-speed ultrahigh-resolution OCT images were obtained in 588 eyes of 327 patients with selected macular diseases. Ultrahigh-resolution OCT using Fourier/spectral domain detection achieves ~3-μm axial image resolutions, acquisition speeds of ~25 000 axial scans per second, and >3 times finer resolution and >50 times higher speed than standard OCT. Three scan protocols were investigated. The first acquires a small number of high-definition images through the fovea. The second acquires a raster series of high-transverse pixel density images. The third acquires 3-dimensional OCT data using a dense raster pattern. Three-dimensional OCT can generate OCT fundus images that enable precise registration of OCT images with the fundus. Using the OCT fundus images, OCT results were correlated with standard ophthalmoscopic examination techniques.
Main Outcome Measures
High-definition macular pathologies.
Macular holes, age-related macular degeneration, epiretinal membranes, diabetic retinopathy, retinal dystrophies, central serous chorioretinopathy, and other pathologies were imaged and correlated with ophthalmic examination, standard OCT, fundus photography, and fluorescein angiography, where applicable. High-speed ultrahigh-resolution OCT generates images of retinal pathologies with improved quality, more comprehensive retinal coverage, and more precise registration than standard OCT. The speed preserves retinal topography, thus enabling the visualization of subtle changes associated with disease. High-definition high-transverse pixel density OCT images improve visualization of photoreceptor and pigment epithelial morphology, as well as thin intraretinal and epiretinal structures. Three-dimensional OCT enables comprehensive retinal coverage, reduces sampling errors, and enables assessment of 3-dimensional pathology.
High-definition 3-dimensional imaging using high-speed ultrahigh-resolution OCT improves image quality, retinal coverage, and registration. This new technology has the potential to become a useful tool for elucidating disease pathogenesis and improving disease diagnosis and management.
PMCID: PMC1939823  PMID: 17074565
6.  Macula assessment using optical coherence tomography for glaucoma diagnosis 
The British journal of ophthalmology  2012;96(12):1452-1455.
Optical coherence tomography (OCT) is an interferometry-based imaging modality that generates high-resolution cross-sectional images of the retina. Circumpapillary retinal nerve fiber layer (cpRNFL) and optic nerve head assessments are the mainstay of glaucomatous structural measurements in OCT. 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 shown to provide good glaucoma diagnostic capabilities. With the adoption of spectral-domain OCT, which allows a higher image resolution than TD-OCT, segmentation of inner macular layers becomes possible. These layers are specifically prone to glaucomatous damage and thickness measurements show a comparable performance to that of glaucomatous cpRNFL measurements. The role of macular measurements for detection of glaucoma progression is still under investigation. More sophisticated measurement and analysis tools that can amplify the advantages of macular measurements are expected. For example, improvement of image quality would allow better visualization, development of various scanning modes would optimize 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.
PMCID: PMC3718015  PMID: 23018425
7.  Retinal Nerve Fiber Layer Thickness Measurement Comparability between Time Domain Optical Coherence Tomography (OCT) and Spectral Domain OCT 
The authors developed an algorithm for measurement comparability between time domain optical coherence tomography (TD-OCT) and spectral domain OCT (SD-OCT). This method may facilitate bridging the gap between measurements obtained by the different generations of OCT technology.
Time domain optical coherence tomography (TD-OCT) has been used commonly in clinical practice, producing a large inventory of circular scan data for retinal nerve fiber layer (RNFL) assessment. Spectral domain (SD)-OCT produces three-dimensional (3-D) data volumes. The purpose of this study was to create a robust technique that makes TD-OCT circular scan RNFL thickness measurements comparable with those from 3-D SD-OCT volumes.
Eleven eyes of 11 healthy subjects and 7 eyes of 7 subjects with glaucoma were enrolled. Each eye was scanned with one centered and eight displaced TD-OCT scanning circles. One 3-D SD-OCT cube scan was obtained at the same visit. The matching location of the TD-OCT scanning circle was automatically detected within the corresponding 3-D SD-OCT scan. Algorithm performance was assessed by estimating the difference between the detected scanning circle location on 3-D SD-OCT volume and the TD-OCT circle location. Global and sectoral RNFL thickness measurement errors between the two devices were also compared.
The difference (95% confidence interval) in scanning circle center locations between TD- and SD-OCT was 2.3 (1.5–3.2) pixels (69.0 [45.0–96.0] μm on the retina) for healthy eyes and 3.1 (2.0–4.1) pixels (93.0 [60.0–123.0] μm on the retina) for glaucomatous eyes. The absolute RNFL thickness measurement difference was significantly smaller with the matched scanning circle.
Scan location matching may bridge the gap in RNFL thickness measurements between TD-OCT circular scan data and 3-D SD-OCT scan data, providing follow-up comparability across the two generations of OCTs.
PMCID: PMC2868471  PMID: 19737886
8.  Optical coherence tomography – current and future applications 
Current opinion in ophthalmology  2013;24(3):213-221.
Purpose of review
Optical coherence tomography (OCT) has revolutionized the clinical practice of ophthalmology. It is a noninvasive imaging technique that provides high-resolution, cross-sectional images of the retina, retinal nerve fiber layer and the optic nerve head. This review discusses the present applications of the commercially available spectral-domain OCT (SD-OCT) systems in the diagnosis and management of retinal diseases, with particular emphasis on choroidal imaging. Future directions of OCT technology and their potential clinical uses are discussed.
Recent findings
Analysis of the choroidal thickness in healthy eyes and disease states such as age-related macular degeneration, central serous chorioretinopathy, diabetic retinopathy and inherited retinal dystrophies has been successfully achieved using SD-OCT devices with software improvements. Future OCT innovations such as longer-wavelength OCT systems including the swept-source technology, along with Doppler OCT and en-face imaging, may improve the detection of subtle microstructural changes in chorioretinal diseases by improving imaging of the choroid.
Advances in OCT technology provide for better understanding of pathogenesis, improved monitoring of progression and assistance in quantifying response to treatment modalities in diseases of the posterior segment of the eye. Further improvements in both hardware and software technologies should further advance the clinician’s ability to assess and manage chorioretinal diseases.
PMCID: PMC3758124  PMID: 23429598
applications of optical coherence tomography; chorioretinal diseases; retina; spectral-domain optical coherence tomography; swept-source optical coherence tomography
9.  Noninvasive Volumetric Imaging and Morphometry of the Rodent Retina with High-Speed, Ultrahigh-Resolution Optical Coherence Tomography 
To demonstrate high-speed, ultrahigh-resolution optical coherence tomography (OCT) for noninvasive, in vivo, three-dimensional imaging of the retina in rat and mouse models.
A high-speed, ultrahigh-resolution OCT system using spectral, or Fourier domain, detection has been developed for small animal retinal imaging. Imaging is performed with a contact lens and postobjective scanning. An axial image resolution of 2.8 μm is achieved with a spectrally broadband superluminescent diode light source with a bandwidth of ~150 nm at ~900-nm center wavelength. Imaging can be performed at 24,000 axial scans per second, which is ~100 times faster than previous ultrahigh-resolution OCT systems. High-definition and three-dimensional retinal imaging is performed in vivo in mouse and rat models.
High-speed, ultrahigh-resolution OCT enabled high-definition, high transverse pixel density imaging of the murine retina and visualization of all major intraretinal layers. Raster scan protocols enabled three-dimensional volumetric imagingand comprehensive retinal segmentation algorithms allowed measurement of retinal layers. An OCT fundus image, akin to a fundus photograph was generated by axial summation of three-dimensional OCT data, thus enabling precise registration of OCT measurements to retinal fundus features.
High-speed, ultrahigh-resolution OCT enables imaging of retinal architectural morphology in small animal models. OCT fundus images allow precise registration of OCT images and repeated measurements with respect to retinal fundus features. Three-dimensional OCT imaging enables visualization and quantification of retinal structure, which promises to allow repeated, noninvasive measurements to track disease progression, thereby reducing the need for killing the animal for histology. This capability can accelerate basic research studies in rats and mice and their translation into clinical patient care.
PMCID: PMC1941766  PMID: 17122144
10.  Comparison of Spectral / Fourier Domain Optical Coherence Tomography Instruments for Assessment of Normal Macular Thickness 
Retina (Philadelphia, Pa.)  2010;30(2):235.
To report normal macular thickness measurements and assess reproducibility of retinal thickness measurements acquired by a time domain optical coherence tomography (OCT)(Stratus [Carl Zeiss Meditec, Inc., Dublin, CA, USA]) and three commercially available spectral / Fourier domain OCT instruments (Cirrus HD-OCT [Carl Zeiss Meditec, Inc., Dublin, CA, USA], RTVue-100 [Optovue, Inc., Fremont, CA, USA], 3D OCT-1000 [Topcon, Inc., Paramus, NJ, USA]).
Forty randomly selected eyes of 40 normal, healthy volunteers were imaged. Subjects were scanned twice during one visit and a subset of 25 was scanned again within 8 weeks. Retinal thickness measurements were automatically generated by OCT software and recorded after manual correction. Regression and Bland-Altman plots were used to compare agreement between instruments. Reproducibility was analyzed by using intraclass correlation coefficients (ICC), and incidence of artifacts was determined.
Macular thickness measurements were found to have high reproducibility across all instruments, with ICC values ranging 84.8–94.9% for Stratus OCT; 92.6–97.3% for Cirrus Cube; 76.4–93.7% for RTVue MM5, 61.1–96.8% for MM6; 93.1–97.9% for 3D OCT-1000 Radial, 31.5–97.5% for 3D Macular scans. Incidence of artifacts was higher in spectral / Fourier domain instruments, ranging 28.75 to 53.16%, compared to 17.46% in Stratus OCT. No significant age or gender trends were found in the measurements.
Commercial spectral / Fourier domain OCT instruments provide higher speed and axial resolution than the Stratus OCT, although they vary greatly in scanning protocols and are currently limited in their analysis functions. Further development of segmentation algorithms and quantitative features are needed to assist clinicians in objective use of these newer instruments to manage diseases.
PMCID: PMC2819609  PMID: 19952997
spectral; Fourier; optical coherence tomography; normal; macular thickness; reproducibility; artifact; segmentation
11.  Adaptive optics–optical coherence tomography: optimizing visualization of microscopic retinal structures in three dimensions 
Adaptive optics–optical coherence tomography (AO-OCT) permits improved imaging of microscopic retinal structures by combining the high lateral resolution of AO with the high axial resolution of OCT, resulting in the narrowest three-dimensional (3D) point-spread function (PSF) of all in vivo retinal imaging techniques. Owing to the high volumetric resolution of AO-OCT systems, it is now possible, for the first time, to acquire images of 3D cellular structures in the living retina. Thus, with AO-OCT, those retinal structures that are not visible with AO or OCT alone (e.g., bundles of retinal nerve fiber layers, 3D mosaic of photoreceptors, 3D structure of microvasculature, and detailed structure of retinal disruptions) can be visualized. Our current AO-OCT instrumentation uses spectrometer-based Fourier-domain OCT technology and two-deformable-mirror-based AO wavefront correction. We describe image processing methods that help to remove motion artifacts observed in volumetric data, followed by innovative data visualization techniques [including two-dimensional (2D) and 3D representations]. Finally, examples of microscopic retinal structures that are acquired with the University of California Davis AO-OCT system are presented.
PMCID: PMC2583222  PMID: 17429483
12.  Peripapillary Nerve Fiber Layer Thickness Profile Determined with High Speed, Ultrahigh Resolution Optical Coherence Tomography High-Density Scanning 
To determine the retinal nerve fiber layer (RNFL) thickness profile in the peripapillary region of healthy eyes.
Three-dimensional, Fourier/spectral domain optical coherence tomography (OCT) data were obtained as raster scan data (512 × 180 axial scans in a 6 × 6-mm region centered on the optic nerve head [ONH]) with high-speed, ultrahigh-resolution OCT (hsUHR-OCT) from 12 healthy subjects. RNFL thickness was measured on this three-dimensional data set with an in-house software program. The disc margin was defined subjectively in each image and RNFL thickness profiles relative to distance from the disc center were computed for quadrants and clock hours. A mixed-effects model was used to characterize the slope of the profiles.
Thickness profiles in the superior, inferior, and temporal quadrants showed an initial increase in RNFL thickness, an area of peak thickness, and a linear decrease as radial distance from the disc center increased. The nasal quadrant showed a constant linear decay without the initial RNFL thickening. A mixed-effects model showed that the slopes of the inferior, superior, and nasal quadrants differed significantly from the temporal slope (P = 0.0012, P = 0.0003, and P = 0.0004, respectively).
RNFL thickness is generally inversely related to the distance from the ONH center in the peripapillary region of healthy subjects, as determined by hsUHR-OCT. However, several areas showed an initial increase in RNFL, followed by a peak and a gradual decrease.
PMCID: PMC1950319  PMID: 17591885
13.  The Impact of Utilizing Different Optical Coherence Tomography Devices for Clinical Purposes and in Multiple Sclerosis Trials 
PLoS ONE  2011;6(8):e22947.
Optical coherence tomography (OCT) derived retinal measures, particularly peri-papillary retinal nerve fiber layer (RNFL) thickness, have been proposed as outcome measures in remyelinating and neuroprotective trials in multiple sclerosis (MS). With increasing utilization of multiple centers to improve power, elucidation of the impact of different OCT technologies is crucial to the design and interpretation of such studies. In this study, we assessed relation and agreement between RNFL thickness and total macular volume (in MS and healthy controls) derived from three commonly used OCT devices: Stratus time-domain OCT, and Cirrus HD-OCT and Spectralis, two spectral-domain (SD) OCT devices. OCT was performed on both Cirrus HD-OCT and Stratus in 229 participants and on both Cirrus HD-OCT and Spectralis in a separate cohort of 102 participants. Pearson correlation and Bland-Altman analyses were used to assess correlation and agreement between devices. All OCT retinal measures correlated highly between devices. The mean RNFL thickness was 7.4 µm lower on Cirrus HD-OCT than Stratus, indicating overall poor agreement for this measurement between these machines. Further, the limits of agreement (LOA) between Cirrus HD-OCT and Stratus were wide (−4.1 to 18.9 µm), indicating poor agreement at an individual subject level. The mean RNFL thickness was 1.94 µm (LOA: −5.74 to 9.62 µm) higher on Spectralis compared to Cirrus HD-OCT, indicating excellent agreement for this measurement across this cohort. Although these data indicate that these three devices agree poorly at an individual subject level (evidenced by wide LOA in both study cohorts) precluding their co-utilization in everyday practice, the small difference for mean measurements between Cirrus HD-OCT and Spectralis indicate pooled results from these two SD-devices could be used as outcome measures in clinical trials, provided patients are scanned on the same machine throughout the trial, similar to the utilization of multiple different MRI platforms in MS clinical trials.
PMCID: PMC3154907  PMID: 21853058
14.  Diagnostic Ability of Fourier-Domain Versus Time-Domain Optical Coherence Tomography for Glaucoma Detection 
American journal of ophthalmology  2009;148(4):597-605.
To compare retinal nerve fiber layer (RNFL) thickness assessments and the discriminating ability of Fourier-domain optical coherence tomography (FD-OCT) with time-domain optical coherence tomography (TD-OCT) for glaucoma detection.
Prospective, non-randomized, observational cohort study.
Normal and glaucomatous eyes underwent complete examination, standard automated perimetry (SAP), optic disc photography, TD-OCT (Stratus™ OCT, Carl Zeiss Meditec, Dublin, CA) and FD-OCT (RTVue™, Optovue, Inc., Fremont, CA). One eye per subject was enrolled. Two consecutive scans were acquired using a 3.46-mm diameter scan with TD-OCT and a 3.45-mm diameter scan with FD-OCT. For each of 5 RNFL parameters the area under the receiver operator characteristic curve (AUROC) was calculated to compare the ability of FD-OCT and TD-OCT to discriminate between normal and glaucomatous eyes.
Fifty normal (mean age 65.3 ± 9.9 years) and 50 glaucoma patients (mean age 67.7 ± 10.5 years) were enrolled. Average, superior, and inferior RNFL thickness measurements (µm) were significantly (p < 0.01) greater with FD-OCT compared with TD-OCT in normal (103.3 ± 12.6 vs. 96.3 ± 10.7, 134.5 ± 18.6 vs. 113.9 ± 16.3, and 129.7 ± 16.9 vs. 125.5 ±15.8, respectively) and glaucomatous (p < 0.001) eyes (77.6 ± 17.6 vs. 70.4 ± 18.6, 108.0 ± 26.8 vs. 86.8 ± 30.2, 82.2 ± 3.3 vs. 73.5 ± 26.1, respectively). The AUROC for RNFL thickness were similar (p > 0.05) using FD-OCT (average 0.88, superior 0.80, inferior 0.94) and TD-OCT (average 0.87, superior 0.79, inferior 0.95).
Cross-sectional peripapillary RNFL thickness measurements obtained using FD-OCT generated with the RTVue™ are greater than TD-OCT, and have similar diagnostic performance for glaucoma detection.
PMCID: PMC2784699  PMID: 19589493
glaucoma; retinal nerve fiber layer; time-domain OCT; Fourier-domain OCT
15.  Comparison of Automated Analysis of Cirrus HD-OCT™ Spectral Domain Optical Coherence Tomography with Stereo Photos of the Optic Disc 
Ophthalmology  2011;118(7):1348-1357.
To evaluate a new automated analysis of optic disc images obtained by spectral domain optical coherence tomography (SD-OCT). Areas of the optic disc, cup, and neural rim in SD-OCT images were compared with these areas from stereoscopic photographs, to represent the current traditional optic nerve evaluation. The repeatability of measurements by each method was determined and compared.
Evaluation of diagnostic technology.
119 healthy eyes, 23 eyes with glaucoma, and 7 suspect eyes
Optic disc and cup margins were traced from stereoscopic photographs by three individuals independently. Optic disc margins and rim widths were determined automatically in SD-OCT. A subset of photographs was examined and traced a second time, and duplicate SD-OCT images were also analyzed.
Agreement among photograph readers, between duplicate readings, and between SD-OCT and photographs were quantified by the intraclass correlation coefficient (ICC), by the root mean square (RMS), and the standard deviation (SD) of the differences.
Optic disc areas tended to be slightly larger when judged in photographs than by SD-OCT, while cup areas were similar. Cup and optic disc areas showed good correlation (0.8) between average photographic reading and SD-OCT, but only fair correlation of rim areas (0.4).
The SD-OCT was highly reproducible (ICC of 0.96 to 0.99). Each reader was also consistent with himself on duplicate readings of 21 photographs (ICC 0.80 to 0.88 for rim area, 0.95 to 0.98 for all other measurements), but reproducibility was not as good as SD-OCT. Measurements derived from SD-OCT did not differ from photographic readings more than the readings of photographs by different readers differed from each other.
Designation of the cup and optic disc boundaries by an automated analysis of SD-OCT was within the range of variable designations by different readers from color stereoscopic photographs, but use of different landmarks typically made the designation of the optic disc size somewhat smaller in the automated analysis. There was better repeatability among measurements from SD-OCT than from among readers of photographs. The repeatability of automated measurement of SD-OCT images is promising for use both in diagnosis and in monitoring of progression.
PMCID: PMC3129482  PMID: 21397334
16.  Three-dimensional ultrahigh resolution optical coherence tomography imaging of age-related macular degeneration◇ 
Optics express  2009;17(5):4046-4060.
Ultrahigh resolution optical coherence tomography (OCT) enhances the ability to visualize different intra retinal layers. In age-related macular degeneration (AMD), pathological changes in individual retinal layers, including photoreceptor inner and outer segments and retinal pigment epithelium, can be detected. OCT using spectral / Fourier domain detection enables high speed, volumetric imaging of the macula, which provides comprehensive three-dimensional tomographic and morphologic information. We present a case series of AMD patients, from mild drusen to more advanced geographic atrophy and exudative AMD. Patients were imaged with a research prototype, ultrahigh resolution spectral / Fourier domain OCT instrument with 3.5 μm axial image resolution operating at 25,000 axial scans per second. These cases provide representative volumetric datasets of well-documented AMD pathologies which could be used for the development of visualization and imaging processing methods and algorithms.
PMCID: PMC2846091  PMID: 19259245
17.  Diagnostic accuracy of nerve fibre layer, macular thickness and optic disc measurements made with the RTVue-100 optical coherence tomograph to detect glaucoma 
Eye  2010;25(1):57-65.
To evaluate the diagnostic accuracy of retinal nerve fibre layer thickness (RNFLT), ganglion cell complex (GCC), and optic disc measurements made with the RTVue-100 Fourier-domain optical coherence tomography (OCT) to detect glaucoma in a Caucasian referral population.
One randomly selected eye of 286 Caucasian patients (93 healthy, 36 ocular hypertensive, 46 preperimetric glaucoma, and 111 perimetric glaucoma eyes) was evaluated.
Using the software-provided classification, for the total population sensitivity did not exceed 73.6% for the optic nerve head parameters, and 62.7% for the other parameters. Specificity was high (94.6–100%) for most RNFLT and GCC parameters, but low (72.0–76.3%) for the optic disc parameters. Positive predictive value varied between 98.1 and 100% for the main RNFLT parameters, 92.6 and 100% for the 16 RNFLT sectors, 92.4 and 99.0% for the GCC parameters, but did not exceed 86.3% for any of the optic disc parameters. Positive likelihood ratio (PLR) was higher than 10 for average, inferior and superior RNFLT (25.5 to infinite), 12 of the 16 RNFLT sectors (12.6 to infinite), and three of the four GCC parameters (40.0 to 48.6). No optic disc parameter had a PLR higher than 3.0.
RNFLT and GCC parameters of the RTVue-100 Fourier-domain OCT showed moderate sensitive but high specificity, positive predictive value and PLR for detection of glaucoma. The optic disc parameters had lower diagnostic accuracy than the RNFLT and GCC parameters.
PMCID: PMC3144640  PMID: 20930859
diagnostic accuracy; glaucoma; optical coherence tomography; RTVue Fourier-domain OCT
18.  Agreement between spectral-domain and time-domain OCT for measuring RNFL thickness 
To evaluate spectral-domain (SD) optical coherence tomography (OCT) reproducibility and assess the agreement between SD-OCT and Time-Domain (TD) OCT retinal nerve fibre layer (RNFL) measurements.
Three Cirrus-SD-OCT scans and one Stratus-TD-OCT scan were obtained from Diagnostic Innovations in Glaucoma Study (DIGS) healthy participants and glaucoma patients on the same day. Repeatability was evaluated using Sw (within-subject standard deviation), CV (coefficient of variation) and ICC (intraclass correlation coefficient). Agreement was assessed using correlation and Bland–Altman plots.
16 healthy participants (32 eyes) and 39 patients (78 eyes) were included. SD-OCT reproducibility was excellent in both groups. The CV and ICC for Average RNFL thickness were 1.5% and 0.96, respectively, in healthy eyes and 1.6% and 0.98, respectively, in patient eyes. Correlations between RNFL parameters were strong, particularly for average RNFL thickness (R2 = 0.92 in patient eyes). Bland–Altman plots showed good agreement between instruments, with better agreement for average RNFL thickness than for sectoral RNFL parameters (for example, at 90 μm average RNFL thickness, 95% limits of agreement were −13.1 to 0.9 for healthy eyes and −16.2 to −0.3 μm for patient eyes).
SD-OCT measurements were highly repeatable in healthy and patient eyes. Although the agreement between instruments was good, TD-OCT provided thicker RNFL measurements than SD-OCT. Measurements with these instruments should not be considered interchangeable.
PMCID: PMC3465953  PMID: 19304586
19.  Retinal nerve fibre layer thickness measurement reproducibility improved with spectral domain optical coherence tomography 
The British journal of ophthalmology  2009;93(8):1057-1063.
To investigate retinal nerve fibre layer (RNFL) thickness measurement reproducibility using conventional time-domain optical coherence tomography (TD-OCT) and spectral-domain OCT (SD-OCT), and to evaluate two methods defining the optic nerve head (ONH) centring: Centred Each Time (CET) vs Centred Once (CO), in terms of RNFL thickness measurement variability on SD-OCT.
Twenty-seven eyes (14 healthy subjects) had three circumpapillary scans with TD-OCT and three raster scans (three-dimensional or 3D image data) around ONH with SD-OCT. SD-OCT images were analysed in two ways: (1) CET: ONH centre was defined on each image separately and (2) CO: ONH centre was defined on one image and exported to other images after scan registration. After defining the ONH centre, a 3.4 mm diameter virtual circular OCT was resampled on SD-OCT images to mimic the conventional circumpapillary RNFL thickness measurements taken with TD-OCT.
CET and CO showed statistically significantly better reproducibility than TD-OCT except for 11:00 with CET. CET and CO methods showed similar reproducibility.
SD-OCT 3D cube data generally showed better RNFL measurement reproducibility than TD-OCT. The choice of ONH centring methods did not affect RNFL measurement reproducibility.
PMCID: PMC2861342  PMID: 19429591
20.  Comparison of Time Domain and Spectral Domain Optical Coherence Tomography in Measurement of Macular Thickness in Macular Edema Secondary to Diabetic Retinopathy and Retinal Vein Occlusion 
Journal of Ophthalmology  2012;2012:354783.
Purpose. To evaluate macular thickness, agreement, and intraclass repeatability in three optical coherence tomography (OCT) devices: the time domain (TD) Stratus OCT and two spectral domain (SD) OCTs, Spectralis and Cirrus SD-OCT, in eyes with macular edema secondary to diabetic retinopathy (DR) and retinal vein occlusion (VO). Methods. In a prospective observational study at a university-based retina practice, retinal thickness tomography was performed simultaneously for fifty-eight patients (91 eyes) with DR and VO employing a time domain and two spectral domain OCTs. Agreement in macular measurements was assessed by constructing Bland-Altman plots. Intraclass repeatability was assessed by intraclass correlation coefficients (ICCs). Results. Based on the Bland-Altman plots for central macular thickness, there was low agreement between the measurements of Cirrus SD-OCT and Stratus OCT, Spectralis OCT and Stratus OCT, as well as Spectralis OCT and Cirrus SD-OCT among DR and RVO patients. All three devices demonstrated high intraclass repeatability, with ICC of 98% for Stratus OCT, 97% for Cirrus SD-OCT, and 100% for Spectralis OCT among DR patients. The ICC was 97% for Stratus OCT, 79% for Cirrus SD-OCT, and 91% for Spectralis OCT among RVO patients. Conclusion. There are low agreements among interdevice measurements. However, intraclass repeatability is high in both TD and SD-OCT devices.
PMCID: PMC3410350  PMID: 22888403
21.  A Formula to Predict Spectral Domain Optical Coherence Tomography (OCT) Retinal Nerve Fiber Layer Measurements Based on Time Domain OCT Measurements 
To establish and validate a formula to predict spectral domain (SD)-optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness from time domain (TD)-OCT RNFL measurements and other factors.
SD-OCT and TD-OCT scans were obtained on the same day from healthy participants and patients with glaucoma. Univariate and multivariate linear regression relationships were analyzed to convert average Stratus TD-OCT measurements to average Cirrus SD-OCT measurements. Additional baseline characteristics included age, sex, intraocular pressure, central corneal thickness, spherical equivalent, anterior chamber depth, optic disc area, visual field (VF) mean deviation, and pattern standard deviation. The formula was generated using a training set of 220 patients and then evaluated on a validation dataset of 105 patients.
The training set included 71 healthy participants and 149 patients with glaucoma. The validation set included 27 healthy participants and 78 patients with glaucoma. Univariate analysis determined that TD-OCT RNFL thickness, age, optic disc area, VF mean deviation, and pattern standard deviation were significantly associated with SD-OCT RNFL thickness. Multivariate regression analysis using available variables yielded the following equation: SD-OCT RNFL = 0.746 × TD-OCT RNFL + 17.104 (determination coefficient [R2] = 0.879). In the validation sample, the multiple regression model explained 85.6% of the variance in the SD-OCT RNFL thickness.
The proposed formula based on TD-OCT RNFL thickness may be useful in predicting SD-OCT RNFL thickness. Other factors associated with SD-OCT RNFL thickness, such as age, disc area, and mean deviation, did not contribute to the accuracy of the final equation.
PMCID: PMC3464321  PMID: 23060724
Glaucoma; Retinal nerve fiber layer; Spectral domain optical coherence tomography; Time domain optical coherence tomography
22.  Glaucoma masqueraders: Diagnosis by spectral domain optical coherence tomography 
Saudi Journal of Ophthalmology  2012;26(4):433-440.
Advances in optic nerve and retinal imaging have dramatically changed the care of glaucoma patients, complementing the importance of the clinical exam of the optic nerve and automated perimetry in making the diagnosis of glaucoma. Computerized imaging, however, does not replace the clinical exam, as there can be overlap in the appearance of non-glaucomatous optic neuropathies with glaucoma.
The spectral domain optic coherence tomography (SD-OCT) images of five patients with non-glaucomatous optic nerve pathology are presented.
The first patient had bilateral temporal thinning on OCT imaging and subsequent positive syphilis testing. The second patient had a glaucomatous-appearing inferior arcuate scotoma and associated superior thinning on OCT; these findings were due to buried optic nerve head drusen, clearly appreciated on OCT of the optic nerve head. Bilateral diffuse macular thinning, with preservation of the superior and inferior fiber bundles, was seen in the third patient, who had multiple sclerosis, with no clinical history of optic neuritis. Dense and marked thinning of a macular half, respecting the horizontal meridian, is seen in two patients, one patient with non-arteritic anterior ischemic optic neuropathy and lastly, in a patient with hemi-retinal vein occlusion.
SD-OCT of the optic nerve and retina complements the essential clinical examination of patients with glaucomatous and non-glaucomatous optic neuropathies.
PMCID: PMC3729362  PMID: 23961029
OCT; Glaucoma; Optic neuropathy; Macular OCT
23.  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
24.  Assessment of Artifacts and Reproducibility across Spectral and Time Domain Optical Coherence Tomography Devices 
Ophthalmology  2009;116(10):1960-1970.
To report the frequency of optical coherence tomography (OCT) scan artifacts and compare macular thickness measurements, inter-scan reproducibility and inter-device agreeability across three spectral / Fourier domain (SD) OCTs (Cirrus HD-OCT, RTVue-100 and Topcon 3D-OCT 1000) and one time domain (TD) OCT (Stratus OCT).
Prospective, non-comparative, non-interventional case series.
52 patients seen at New England Eye Center, Tufts Medical Center retina service between February and August 2008.
Two scans were performed for each of the SD-OCT protocols: Cirrus macular cube 512×128, RTVue (E)MM5 and MM6, Topcon 3D macular and radial, in addition to one TD-OCT scan via Stratus macular thickness protocol. Scans were inspected for six types of OCT scan artifacts and analyzed. Inter-scan reproducibility and inter-device agreeability were assessed by intraclass correlation coefficients (ICCs) and Bland-Altman plots, respectively.
OCT image artifacts, Macular thickness, Reproducibility, Agreeability.
TD-OCT scans contained a significantly higher percentage of clinically significant improper central foveal thickness (IFT) post-manual correction (greater than or equal to 11 μm change) compared to SD-OCT scans. Cirrus HD-OCT had a significantly lower percentage of clinically significant IFT (11.1%) compared to the other SD-OCT devices (Topcon 3D: 20.4%, Topcon Radial: 29.6%, RTVue (E)MM5: 42.6%, RTVue MM6: 24.1%; p= 0.001). All three SD-OCT had central foveal subfield thicknesses significantly greater than TD-OCT post manual correction (p< 0.0001). All 3 SD-OCT demonstrated a high degree of reproducibility in the central foveal region (ICC= 0.92 to 0.97). Bland-Altman plots showed low agreeability between TD- and SD-OCT scans.
Cirrus HD-OCT scans exhibited the lowest occurrence of any artifacts (68.5%), IFT (40.7%) and clinically significant IFT (11.1%) compared to all other OCT devices examined, while Stratus OCT scans exhibited the highest occurrence of clinically significant IFT compared to all 3 SD-OCT examined. Significant differences in macular thickness occurred among SD- and TD-OCT. All SD-OCT examined revealed high reproducibility in the central foveal subfield (ICC 0.92 to 0.97). Higher scan density and speed obtainable with SD-OCT appear to improve reproducibility. Although software breakdown occurred to a variable degree with different commercial OCT, further work on improving segmentation algorithm to decrease artifacts is warranted.
PMCID: PMC2757525  PMID: 19592109
25.  In vivo visualization of photoreceptor layer and lipofuscin accumulation in stargardt’s disease and fundus flavimaculatus by high resolution spectral-domain optical coherence tomography 
To assess photoreceptor (PR) layer morphology in patients with Stargardt’s disease (STGD) and fundus flavimaculatus (FFM) using high resolution spectral domain optical coherence tomography (HD-OCT; OCT 4000 Cirrus, Humphrey-Zeiss, San Leandro, CA).
This was a prospective observational case series. Sixteen consecutive patients with STGD and FFM underwent a complete ophthalmologic examination. Optical coherence tomography examination was performed with HD-OCT, a high-speed (27,000 axial scans per second) OCT system using spectral/Fourier domain detection, with an axial image resolution of 5 μm.
A total of 31 eyes were included in the study. Transverse loss of the PR layer in the foveal region was shown by HD-OCT. Twenty eyes with clinically evident central atrophy had a disruption of either the Verhoeff‘s membrane (VM) or the layer corresponding to the interface of inner segment (IS) and outer segment (OS) of PR in the foveal region. Among these eyes, 12/20 eyes had a loss of the PR layer (loss of both VM and IS-OS interface) in the foveal region. Eleven eyes (11/31) without clinically evident central atrophy had an intact interface of IS and OS of PR centrally. Moreover, we observed hyperreflective deposits: type 1 lesions located within the retinal pigment epithelium (RPE) layer and at the level of the outer segments of PR, and type 2 lesions located at the level of the outer nuclear layer and clearly separated from the RPE layer. Type 1 lesions alone were associated with absence of loss of the PR layer in the foveal region in all eyes; type 2 lesions were always associated with presence of type 1 lesions, and often (8/12 eyes) associated with loss of the PR layer within the foveal region. Mean best-corrected visual acuity (BCVA) was significantly correlated with loss of the PR layer in the foveal region (P < 0.001), as well as to presence of type 2 flecks (P = 0.03).
Type 2 deposits in STGD/FFM patients seem to represent a marker of the possible evolution towards foveal atrophy.
PMCID: PMC2801640  PMID: 20054419
fundus flavimaculatus; high definition optical coherence tomography; retinal dystrophy; stargardt’s disease

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