Glen P. Sharpe

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.

Laminar and Prelaminar Tissue Displacement During Intraocular Pressure Elevation in Glaucoma Patients and Healthy Controls

OBJECTIVE To determine the response of the anterior lamina cribrosa and prelaminar tissue to acute elevation of intraocular pressure (IOP) in glaucoma patients and healthy subjects. DESIGN Prospective case-control series. PARTICIPANTS AND CONTROLS Patients with open-angle glaucoma (n = 12; mean age ± standard deviation [SD], 66.8 ± 6.0 years), age-matched healthy controls (n = 12; mean age ± SD, 67.1 ± 6.2 years), and young controls (n = 12; mean age ± SD, 36.1 ± 11.7 years). METHODS One eye was imaged with spectral-domain optical coherence tomography to obtain 12 high-resolution radial scans centered on the optic disc. Imaging was repeated at precisely the same locations with an ophthalmodynamometer held perpendicular to the globe via the inferior lid to raise the IOP. A line joining Bruchs membrane opening in 4 radial scans was used as reference in the baseline and elevated IOP images. The vertical distance from the reference line to the anterior prelaminar tissue surface and anterior laminar surface was measured at equidistant points along the reference line in the 2 sets of images. The difference between the 2 sets of corresponding measurements were used to determine laminar displacement (LD) and prelaminar tissue displacement (PTD). MAIN OUTCOME MEASURES Laminar displacement and PTD. RESULTS Intraocular pressure elevation among patients, age-matched controls, and young controls was similar (mean ± SD, 12.4 ± 3.2 mmHg). The mean ± SD LD and PTD were 0.5 ± 3.3 μm and 15.7 ± 15.5 μm, respectively. The LD was not statistically different from 0 (P = 0.366), but PTD was (P < 0.001). The mean ± SD LD was similar among the groups (-0.5 ± 3.7 μm, 0.2 ± 2.0 μm, and 2.0 ± 3.6 μm, respectively; P = 0.366), whereas the mean ± SD PTD was different (6.8 ± 13.7 μm, 20.8 ± 17.5 μm, and 19.6 ± 11.8 μm, respectively; P = 0.045). In all subjects, the PTD was greater than LD. In multivariate regression analyses, LD was negatively associated with optic disc size (P = 0.007), whereas PTD was positively associated with the degree of IOP elevation (P = 0.013). CONCLUSIONS In glaucoma patients and controls, the anterior laminar surface is noncompliant to acute IOP elevation. Acute optic disc surface changes represent compression of prelaminar tissue and not laminar displacement.

Enhanced Structure–Function Relationship in Glaucoma With an Anatomically and Geometrically Accurate Neuroretinal Rim Measurement

PURPOSE To evaluate the structure-function relationship between disc margin-based rim area (DM-RA) obtained with confocal scanning laser tomography (CSLT), Bruchs membrane opening-based horizontal rim width (BMO-HRW), minimum rim width (BMO-MRW), peripapillary retinal nerve fiber layer thickness (RNFLT) obtained with spectral-domain optical coherence tomography (SD-OCT), and visual field sensitivity. METHODS We examined 151 glaucoma patients with CSLT, SD-OCT, and standard automated perimetry on the same day. Optic nerve head (ONH) and RNFL with SD-OCT were acquired relative to a fixed coordinate system (acquired image frame [AIF]) and to the eye-specific fovea-BMO center (FoBMO) axis. Visual field locations were mapped to ONH and RNFL sectors with fixed Garway-Heath (VF(GH)) and patient-specific (VF(PS)) maps customized for various biometric parameters. RESULTS Globally and sectorally, the structure-function relationships between DM-RA and VF(GH), BMO-HRW(AIF) and VF(GH), and BMO-HRW(FoBMO) and VF(PS) were equally weak. The R(2) for the relationship between DM-RA and VF(GH) ranged from 0.1% (inferonasal) to 11% (superotemporal) whereas that between BMO-HRW(AIF) and VF(GH) ranged from 0.1% (nasal) to 10% (superotemporal). Relatively stronger global and sectoral structure-function relationships with BMO-MRW(AIF) and with BMO-MRW(FoBMO) were obtained. The R(2) between BMO-MRW(AIF) and VF(GH) ranged from 5% (nasal) to 30% (superotemporal), whereas that between BMO-MRW(FoBMO) and VF(PS) ranged from 5% (nasal) to 25% (inferotemporal). The structure-function relationship with RNFLT was not significantly different from that with BMO-MRW, regardless of image acquisition method. CONCLUSIONS The structure-function relationship was enhanced with BMO-MRW compared with the other neuroretinal rim measurements, due mainly to its geometrically accurate properties.

Bruch's Membrane Opening Minimum Rim Width and Retinal Nerve Fiber Layer Thickness in a Normal White Population: A Multicenter Study

PURPOSE Conventional optic disc margin-based neuroretinal rim measurements lack a solid anatomic and geometrical basis. An optical coherence tomography (OCT) index, Bruchs membrane opening minimum rim width (BMO-MRW), addresses these deficiencies and has higher diagnostic accuracy for glaucoma. We characterized BMO-MRW and peripapillary retinal nerve fiber layer thickness (RNFLT) in a normal population. DESIGN Multicenter cross-sectional study. PARTICIPANTS Normal white subjects. METHODS An approximately equal number of subjects in each decade group (20-90 years of age) was enrolled in 5 centers. Subjects had normal ocular and visual field examination results. We obtained OCT images of the optic nerve head (24 radial scans) and peripapillary retina (1 circular scan). The angle between the fovea and BMO center (FoBMO angle), relative to the horizontal axis of the image frame, was first determined and all scans were acquired and analyzed relative to this eye-specific FoBMO axis. Variation in BMO-MRW and RNFLT was analyzed with respect to age, sector, and BMO shape. MAIN OUTCOME MEASURES Age-related decline and between-subject variability in BMO-MRW and RNFLT. RESULTS There were 246 eyes of 246 subjects with a median age of 52.9 years (range, 19.8-87.3 years). The median FoBMO angle was -6.7° (range, 2.5° to -17.5°). The BMO was predominantly vertically oval with a median area of 1.74 mm(2) (range, 1.05-3.40 mm(2)). Neither FoBMO angle nor BMO area was associated with age or axial length. Both global mean BMO-MRW and RNFLT declined with age at a rate of -1.34 μm/year and -0.21 μm/year, equivalent to 4.0% and 2.1% loss per decade of life, respectively. Sectorially, the most rapid decrease occurred inferiorly and the least temporally; however, the age association was always stronger with BMO-MRW than with RNFLT. There was a modest relationship between mean global BMO-MRW and RNFLT (r = 0.35), whereas sectorially the relationship ranged from moderate (r = 0.45, inferotemporal) to nonexistent (r = 0.01, temporal). CONCLUSIONS There was significant age-related loss of BMO-MRW in healthy subjects and notable differences between BMO-MRW and RNFLT in their relationship with age and between each other. Adjusting BMO-MRW and RNFLT for age and sector is important in ensuring optimal diagnostics for glaucoma.

Longitudinal In Vivo Imaging of Retinal Ganglion Cells and Retinal Thickness Changes Following Optic Nerve Injury in Mice

Background Retinal ganglion cells (RGCs) die in sight-threatening eye diseases. Imaging RGCs in humans is not currently possible and proof of principle in experimental models is fundamental for future development. Our objective was to quantify RGC density and retinal thickness following optic nerve transection in transgenic mice expressing cyan fluorescent protein (CFP) under control of the Thy1 promoter, expressed by RGCs and other neurons. Methodology/Principal Findings A modified confocal scanning laser ophthalmoscopy (CSLO)/spectral-domain optical coherence tomography (SD-OCT) camera was used to image and quantify CFP+ cells in mice from the B6.Cg-Tg(Thy1-CFP)23Jrs/J line. SD-OCT circle (1 B-scan), raster (37 B-scans) and radial (24 B-scans) scans of the retina were also obtained. CSLO was performed at baseline (n = 11) and 3 (n = 11), 5 (n = 4), 7 (n = 10), 10 (n = 6), 14 (n = 7) and 21 (n = 5) days post-transection, while SD-OCT was performed at baseline and 7, 14 and 35 days (n = 9) post-transection. Longitudinal change in CFP+ cell density and retinal thickness were computed. Compared to baseline, the mean (SD) percentage CFP+ cells remaining at 3, 5, 7, 10, 14 and 21 days post-transection was 86 (9)%, 63 (11)%, 45 (11)%, 31 (9)%, 20 (9)% and 8 (4)%, respectively. Compared to baseline, the mean (SD) retinal thickness at 7 days post-transection was 97 (3)%, 98 (2)% and 97 (4)% for the circle, raster and radial scans, respectively. The corresponding figures at 14 and 35 days post-transection were 96 (3)%, 97 (2)% and 95 (3)%; and 93 (3)%, 94 (3)% and 92 (3)%. Conclusions/Significance Longitudinal imaging showed an exponential decline in CFP+ cell density and a small (≤8%) reduction in SD-OCT measured retinal thickness post-transection. SD-OCT is a promising tool for detecting structural changes in experimental optic neuropathy. These results represent an important step towards translation for clinical use.

Importance of Normal Aging in Estimating the Rate of Glaucomatous Neuroretinal Rim and Retinal Nerve Fiber Layer Loss

PURPOSE To describe longitudinal rates of change of neuroretinal parameters in patients with glaucoma and healthy controls, and to evaluate the influence of covariates. DESIGN Prospective longitudinal study. PARTICIPANTS Treated patients with glaucoma (n = 192) and healthy controls (n = 37). METHODS Global disc margin-based neuroretinal rim area (DMRA) was measured with confocal scanning laser tomography, while Bruchs membrane opening-minimum rim width (BMO-MRW), BMO area (BMOA), and peripapillary retinal nerve fiber layer thickness (RNFLT) were measured with optical coherence tomography at 6-month intervals. Individual rates of change were estimated with ordinary least-squares regression, and linear mixed effects modeling was used to estimate the average rate of change and differences between the groups, and to evaluate the effects of baseline measurement and baseline age on rates of change. MAIN OUTCOME MEASURES Rates of change for each parameter. RESULTS Subjects were followed for a median (range) of 4 (2-6) years. The proportion of controls who had significant reduction of neuroretinal parameters was 35% for BMO-MRW, 31% for RNFLT, and 11% for DMRA. The corresponding figures for patients with glaucoma were not statistically different (42%, P = 0.45; 31%, P = 0.99; 14%, P = 0.99, respectively). Controls had a significant reduction of BMO-MRW (mean: -1.92 μm/year, P < 0.01) and RNFLT (mean: -0.44 μm/year, P = 0.01), but not DMRA (mean: -0.22×10(-2) mm(2)/year, P = 0.41). After adjusting for covariates, patients with glaucoma had faster, but not statistically different, rates of deterioration compared with controls, by -1.26 μm/year (P = 0.07) for BMO-MRW, -0.40 μm/year (P = 0.11) for RNFLT, and -0.38×10(-2) mm(2)/year (P = 0.23) for DMRA. Baseline BMO-MRW and RNFLT significantly influenced the respective rates of change, with higher baseline values relating to faster reductions. Older age at baseline was associated with a slower reduction in rates of BMO-MRW. Reductions in intraocular pressure were related to increases in BMO-MRW and DMRA. There was a tendency for BMOA to decrease over time (-0.38×10(-2) mm(2)/year; P = 0.04). CONCLUSIONS Age-related loss of neuroretinal parameters may explain a large proportion of the deterioration observed in treated patients with glaucoma and should be carefully considered in estimating rates of change.

Automated Segmentation of Optic Nerve Head Structures With Optical Coherence Tomography

PURPOSE To quantify and characterize the difference between automated and manual segmentation of optic nerve head structures with spectral-domain optical coherence tomography (SD-OCT). METHODS Optic nerve head radial scans in 107 glaucoma patients and 48 healthy controls were conducted with SD-OCT. Independent segmentations of the internal limiting membrane (ILM) and Bruchs membrane opening (BMO) were performed manually with custom software and with an automated algorithm in each radial scan. The minimum distance between BMO and ILM, termed BMO-minimum rim width (BMO-MRW) was calculated with each segmentation method. Absolute differences between automated and manual segmentations of ILM (ΔILM) and BMO (ΔBMO), and the resulting computation of BMO-MRW (ΔBMO-MRW) were computed. Finally, the relationship between image quality score and ΔILM and ΔBMO was explored. RESULTS The median (interquartile range, IQR) ΔILM was 8.9 (6.5, 13.4) μm in patients and 7.3 (5.3, 9.9) μm in controls. The corresponding values for ΔBMO were 11.5 (6.6, 22.1) μm and 12.4 (6.8, 25.4) μm. Subject-averaged ΔILM was higher in patients than controls (P < 0.01); however, mean ΔBMO was not (P = 0.09). The median (IQR) subject-averaged absolute ΔBMO-MRW was 13.4 (10.6, 16.8) μm in patients and 12.1 (10.0, 16.8) μm in controls and not statistically different (P = 0.21). Mean image quality score was statistically higher in controls than patients (P = 0.03) but not related to subject-averaged ΔILM or ΔBMO. CONCLUSIONS In individual scans, the median difference in ILM and BMO segmentations was <2 and <3 image pixels, respectively. There were no differences between patients and controls in ΔBMO-MRW.

Beta and Gamma Peripapillary Atrophy in Myopic Eyes With and Without Glaucoma

PURPOSE To determine whether beta and gamma peripapillary atrophy (PPA) areas measured with optical coherence tomography (OCT) enhances glaucoma diagnosis in myopic subjects. METHODS We included 55 myopic glaucoma patients and 74 myopic nonglaucomatous controls. Beta-PPA comprised the area external to the clinical disc margin, with absence of retinal pigment epithelium and presence of Bruchs membrane. Gamma-PPA comprised the area external to the disc margin, with absence of both RPE and Bruchs membrane. OCT scans colocalized to fundus photographs were used to measure PPA, choroidal thickness, border tissue of Elschnig configuration, optic disc area, and optic disc ovality. RESULTS Beta-PPA area was larger in glaucoma patients compared with controls (median [interquartile range], 1.0 [0.66-1.53] mm2 and 0.74 [0.50-1.38] mm2, respectively), whereas gamma-PPA was smaller in glaucoma patients compared with controls (0.28 [0.14-0.50] mm2 and 0.42 [0.17-0.74] mm2, respectively). However, the distributions of both beta- and gamma-PPA in the two groups overlapped widely. The areas under the receiver operating characteristic curve of beta- and gamma-PPA areas were 0.60 and 0.59, respectively. Larger beta-PPA area was associated with larger disc area, thinner choroidal thickness, longer axial length, less oblique border tissue configuration, older age, and greater disc ovality. Larger gamma-PPA area was associated with greater disc ovality, more oblique border tissue configuration, and longer axial length. CONCLUSIONS Subclassifying PPA with OCT into beta and gamma zones reveals association with different covariates, but does not enhance the diagnostic performance for glaucoma in a population of predominantly Caucasians myopic subjects.

Visibility of Optic Nerve Head Structures With Spectral-domain and Swept-source Optical Coherence Tomography

Purpose: To compare the visibility of deep optic nerve head (ONH) structures and the visible area of the anterior surface of the lamina cribrosa (ASLC) with spectral-domain optical coherence tomography (SD-OCT) and swept-source OCT (SS-OCT). Materials and Methods: In total, 33 glaucoma patients were imaged with SD-OCT (Spectralis, 24 radial B-scans centered on the ONH) and SS-OCT (Atlantis, 12 radial and a horizontal and vertical raster scan pattern containing 5 lines each, centered on the ONH). One of the SS-OCT horizontal and vertical scans that was best matching with the horizontal and vertical scan lines with those of SD-OCT was selected. All B-scans were then exported and deidentified. An independent observer determined whether the posterior choroid, border tissue, anterior scleral canal opening, and LC insertion into the sclera were detectable in the matched scan lines. Bruch membrane opening (BMO) and ASLC were segmented manually in radial scans. The segmented points were combined into a single plane and a linear interpolation was used to define BMO and ASLC areas. Results: The posterior choroid, border tissue, and anterior scleral canal opening were detectable in most patients (94% to 100%, 88% to 100%, and 76% to 100%, respectively) and were not different between SD-OCT and SS-OCT. The LC insertion detection rate was nonstatistically higher for SS-OCT compared with SD-OCT (58% to 85% vs. 42% to 73%; P>0.10). The mean (SD) ASLC visible area (percentage of the respective BMO area) was 124 (30%) with SD-OCT and 135 (32%) with SS-OCT (P<0.01). Conclusion: SD-OCT and SS-OCT had comparable detection rates of deep ONH structures; however, a larger area of ASLC was visible with SS-OCT.

Factors Influencing Central Lamina Cribrosa Depth: A Multicenter Study

Purpose To quantify the influence of ocular and demographic factors on central laminar depth (LD) in healthy participants. Methods A total of 362 normal subjects underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head (ONH) with a 24 radial B-scan pattern aligned to the fovea–to–Bruchs membrane opening (BMO) axis. BMO, anterior lamina, anterior scleral canal opening (ASCO), Bruchs membrane (BM), and the peripapillary scleral surface were manually segmented. The extent of laminar segmentation was quantified within 72 ASCO subsectors. Central LD was quantified relative to four reference planes: BMO, ASCO, BM, and scleral. The effects of age, sex, ethnicity, IOP, BMO area, ASCO area, and axial length on LD were assessed. Results Laminar visibility was most consistent within the central ASCO (median 89%, range, 69%–95%). LDBMO and LDBM were significantly shallower in eyes with greater age, BMO area, and axial length and in females. LDASCO was shallower in eyes with greater ASCO area and axial length and in European and Hispanic descent compared to African descent eyes. LDSclera behaved similarly, but was not associated with axial length. BMO and ASCO area were not different between African descent and European descent eyes. Conclusions Central LD was deeper in African descent eyes and influenced least by age, axial length, and sex, but more by ASCO area, when measured relative to the ASCO and sclera. However, the magnitude of these effects for all four reference planes was small, and their clinical importance in the detection of glaucoma and its progression remains to be determined.