Hongli Yang

Optic Disc Margin Anatomy in Patients with Glaucoma and Normal Controls with Spectral Domain Optical Coherence Tomography

OBJECTIVE To characterize optic nerve head (ONH) anatomy related to the clinical optic disc margin with spectral domain-optical coherence tomography (SD-OCT). DESIGN Cross-sectional study. PARTICIPANTS Patients with open-angle glaucoma with focal, diffuse, and sclerotic optic disc damage, and age-matched normal controls. METHODS High-resolution radial SD-OCT B-scans centered on the ONH were analyzed at each clock hour. For each scan, the border tissue of Elschnig was classified for obliqueness (internally oblique, externally oblique, or nonoblique) and the presence of Bruchs membrane overhanging the border tissue. Optic disc stereophotographs were co-localized to SD-OCT data with customized software. The frequency with which the disc margin identified in stereophotographs coincided with (1) Bruchs membrane opening (BMO), defined as the innermost edge of Bruchs membrane; (2) Bruchs membrane/border tissue, defined as any aspect of either outside BMO or border tissue; or (3) border tissue, defined as any aspect of border tissue alone, in the B-scans was computed at each clock hour. MAIN OUTCOME MEASURES The SD-OCT structures coinciding with the disc margin in stereophotographs. RESULTS There were 30 patients (10 with each type of disc damage) and 10 controls, with a median (range) age of 68.1 (42-86) years and 63.5 (42-77) years, respectively. Although 28 patients (93%) had 2 or more border tissue configurations, the most predominant one was internally oblique, primarily superiorly and nasally, frequently with Bruchs membrane overhang. Externally oblique border tissue was less frequent, observed mostly inferiorly and temporally. In controls, there was predominantly internally oblique configuration around the disc. Although the configurations were not statistically different between patients and controls, they were among the 3 glaucoma groups. At most locations, the SD-OCT structure most frequently identified as the disc margin was some aspect of Bruchs membrane and border tissue external to BMO. Bruchs membrane overhang was regionally present in the majority of patients with glaucoma and controls; however, in most cases it was not visible as the disc margin. CONCLUSIONS The clinically perceived disc margin is most likely not the innermost edge of Bruchs membrane detected by SD-OCT. These findings have important implications for the automated detection of the disc margin and estimates of the neuroretinal rim.

Longitudinal change detected by spectral domain optical coherence tomography in the optic nerve head and peripapillary retina in experimental glaucoma.

PURPOSE To investigate whether longitudinal changes deep within the optic nerve head (ONH) are detectable by spectral domain optical coherence tomography (SDOCT) in experimental glaucoma (EG) and whether these changes are detectable at the onset of Heidelberg Retina Tomography (HRT; Heidelberg Engineering, Heidelberg, Germany)-defined surface topography depression. METHODS Longitudinal SDOCT imaging (Spectralis; Heidelberg Engineering) was performed in both eyes of nine rhesus macaques every 1 to 3 weeks. One eye of each underwent trabecular laser-induced IOP elevation. Four masked operators delineated internal limiting membrane (ILM), retinal nerve fiber layer (RNFL), Bruchs membrane/retinal pigment epithelium (BM/RPE), neural canal opening (NCO), and anterior lamina cribrosa surface (ALCS) by using custom software. Longitudinal changes were assessed and compared between the EG and control (nonlasered) eyes at the onset of HRT-detected surface depression (follow-up 1; [FU1]) and at the most recent image (follow-up 2; [FU2]). RESULTS Mean IOP in EG eyes was 7.1 to 24.6 mm Hg at FU1 and 13.5 to 31.9 mm Hg at FU2. In control eyes, the mean IOP was 7.2 to 12.6 mm Hg (FU1) and 8.9 to 16.0 mm Hg (FU2). At FU1, neuroretinal rim decreased and ALCS depth increased significantly (paired t-test, P < 0.01); no change in RNFL thickness was detected. At FU2, however, significant prelaminar tissue thinning, posterior displacement of NCO, and RNFL thinning were observed. CONCLUSIONS Longitudinal SDOCT imaging can detect deep ONH changes in EG eyes, the earliest of which are present at the onset of HRT-detected ONH surface height depression. These parameters represent realistic targets for SDOCT detection of glaucomatous progression in human subjects.

Posterior (Outward) Migration of the Lamina Cribrosa and Early Cupping in Monkey Experimental Glaucoma

PURPOSE To quantify the lamina cribrosa insertion into the peripapillary sclera and optic nerve pia in normal (N) and early experimental glaucoma (EEG) monkey eyes. METHODS Perfusion-fixed optic nerve heads (ONHs) from 21 animals were digitally reconstructed three dimensionally and delineated. Anterior Laminar Insertion Position (ALIP), Posterior Laminar Insertion Position (PLIP), Laminar Insertion Length (LIL; distance between the anterior and posterior laminar insertions), and Scleral Thickness (at the Anterior Sub-arachnoid space) were calculated for each ONH. Animals were pooled into four groups based on the kill condition (N vs. EEG) and perfusion IOP (10, 30, or 45 mm Hg) of each eye: N10-N10 (n = 6), N30/45-N10 (n = 6), EEG10-N10 (n = 3), and EEG30/45-N10 (n = 6). Glaucomatous EEG versus N eye differences in each group and each animal were required not only to achieve statistical significance (P < 0.05) but also to exceed physiologic intereye differences within the bilaterally normal groups. RESULTS ALIP was significantly posterior (outward) in the EEG compared with N10 eyes of the EEG30/45-N10 group and 5 of 9 individual EEG eyes (difference range, 12-49 μm). PLIP was significantly posterior in the EEG eyes of both EEG groups and in 6 of 9 individual EEG eyes (range, 25-83 μm). LIL ranged from 90 to 190 μm in normal eyes and was significantly increased within the EEG eyes of both EEG groups and in 7 of 9 individual EEG eyes (difference range, 30-47 μm). CONCLUSIONS Posterior migration of the lamina cribrosa is a component of early cupping in monkey EEG.

Deformation of the Early Glaucomatous Monkey Optic Nerve Head Connective Tissue after Acute IOP Elevation in 3-D Histomorphometric Reconstructions

PURPOSE To retest the hypothesis that monkey ONH connective tissues become hypercompliant in early experimental glaucoma (EEG), by using 3-D histomorphometric reconstructions, and to expand the characterization of EEG connective tissue deformation to nine EEG eyes. METHODS Trephinated ONH and peripapillary sclera from both eyes of nine monkeys that were perfusion fixed, with one normal eye at IOP 10 mm Hg and the other EEG eye at 10 (n=3), 30 (n=3), or 45 (n=3) mm Hg were serial sectioned, 3-D reconstructed, 3-D delineated, and quantified with 3-D reconstruction techniques developed in prior studies by the authors. Overall, and for each monkey, intereye differences (EEG eye minus normal eye) for each parameter were calculated and compared by ANOVA. Hypercompliance in the EEG 30 and 45 eyes was assessed by ANOVA, and deformations in all nine EEG eyes were separately compared by region without regard for fixation IOP. RESULTS Hypercompliant deformation was not significant in the overall ANOVA, but was suggested in a subset of EEG 30/45 eyes. EEG eye deformations included posterior laminar deformation, neural canal expansion, lamina cribrosa thickening, and posterior (outward) bowing of the peripapillary sclera. Maximum posterior laminar deformation and scleral canal expansion co-localized to either the inferior nasal or superior temporal quadrants in the eyes with the least deformation and involved both quadrants in the eyes achieving the greatest deformation. CONCLUSIONS The data suggest that, in monkey EEG, ONH connective tissue hypercompliance may occur only in a subset of eyes and that early ONH connective tissue deformation is maximized in the superior temporal and/or inferior nasal quadrants.

Comparison of Clinical and Spectral Domain Optical Coherence Tomography Optic Disc Margin Anatomy

PURPOSE To investigate spectral domain optical coherence tomography (SD-OCT)-detected optic disc margin anatomy in the monkey eye by colocalizing disc photographs to SD-OCT scans acquired from the same eyes. METHODS The neural canal opening (NCO) was delineated within 40 digital radial sections generated from SD-OCT volumes acquired from 33 normal monkey eyes (15 degrees, 290 x 768 horizontal grid pattern). Each volume was colocalized to its disc photograph by matching the retinal vessels within each photograph to vessel outlines visible within en face SD-OCT images. Border tissue was delineated where it extended internally to the NCO. A clinician (masked to delineated points) marked the disc margin onto each photograph while viewing the relevant stereophotograph pair. Alignment of the clinician-ascribed disc margin to the NCO and border tissue delineation was assessed. The process was repeated in a single myopic human eye. RESULTS In 23 eyes, the NCO aligned to the disc margin. In 10 eyes, externally oblique border tissue was detectable in the temporal disc. In these regions of the disc, the termination of border tissue was the disc margin. An exaggerated form of this phenotype was observed in the myopic human eye. In this case, temporal border tissue terminated at the anterior scleral canal opening, which was detected as the disc margin. CONCLUSIONS The termination of Bruchs membrane, border tissue, and the anterior scleral canal opening may constitute the disc margin within the same eye, depending on the border tissue architecture; this anatomy is consistently visualized by SD-OCT.

IOP-induced lamina cribrosa displacement and scleral canal expansion: an analysis of factor interactions using parameterized eye-specific models.

PURPOSE To study the anterior-posterior lamina cribrosa deformation (LCD) and the scleral canal expansion (SCE) produced by an increase in IOP and identify the main factors and interactions that determine these responses in the monkey. METHODS Eye-specific baseline models of the LC and sclera of both eyes of three normal monkeys were constructed. Morphing techniques were used to generate 888 models with controlled variations in LC thickness, position and modulus (stiffness), scleral thickness and modulus, and scleral canal size and eccentricity. Finite element modeling was used to simulate an increase in IOP from 10 to 15 mm Hg. A two-level, full-factorial experimental design was used to select factor combinations and to determine the sensitivity of LCD and SCE to the eight factors, independently and in interaction. RESULTS LCD was between 53.6 μm (posteriorly) and -12.9 μm (anteriorly), whereas SCE was between 0.5 and 15.2 μm (all expansions). LCD was most sensitive to laminar modulus and position (24% and 21% of the variance in LCD, respectively), whereas SCE was most sensitive to scleral modulus and thickness (46% and 36% of the variance in SCE, respectively). There were also strong interactions between factors (35% and 7% of the variance in LCD and SCE, respectively). CONCLUSIONS IOP-related LCD and SCE result from a complex combination of factors, including geometry and material properties of the LC and sclera. This work lays the foundation for interpreting the range of individual sensitivities to IOP and illustrates that predicting individual ONH response to IOP will require the measurement of multiple factors.

Effect of Acute Intraocular Pressure Elevation on the Monkey Optic Nerve Head as Detected by Spectral Domain Optical Coherence Tomography

PURPOSE To determine whether acutely elevated IOP alters optic nerve head (ONH) structural parameters characterized in vivo using spectral domain optical coherence tomography (SD-OCT). METHODS Five rhesus macaques were tested under isoflurane anesthesia. SD-OCT images of the ONH of both eyes were acquired 30 minutes after IOP was stabilized to 10 mm Hg and 60 minutes after stabilization to 45 mm Hg. The internal limiting membrane, Bruchs membrane/retinal pigment epithelium, neural canal opening (NCO), and anterior lamina cribrosa surface (ALCS) were delineated using custom software. Differences in SD-OCT structural parameters between the two IOP levels were assessed using generalized estimating equations. In six eyes of three animals, images were acquired after 10 minutes and 30 minutes of IOP stabilization to 10 mm Hg (control experiment). RESULTS Acute IOP elevation resulted in a reduction in prelaminar tissue thickness (mean, -47 μm; SD, 25 μm; P = 0.002), rim volume (-0.05 mm(3), 0.02 mm(3); P = 0.002), rim width (-30 μm, 7 μm; P = 0.002), and in an increase in NCO depth (38 μm, 15 μm; P = 0.002). An increase in ALCS depth was significant relative to peripheral Bruchs membrane (48 μm, 24 μm; P = 0.002) but not relative to the NCO. No significant parameter changes were detected in the control eyes. CONCLUSIONS Surface compliance changes in the normal monkey ONH primarily reflect prelaminar and peripapillary deformation. SD-OCT compliance testing will further our understanding of the effects of IOP on the ONH and help improve and validate numerical models of ONH biomechanics.

Deformation of the normal monkey optic nerve head connective tissue after acute IOP elevation within 3-D histomorphometric reconstructions.

PURPOSE To characterize optic nerve head (ONH) connective tissue deformation after acute (15 or 30 minutes) intraocular pressure (IOP) elevation in six adult normal monkeys using three-dimensional (3-D) histomorphometry. METHODS Trephined ONH and peripapillary sclera from both eyes of six monkeys, each perfusion fixed with one eye at IOP 10 mm Hg (IOP-10) and the other at IOP 30 or 45 mm Hg (IOP-30 or IOP-45, by anterior chamber manometer), were serially sectioned, 3-D reconstructed, 3-D delineated, and quantified according to standard parameters. For each monkey, intereye differences (high-IOP eye minus IOP-10) for each parameter were calculated and compared by ANOVA and EPIDmax both overall and regionally. EPIDmax deformations for each parameter were defined to be those statistically significant differences that exceeded the maximum physiologic intereye difference within six bilaterally normal monkeys in a previous report. RESULTS Regional EPIDmax laminar thinning, posterior bowing of the peripapillary sclera, and thinning and expansion of the scleral canal were present in most high-IOP eyes and were colocalized in those demonstrating the most deformation. Laminar deformation was minimal, not only posteriorly but in some cases anteriorly in the high-IOP eyes. No increase in deformation was seen in the IOP-45 versus the IOP-30 eyes. CONCLUSIONS ONH connective tissue alterations after acute IOP elevation involve regional thinning, stretching, and deformation of the lamina cribrosa and peripapillary sclera that are minimal to modest in magnitude. The time-dependent character of these alterations and their compressive, expansile, and shear effects on the axons, the astrocytes, and the laminar and posterior ciliary circulations remain to be determined.

Detection of optic nerve head neural canal opening within histomorphometric and spectral domain optical coherence tomography data sets.

PURPOSE To assess the ability to detect the neural canal opening (NCO) and its characteristics within three-dimensional (3-D) histomorphometric and 3-D spectral domain optical coherence tomography (SD-OCT) reconstructions of the optic nerve head from nonhuman primate (NHP) eyes. METHODS NCO was delineated within 40 radial, sagittal sections of 3-D histomorphometric reconstructions of 44 normal eyes of 38 NHPs, each perfusion fixed at IOP 10 mm Hg, and 3-D SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) volumes acquired in vivo from a separate group of 33 normal eyes of 24 NHPs. Within all reconstructions, a least-squares ellipse was fitted to the 80 NCO points. For each eye, the dimensions and plane error (a gauge of planarity) of the fitted ellipse were calculated. RESULTS The NCO was successfully delineated within every section of each histomorphometric and SD-OCT reconstruction. Median plane error was similar within histomorphometric and SD-OCT volumes (8 microm, range 4-19, histomorphometry, and 10 microm, range 4-26, SD-OCT) and was small relative to the size of the ellipse. Median histomorphometric ellipse dimensions were 1453 mum (major axis, range 1218-1737) and 1066 microm (minor axis, range 808-1263). Median SD-OCT ellipse dimensions were 1512 microm (major axis, range 1191-1865) and 1060 microm (minor axis, range 772-1248). CONCLUSIONS The NCO is biologically continuous and relatively planar within all 3-D histomorphometric and SD-OCT reconstructions. These characteristics support its further evaluation as a reference plane for cross-sectional and longitudinal measurement of optic nerve head structures using 3-D SD-OCT.

A method to estimate the amount of neuroretinal rim tissue in glaucoma: comparison with current methods for measuring rim area.

PURPOSE To test whether the minimum rim area assessed by spectral domain optical coherence tomography (SD-OCT), based on the shortest distance from the Bruch membrane opening (BMO) to the inner limiting membrane, corresponds more closely to retinal nerve fiber layer (RNFL) thickness and visual field mean deviation (MD) than current rim measures in early glaucoma. DESIGN Prospective cross-sectional study. METHODS We studied 221 participants with non-endstage glaucoma or high-risk ocular hypertension and performed standard automated perimetry. We received SD-OCT and confocal scanning laser ophthalmoscopy (CSLO) scans on the same day. Rim area measured by CSLO was compared with 3 SD-OCT rim measures from radial B-scans: horizontal rim area between BMO and inner limiting membrane within the BMO plane; mean minimum rim width (BMO-MRW); and minimum rim area (BMO-MRA) optimized within sectors and then summed. Correlations between these measures and either MD from perimetry or RNFL thickness from SD-OCT were compared using the Steiger test. RESULTS RNFL thickness was better correlated with BMO-MRA (r = 0.676) or BMO-MRW (r = 0.680) than with either CSLO rim area (r = 0.330, P < 0.001) or horizontal rim area (r = 0.482, P < 0.001). MD was better correlated with BMO-MRA (r = 0.534) or BMO-MRW (r = 0.546) than with either CSLO rim area (r = 0.321, P < 0.001) or horizontal rim area (0.403, P < 0.001). The correlation between MD and RNFL thickness was r = 0.646. CONCLUSIONS Minimum rim measurements from SD-OCT are significantly better correlated to both RNFL thickness and MD than rim measurements within the BMO plane or based on the clinical disc margin. They provide new structural parameters for both diagnostic and research purposes in glaucoma.