Faculty Bibliography

PURPOSE: To determine the intra- and inter-visit reproducibility of ganglion cell-inner plexiform layer thickness measures using handheld optical coherence tomography (OCT) in sedated children with optic pathway gliomas and/or neurofibromatosis type 1 (NF1). DESIGN: Prospective longitudinal cohort study. METHODS: Children with sporadic optic pathway gliomas and/or NF1 who had >/=2 volumes acquired over the macula using handheld OCT during sedation for clinically indicated magnetic resonance imaging were eligible for the intra-visit cohort. Children with repeat handheld OCT imaging within 6 months were eligible for the inter-visit cohort. Total retinal thickness and ganglion cell-inner plexiform layer thickness were measured using custom-designed automated segmentation software. Reproducibility was compared across average and anatomic quadrant by calculating the coefficient of variation (CV) and intraclass correlation coefficient (ICC). RESULTS: Forty-two subjects (median age 5.4 years, range 0.8-12.7 years) contributed 45 eyes to the intra-visit cohort. Thirty-one subject eyes had normal vision and 14 had abnormal vision (decreased visual acuity and/or visual field). Average and quadrant ganglion cell-inner plexiform layer measures demonstrated CVs 0.935). The superior quadrant CV differed between subjects with (4.4%) and without (2.1%) vision loss (P < .05). Twenty-five subject eyes were eligible for the inter-visit cohort, demonstrating CVs from 1.6% to 5.2%. Inter-visit ICCs were excellent (0.955-0.995). DISCUSSION: Handheld OCT imaging in sedated children with optic pathway gliomas produces highly reproducible measures of ganglion cell-inner plexiform layer thickness.

PURPOSE: To determine the intra- and intervisit reproducibility of circumpapillary retinal nerve fiber layer (RNFL) measures using handheld optical coherence tomography (OCT) in sedated children. DESIGN: Prospective cross-sectional and longitudinal study. METHODS: Children undergoing sedation for a clinically indicated magnetic resonance imaging for an optic pathway glioma and/or neurofibromatosis type 1 (NF1) had multiple 6 x 6 mm volumes (isotropic 300 x 300 or nonisotropic 1000 x 100 samplings) acquired over the optic nerve. Children with 2 handheld OCT sessions within 6 months were included in the intervisit cohort. The intra- and intervisit coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for the average and anatomic quadrant circumpapillary RNFL thickness. RESULTS: Fifty-nine subjects (mean age 5.1 years, range 0.8-13.0 years) comprised the intravisit cohort and 29 subjects (mean age 5.7 years, range 1.8-12.7 years) contributed to the intervisit cohort. Forty-nine subjects had an optic pathway glioma and 10 subjects had NF1 without an optic pathway glioma. The CV was comparable regardless of imaging with an isotropic and nonisotropic volume in both the intra- and intervisit cohorts. The average circumpapillary RNFL demonstrated the lowest CV and highest ICC compared to the quadrants. For the intervisit cohort, the average ICC was typically higher while the CV was typically lower, but not statistically different compared to the other quadrants. DISCUSSION: Circumpapillary RNFL measures acquired with handheld OCT during sedation demonstrate good intra- and intervisit reproducibility. Handheld OCT has the potential to monitor progressive optic neuropathies in young children who have difficulty cooperating with traditional OCT devices.

PURPOSE: To characterize the in vivo three-dimensional (3D) lamina cribrosa (LC) microarchitecture of healthy eyes using adaptive optics spectral-domain optical coherence tomography (AO-SDOCT). METHODS: A multimodal retinal imaging system with a light source centered at 1050 nm and AO confocal scanning laser ophthalmoscopy was used in this study. One randomly selected eye from 18 healthy subjects was scanned in a 6 degrees x 6 degrees window centered on the LC. Subjects also underwent scanning with Cirrus HD-OCT. Lamina cribrosa microarchitecture was semiautomatically segmented and quantified for connective tissue volume fraction (CTVF), beam thickness, pore diameter, pore area, and pore aspect ratio. The LC was assessed in central and peripheral regions of equal areas and quadrants and with depth. A linear mixed effects model weighted by the fraction of visible LC was used to compare LC structure between regions. RESULTS: The nasal quadrant was excluded due to poor visualization. The central sector showed greater CTVF and thicker beams as compared to the periphery (P < 0.01). Both superior and inferior quadrants showed greater CTVF, pore diameter, and pore mean area than the temporal quadrant (P < 0.05). Depth analysis showed that the anterior and posterior aspects of the LC contained smaller pores with greater density and thinner beams as compared to the middle third (P < 0.05). The anterior third also showed a greater CTVF than the middle third (P < 0.05). CONCLUSIONS: In vivo analysis of healthy eyes using AO-SDOCT showed significant, albeit small, regional variation in LC microarchitecture by quadrant, radially, and with depth, which should be considered in further studies of the LC.

Variability in illumination, signal quality, tilt and the amount of motion pose challenges for post-processing based 3D-OCT motion correction algorithms. We present an advanced 3D-OCT motion correction algorithm using image registration and orthogonal raster scan patterns aimed at addressing these challenges. An intensity similarity measure using the pseudo Huber norm and a regularization scheme based on a pseudo L0.5 norm are introduced. A two-stage registration approach was developed. In the first stage, only axial motion and axial tilt are coarsely corrected. This result is then used as the starting point for a second stage full optimization. In preprocessing, a bias field estimation based approach to correct illumination differences in the input volumes is employed. Quantitative evaluation was performed using a large set of data acquired from 73 healthy and glaucomatous eyes using SD-OCT systems. OCT volumes of both the optic nerve head and the macula region acquired with three independent orthogonal volume pairs for each location were used to assess reproducibility. The advanced motion correction algorithm using the techniques presented in this paper was compared to a basic algorithm corresponding to an earlier version and to performing no motion correction. Errors in segmentation-based measures such as layer positions, retinal and nerve fiber thickness, as well as the blood vessel pattern were evaluated. The quantitative results consistently show that reproducibility is improved considerably by using the advanced algorithm, which also significantly outperforms the basic algorithm. The mean of the mean absolute retinal thickness difference over all data was 9.9 um without motion correction, 7.1 um using the basic algorithm and 5.0 um using the advanced algorithm. Similarly, the blood vessel likelihood map error is reduced to 69% of the uncorrected error for the basic and to 47% of the uncorrected error for the advanced algorithm. These results demonstrate that our advanced motion correction algorithm has the potential to improve the reliability of quantitative measurements derived from 3D-OCT data substantially.

PURPOSE: To compare three methods of Schlemm's canal (SC) cross-sectional area (CSA) measurement. METHODS: Ten eyes (10 healthy volunteers) were imaged three times using spectral-domain optical coherence tomography (Cirrus HD-OCT, Zeiss, Dublin, California, USA). Aqueous outflow vascular structures and SC collector channel ostia were used as landmarks to identify a reference location within the limbus. SC CSA was assessed within a 1 mm segment (+/-15 frames of the reference, 31 frames in all) by three techniques. (1) Using a random number table, SC CSA in five random frames from the set of 31 surrounding the reference were measured and averaged. (2) The most easily visualised SC location (subjective) was measured, and (3) SC CSA was measured in all 31 consecutive B-scans, and averaged. (comprehensive average, gold standard). Subjective and random CSAs were compared with the comprehensive by general estimating equation modelling, and structural equation modelling quantified agreement. RESULTS: The average from five random locations (4175+/-1045 microm(2)) was not significantly different than that obtained from the gold standard comprehensive assessment (4064+/-1308 microm(2), p=0.6537). Subjectively located SC CSA (7614+/-2162 microm(2)) was significantly larger than the comprehensive gold standard SC CSA (p<0.0001). The average of five random frames produced significantly less bias than did subjective location, yielding a calibration line crossing the 'no-bias' line. DISCUSSION: Subjectively located SC CSA measurements produce high estimates of SC CSA. SC assessed by measuring five random locations estimate CSA was similar to the gold standard estimate.

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.

Optic nerve head (ONH) tissue properties and biomechanics remain mostly unmeasurable in the experiment. We hypothesized that these can be estimated numerically from ocular parameters measurable in vivo with optical coherence tomography (OCT). Using parametric models representing human ONHs we simulated acute intraocular pressure (IOP) increases (10 mmHg). Statistical models were fit to predict, from OCT-measurable parameters, 15 outputs, including ONH tissue properties, stresses, and deformations. The calculations were repeated adding parameters that have recently been proposed as potentially measurable with OCT. We evaluated the sensitivity of the predictions to variations in the experimental parameters. Excellent fits were obtained to predict all outputs from the experimental parameters, with cross-validated R2s between 0.957 and 0.998. Incorporating the potentially measurable parameters improved fits significantly. Predictions of tissue stiffness were accurate to within 0.66 MPa for the sclera and 0.24 MPa for the lamina cribrosa. Predictions of strains and stresses were accurate to within 0.62% and 4.9 kPa, respectively. Estimates of ONH biomechanics and tissue properties can be obtained quickly from OCT measurements using an applet that we make freely available. These estimates may improve understanding of the eye sensitivity to IOP and assessment of patient risk for development or progression of glaucoma.

We demonstrate the repeatability of lamina cribrosa (LC) microarchitecture for in vivo 3D optical coherence tomography (OCT) scans of healthy, glaucoma suspects, and glaucomatous eyes. Eyes underwent two scans using a prototype adaptive optics spectral domain OCT (AO-SDOCT) device from which LC microarchitecture was semi-automatically segmented. LC segmentations were used to quantify pore and beam structure through several global microarchitecture parameters. Repeatability of LC microarchitecture was assessed qualitatively and quantitatively by calculating parameter imprecision. For all but one parameters (pore volume) measurement imprecision was <4.7% of the mean value, indicating good measurement reproducibility. Imprecision ranged between 27.3% and 54.5% of the population standard deviation for each parameter, while there was not a significant effect on imprecision due to disease status, indicating utility in testing for LC structural trends.

PURPOSE: Previously, we demonstrated reduced Schlemm's canal cross-sectional area (SC-CSA) with increased perfusion pressure in a cadaveric flow model. The purpose of the present study was to determine the effect of acute IOP elevation on SC-CSA in living human eyes. METHODS: The temporal limbus of 27 eyes of 14 healthy subjects (10 male, 4 female, age 36 +/- 13 years) was imaged by spectral-domain optical coherence tomography at baseline and with IOP elevation (ophthalmodynamometer set at 30-g force). Intraocular pressure was measured at baseline and with IOP elevation by Goldmann applanation tonometry. Vascular landmarks were used to identify corresponding locations in baseline and IOP elevation scan volumes. Schlemm's canal CSA at five locations within a 1-mm length of SC was measured in ImageJ as described previously. A linear mixed-effects model quantified the effect of IOP elevation on SC-CSA. RESULTS: The mean IOP increase was 189%, and the mean SC-CSA decrease was 32% (P < 0.001). The estimate (95% confidence interval) for SC-CSA response to IOP change was -66.6 (-80.6 to -52.7) mum(2)/mm Hg. CONCLUSIONS: Acute IOP elevation significantly reduces SC-CSA in healthy eyes. Acute dynamic response to IOP elevation may be a useful future characterization of ocular health in the management of glaucoma.

IMPORTANCE: Monitoring young children with optic pathway gliomas (OPGs) for visual deterioration can be difficult owing to age-related noncompliance. Optical coherence tomography (OCT) measures of retinal nerve fiber layer (RNFL) thickness have been proposed as a surrogate marker of vision but this technique is also limited by patient cooperation. OBJECTIVE: To determine whether measures of circumpapillary RNFL thickness, acquired with handheld OCT (HH-OCT) during sedation, can differentiate between young children with and without vision loss from OPGs. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis of a prospective observational study was conducted at a tertiary-care children's hospital. Children with an OPG (sporadic or secondary to neurofibromatosis type 1) who were cooperative for visual acuity testing, but required sedation to complete magnetic resonance imaging, underwent HH-OCT imaging of the circumpapillary RNFL while sedated. MAIN OUTCOMES AND MEASURES: Area under the curve of the receiver operating characteristic, sensitivity, specificity, positive predictive value, and negative predictive value of the average and quadrant-specific RNFL thicknesses. RESULTS: Thirty-three children (64 eyes) met inclusion criteria (median age, 4.8 years; range, 1.8-12.6 years). In children with vision loss (abnormal visual acuity and/or visual field), RNFL thickness was decreased in all quadrants compared with the normal-vision group (P < .001 for all comparisons). Using abnormal criteria of less than 5% and less than 1%, the area under the curve was highest for the average RNFL thickness (0.96 and 0.97, respectively) compared with specific anatomic quadrants. The highest discrimination and predictive values were demonstrated for participants with 2 or more quadrants meeting less than 5% (sensitivity = 93.3; specificity = 97.9; positive predictive value = 93.3; and negative predictive value = 97.9) and less than 1% (sensitivity = 93.3; specificity = 100; positive predictive value = 100; and negative predictive value = 98.0) criteria. CONCLUSIONS AND RELEVANCE: Measures of RNFL thickness acquired with HH-OCT during sedation can differentiate between young children with and without vision loss from OPGs. For young children who do not cooperate with vision testing, HH-OCT measures may be a surrogate marker of vision. Longitudinal studies are needed to delineate the temporal relationship between RNFL decline and vision loss.