Christy Hardin

Anterior Lamina Cribrosa Surface Depth, Age, and Visual Field Sensitivity in the Portland Progression Project

PURPOSE To assess the effect of age on spectral-domain optical coherence tomography (SDOCT)-detected lamina cribrosa depth while controlling for visual field (VF) status and retinal nerve fiber layer thickness (RNFLT) in 221 high-risk ocular hypertension and glaucoma patients enrolled in the Portland Progression Project. METHODS In this cross-sectional study, each participant underwent 870-nm SDOCT to obtain high-resolution radial B-scans centered on the optic nerve head (ONH) and a standardized ophthalmologic examination, including automated perimetry, on the same day. For each ONH, an anterior lamina cribrosa surface depth (ALCSD) parameter was generated as the average perpendicular distance from each anterior lamina cribrosa surface point relative to Bruchs membrane opening (BMO) reference plane within all 24 delineated B-scans. The relative effects of age, age-corrected VF status (mean deviation [MD]), and RNFLT on ALCSD were analyzed. RESULTS The mean age ± SD of participants was 64 ± 11 years (range, 33-90 years). The relationship between ALCSD and MD was age-dependent. ALCSD = 407.68 - 67.13 × MD - 0.08 × Age + 0.89 × MD × Age (MD, P = 0.001; MD × Age, P = 0.004). The relationship between ALCSD and RNFLT may also be age-dependent but did not achieve significance (interaction term, P = 0.067). ALCSD increased with worse VF status in younger eyes but not in older eyes. In older eyes, the anterior lamina was shallower than in younger eyes for the same VF status and RNFLT. CONCLUSIONS These data are consistent with the concept that structure/structure and structure/function relationships change with age.

Longitudinal Detection of Optic Nerve Head Changes by Spectral Domain Optical Coherence Tomography in Early Experimental Glaucoma

PURPOSE We determined if the detection of spectral-domain optical coherence tomography (SDOCT) optic nerve head (ONH) change precedes the detection of confocal scanning laser tomography (CSLT) ONH surface, SDOCT retinal nerve fiber layer (RNFL), scanning laser perimetry (SLP), and multifocal electroretinography (mfERG) change in eight experimental glaucoma (EG) eyes. METHODS Both eyes from eight monkeys were tested at least three times at baseline, and then every 2 weeks following laser-induced chronic unilateral IOP elevation. Event and trend-based definitions of onset in the control and EG eyes for 11 SDOCT neural and connective tissue, CSLT surface, SDOCT RNFL, SLP, and mfERG parameters were explored. The frequency and timing of onset for each parameter were compared using a logrank test. RESULTS Maximum post-laser IOP was 18 to 42 mm Hg in the EG eyes and 12 to 20 mm Hg in the control eyes. For event- and trend-based analyses, onsets were achieved earliest and most frequently within the ONH neural and connective tissues using SDOCT, and at the ONH surface using CSLT. SDOCT ONH neural and connective tissue parameter change preceded or coincided with CSLT ONH surface change in most EG eyes. The SDOCT and SLP measures of RNFL thickness, and mfERG measures of visual function demonstrated similar onset rates, but occurred later than SDOCT ONH and CSLT surface change, and in fewer eyes. CONCLUSIONS SDOCT ONH change detection commonly precedes or coincides with CSLT ONH surface change detection, and consistently precedes RNFLT, SLP, and mfERG change detection in monkey experimental glaucoma.

Anatomic vs. acquired image frame discordance in spectral domain optical coherence tomography minimum rim measurements.

Purpose To quantify the effects of using the fovea to Bruchs membrane opening (FoBMO) axis as the nasal-temporal midline for 30° sectoral (clock-hour) spectral domain optical coherence tomography (SDOCT) optic nerve head (ONH) minimum rim width (MRW) and area (MRA) calculations. Methods The internal limiting membrane and BMO were delineated within 24 radial ONH B-scans in 222 eyes of 222 participants with ocular hypertension and glaucoma. For each eye the fovea was marked within the infrared reflectance image, the FoBMO angle (θ) relative to the acquired image frame (AIF) horizontal was calculated, the ONH was divided into 30°sectors using a FoBMO or AIF nasal/temporal axis, and SDOCT MRW and MRA were quantified within each FoBMO vs. AIF sector. For each sector, focal rim loss was calculated as the MRW and MRA gradients (i.e. the difference between the value for that sector and the one clockwise to it divided by 30°). Sectoral FoBMO vs. AIF discordance was calculated as the difference between the FoBMO and AIF values for each sector. Generalized estimating equations were used to predict the eyes and sectors of maximum FoBMO vs. AIF discordance. Results The mean FoBMO angle was −6.6±4.2° (range: −17° to +7°). FoBMO vs. AIF discordance in sectoral mean MRW and MRA was significant for 7 of 12 and 6 of 12 sectors, respectively (p<0.05, Wilcoxon test, Bonferroni correction). Eye-specific, FoBMO vs. AIF sectoral discordance was predicted by sectoral rim gradient (p<0.001) and FoBMO angle (p<0.001) and achieved maximum values of 83% for MRW and 101% for MRA. Conclusions Using the FoBMO axis as the nasal-temporal axis to regionalize the ONH rather than a line parallel to the AIF horizontal axis significantly influences clock-hour SDOCT rim values. This effect is greatest in eyes with large FoBMO angles and sectors with focal rim loss.

Spectral-Domain Optical Coherence Tomography Enhanced Depth Imaging of the Normal and Glaucomatous Nonhuman Primate Optic Nerve Head

PURPOSE To test whether the enhanced depth imaging (EDI) modality improves anterior and posterior lamina cribrosa surface (ALCS and PLCS) visibility compared with conventional spectral-domain optical coherence tomography (SD-OCT). METHODS Conventional and EDI SD-OCT scans were obtained 30 minutes after IOP was manometrically lowered to 10 mm Hg in both eyes of 14 nonhuman primates (NHPs) with unilateral experimental glaucoma (EG). Thirteen horizontal and seven vertical radial B-scans of each SD-OCT data set were delineated by one operator masked to image type. Delineated ALCS and PLCS points were projected to 1 of 100 equal-sized subregions of the neural canal opening (NCO) reference plane, and the number of delineated subregions (≥2 points) was counted. Poisson regression was used to analyze the effects of image type, treatment, and quadrant. Two additional delineations were performed for three NHPs to compare reproducibility. RESULTS EDI increased the number of subregions delineated for both the ALCS (by 28%; P < 0.0001) and PLCS (by 225%; P < 0.0001). EDI improvement in ALCS visibility was significant in the superior quadrant only and was not different in EG versus control eyes, whereas EDI improvement in PLCS visibility was significant in all four quadrants (P < 0.005) and greater in EG eyes (P < 0.001), nasally and temporally. Intradelineator reproducibility was not different between image types. EDI and standard ONH parameter values were similar except for PLCS depth which was deeper in the EDI data sets (P = 0.0002). CONCLUSIONS ALCS and PLCS visibility within control and EG NHP ONHs increased in EDI compared to conventional SD-OCT data sets. Further study of EDI effects on PLCS parameterization is required.

Age-related differences in longitudinal structural change by spectral-domain optical coherence tomography in early experimental glaucoma.

PURPOSE To characterize age-related differences in the magnitude of spectral-domain optical coherence tomography (SD-OCT) structural change in early experimental glaucoma (EG). METHODS Both eyes from four young (1.4-2.6 years) and four old (18.6-21.9 years) rhesus monkeys were imaged at least three times at baseline, and then every 2 weeks after laser-induced, chronic, unilateral IOP elevation until the onset of EG (confocal scanning laser tomographic surface change confirmed twice). Two to 20 weeks after EG onset, animals were euthanized and optic nerve axon counts for all eyes were performed. Masked operators delineated retinal and ONH landmarks in 40 radial B-scans from each eye and imaging session to quantify change from baseline in five SD-OCT neural and connective tissue parameters. The effects of EG, age, and EG × age interactions on the magnitude, rate (magnitude per postlaser time), and IOP responsiveness (magnitude per cumulative IOP insult) of postlaser parameter change were individually assessed using general estimating equation models. RESULTS Presac SD-OCT RNFLT and minimum rim width change and postmortem axon loss was not significantly different in old compared with young EG eyes. The rate of change and IOP responsiveness of the parameters anterior lamina cribrosa surface depth relative to Bruchs membrane opening (BMO) and BMO depth relative to peripheral Bruchs membrane were significantly lower (P < 0.05) in the old compared with the young EG eyes. CONCLUSIONS At similar postlaser times, levels of cumulative IOP insult and axonal damage, SD-OCT-detected ONH connective tissue structural change is greater in young compared with old monkey EG eyes.

Experimental Glaucoma Causes Optic Nerve Head Neural Rim Tissue Compression: A Potentially Important Mechanism of Axon Injury.

Purpose We tested the hypothesis that experimental glaucoma (EG) results in greater thinning of the optic nerve head (ONH) neural rim tissue than the peripapillary retinal nerve fiber layer (RNFL) tissue. Methods Longitudinal spectral-domain optical coherence tomography (SDOCT) imaging of the ONH and peripapillary RNFL was performed every other week under manometric IOP control (10 mm Hg) in 51 nonhuman primates (NHP) during baseline and after induction of unilateral EG. The ONH parameter minimum rim area (MRA) was derived from 80 radial B-scans centered on the ONH; RNFL cross-sectional area (RNFLA) from a peripapillary circular B-scan with 12° diameter. Results In control eyes, MRA was 1.00 ± 0.19 mm2 at baseline and 1.00 ± 0.19 mm2 at the final session (P = 0.77), while RNFLA was 0.95 ± 0.09 and 0.95 ± 0.10 mm2, respectively (P = 0.96). In EG eyes, MRA decreased from 1.00 ± 0.19 mm2 at baseline to 0.63 ± 0.21 mm2 at the final session (P < 0.0001), while RNFLA decreased from 0.95 ± 0.09 to 0.74 ± 0.19 mm2, respectively (P < 0.0001). Thus, MRA decreased by 36.4 ± 20.6% in EG eyes, significantly more than the decrease in RNFLA (21.7 ± 19.4%, P < 0.0001). Other significant changes in EG eyes included increased Bruchs membrane opening (BMO) nonplanarity (P < 0.05), decreased BMO aspect ratio (P < 0.0001), and decreased MRA angle (P < 0.001). Bruchs membrane opening area did not change from baseline in either control or EG eyes (P = 0.27, P = 0.15, respectively). Conclusions Optic nerve head neural rim tissue thinning exceeded peripapillary RNFL thinning in NHP EG. These results support the hypothesis that axon bundles are compressed transversely within the ONH rim along with glaucomatous deformation of connective tissues.

Comparing Optic Nerve Head Rim Width, Rim Area, and Peripapillary Retinal Nerve Fiber Layer Thickness to Axon Count in Experimental Glaucoma.

Purpose We compare spectral-domain optical coherence tomography (SDOCT) measurements of minimum rim width (MRW), minimum rim area (MRA), and peripapillary retinal nerve fiber layer thickness (RNFLT) to complete orbital optic nerve axon counts in nonhuman primates (NHP) with unilateral experimental glaucoma (EG). Methods Biweekly SDOCT measurements of MRW, MRA, and RNFLT were acquired under manometric IOP control (10 mm Hg) in 51 NHP during baseline (mean ± SD, 5.0 ± 1.6 sessions) and after laser photocoagulation was applied to the trabecular meshwork of one eye to induce chronic IOP elevation. At the study endpoint (predefined for each NHP), 100% axon counts were obtained from each optic nerve. Results For SDOCT parameters at baseline, the correlation between the two eyes of each animal was strongest for RNFLT (R = 0.97) and MRW (R = 0.97), but lower for MRA (R = 0.85). At the final time point, average values in EG eyes relative to control eyes were: −22% for RNFLT, −38% for MRW, −36% for MRA, and −36% for optic nerve axons. The correlation with axon counts was strongest for RNFLT (R = 0.81), compared to MRW (R = 0.72, P = 0.001) or MRA (R = 0.70, P = 0.001). Diagnostic sensitivity was 75% for RNFLT, 90% for MRW, and 88% for MRA; all had 100% specificity. Conclusions Peripapillary RNFLT was correlated more closely with total orbital optic nerve axon count than were the ONH parameters MRW or MRA. This is likely because glaucomatous deformation (beyond axon loss alone) has a greater influence on the ONH parameters MRW and MRA than on RNFLT.

The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications

&NA; In a series of previous publications we have proposed a framework for conceptualizing the optic nerve head (ONH) as a biomechanical structure. That framework proposes important roles for intraocular pressure (IOP), IOP‐related stress and strain, cerebrospinal fluid pressure (CSFp), systemic and ocular determinants of blood flow, inflammation, auto‐immunity, genetics, and other non‐IOP related risk factors in the physiology of ONH aging and the pathophysiology of glaucomatous damage to the ONH. The present report summarizes 20 years of technique development and study results pertinent to the characterization of ONH connective tissue deformation and remodeling in the unilateral monkey experimental glaucoma (EG) model. In it we propose that the defining pathophysiology of a glaucomatous optic neuropathy involves deformation, remodeling, and mechanical failure of the ONH connective tissues. We view this as an active process, driven by astrocyte, microglial, fibroblast and oligodendrocyte mechanobiology. These cells, and the connective tissue phenomena they propagate, have primary and secondary effects on retinal ganglion cell (RGC) axon, laminar beam and retrolaminar capillary homeostasis that may initially be “protective” but eventually lead to RGC axonal injury, repair and/or cell death. The primary goal of this report is to summarize our 3D histomorphometric and optical coherence tomography (OCT)‐based evidence for the early onset and progression of ONH connective tissue deformation and remodeling in monkey EG. A second goal is to explain the importance of including ONH connective tissue processes in characterizing the phenotype of a glaucomatous optic neuropathy in all species. A third goal is to summarize our current efforts to move from ONH morphology to the cell biology of connective tissue remodeling and axonal insult early in the disease. A final goal is to facilitate the translation of our findings and ideas into neuroprotective interventions that target these ONH phenomena for therapeutic effect. HighlightsONH connective tissue deformation and remodeling define the optic neuropathy of glaucoma.The lamina cribrosa thickens, migrates into the pia, then thins in monkey experimental glaucoma.Lamina cribrosa deformation can be detected early in monkey experimental glaucoma by OCT.There are no experimental models of normal tension glaucoma in the monkey eye.Retinal ganglion cell axon loss, alone, does not create “glaucomatous” cupping.

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.

3D Histomorphometric Reconstruction and Quantification of the Optic Nerve Head Connective Tissues

Accurately characterizing the 3D geometry of the optic nerve head neural and connective tissues has been the goal of a large and important body of scientific work. In the present report, we summarize our methods for the high-resolution, digital, 3D histomorphometric reconstruction of the optic nerve head tissues, including their visualization, parameterization, and quantification. In addition, we present our methods for between-eye comparisons of this anatomy, and their use to determine animal-specific and experiment-wide experimental glaucoma versus Control eye differences in the unilateral, monkey experimental glaucoma model. Finally, we demonstrate its application to finite element modeling, 3D optic nerve head reconstruction of other species, and 3D optic nerve head reconstructions using other imaging modalities.