Optic Nerve Head and Peripapillary Morphometrics in Myopic Glaucoma

Glaucoma Optic Nerve Head and Peripapillary Morphometrics in Myopic Glaucoma

Sieun Lee,1 Sherry X. Han,2 Mei Young,2 Mirza Faisal Beg,1 Marinko V. Sarunic,1 and Paul J. Mackenzie2

1School of Engineering Science, Simon Fraser University, Burnaby, British Columbia, Canada 2Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence: Sieun Lee, School PURPOSE. To investigate morphological characteristics of optic nerve head and peripapillary of Engineering Science, Simon Fraser region with myopia and glaucoma. University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6; METHODS. Ten normal and 17 glaucomatous myopic participants were imaged with a custom [email protected]. 1060-nm swept-source optical coherence tomography system. The three-dimensional images Mirza Faisal Beg, School of Engi- were processed and segmented for inner limiting membrane (ILM), posterior border of retinal neering Science, Simon Fraser Uni- nerve fiber layer (RNFL), Bruch’s membrane (BM), and posterior border of choroid. Seven versity, 8888 University Drive, shape parameters were measured: nerve fiber layer (NFL) thickness; Bruch’s membrane Burnaby, BC, Canada V5A 1S6; opening (BMO) area, eccentricity, and planarity; BMO and BM depths; and choroidal [email protected]. thickness. The results were analyzed by group and regional sector, and multiple regression Marinko V. Sarunic, School of Engi- was performed on each shape parameter with age, axial length, and glaucoma severity, neering Science, Simon Fraser Uni- measured by mean deviation (MD). versity, 8888 University Drive, Burnaby, BC, Canada V5A 1S6; RESULTS. Bruch’s membrane opening area (P < 0.001), eccentricity (P ¼ 0.025), and planarity [email protected]. (P ¼ 0.019) were correlated with axial length but not with MD, such that larger, more PaulJ.Mackenzie,Departmentof elliptical, and less planar BMO was associated with longer axial length. Several BMOs Ophthalmology, University of British displayed a saddle-like shape configuration whose orientation appeared to be aligned with Columbia, 2550 Willow Street, Van- that of the BMO ellipse. All BM showed posterior deformation toward BMO such that BM couver, BC, Canada V5Z 0A6; closer to BMO was more posterior than that farther from BMO. Bruch’s membrane depth was [email protected]. correlated with axial length (P ¼ 0.014) and MD (P ¼ 0.040) in intersubject regression, and Submitted: March 4, 2014 BMO depth (P ¼ 0.003) and BM depth (P ¼ 0.006) were correlated with MD in intereye Accepted: May 5, 2014 regression. Bruch’s membrane depth was also associated with age. Choroidal thickness was negatively correlated with age (P ¼ 0.001) and with axial length to a smaller degree (P ¼ Citation: Lee S, Han SX, Young M, Beg 0.034), but not with glaucoma severity. MF, Sarunic MV, Mackenzie PJ. Optic nerve head and peripapillary mor- CONCLUSIONS. Axial length was a significant factor in BMO and BM shape in normal and phometrics in myopic glaucoma. In- glaucomatous myopic subjects. Posterior deformation of BM was observed in all eyes and vest Ophthalmol Vis Sci. significantly associated with functional glaucomatous damage and age. 2014;55:4378–4393. DOI:10.1167/ iovs.14-14227 Keywords: ONH, glaucoma, myopia, shape analysis, image analysis

he pathophysiology of glaucoma, although not fully and pale neuroretinal rim of high myopia make optic nerve T understood, involves damage to the retinal ganglion cell head assessment difficult. Myopic individuals can show axons at the level of the lamina cribrosa.1–3 Uncontrolled abnormal results on structural and functional testing because intraocular pressure (IOP) likely triggers several parallel, but normal databases are composed of individuals with low interacting, mechanisms including direct axonal damage, refractive error.21,22 Coexisting pathologies, particularly myo- disturbances in neurometabolism and microvascular supply, pic degeneration, cloud interpretation of visual field changes in glial activation, and extensive remodeling of the connective advanced glaucoma. Cup-to-disc ratio and retinal nerve fiber tissues of the lamina cribrosa and surrounding tissues layer (RNFL) thickness measured by commercial optical throughout the development and progression of glaucoma.4–15 coherence tomography (OCT) and confocal scanning laser The peripapillary tissues that surround the optic nerve itself ophthalmoscopy (CSLO) were shown to be less effective in have also been implicated as possible contributors to glau- discriminating glaucomatous and nonglaucomatous subjects comatous changes, in both experimental and modeling with high myopia,23 with several studies reporting RNFL studies.16 Atrophic features of the peripapillary tissues that thinning associated with myopia.24–26 There are theoretical appear to be associated with glaucoma can include thinning of grounds to suggest that myopic eyes may be more sensitive to a the peripapillary scleral tissue17 and loss of almost all retinal given IOP as a result of the larger globe size and thinner, more and deeper layers separating the subarachnoid space from the compliant tissues.27–29 vitreous cavity.18 In studies comparing highly myopic glaucomatous eyes to Myopia presents unique challenges for the management of nonhighly myopic glaucomatous eyes, the former showed glaucoma. Population-based studies have indicated a greater significant histological difference in the peripapillary region, prevalence of glaucoma in myopes.19,20 The shallow cupping including elongation and thinning of the scleral flange.30

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TABLE 1. Demographics and Clinical Characteristics of the Study Subjects by Group

Group No. of Subjects (No. of Eyes Used) Age Axial Length, mm MD, dB

Young normal 5 (10) 29.8 6 3.6 25.9 6 1.4 0.8 6 0.6 Older normal 5 (10) 57.0 6 4.4 25.5 6 1.0 0.5 6 1.1 Glaucomatous, unilateral 7 (14) 57.2 6 12.4 26.2 6 0.9 0.5 6 0.5 Glaucomatous, bilateral 10 (19) 55.7 6 12.6 27.1 6 1.8 14.6 6 8.4

Comparison of color stereo optic disc photography showed house acquisition software that provided real-time en face and more pronounced optic nerve damage, larger and more cross-sectional images to guide acquisition. The 1060-nm light elongated optic discs, and shallower optic cups in myopic source, relative to 830-nm light sources in most commercial glaucomatous eyes.31–33 OCT systems, more clearly visualized deeper structures such as To further understand the features of the myopic optic the choroid. The swept-source configuration allowed an A-scan nerve in glaucoma, we have used a custom 1060-nm swept- line rate of 100 KHz. source OCT system34 to image the optic nerve and surrounding The acquired three-dimensional (3D) image consisted of peripapillary tissues in myopes, both with and without 400 B-scans, each with 400 A-scans, and 1024 pixels per A- glaucoma, and performed quantitative shape measurement scan. The imaged region in physical space spanned an axial and analysis. depth of 2.8 mm and a square area of 5 3 5to83 8mm2. This area, the image dimension in the lateral direction, was calculated for each eye based on the optics of the acquisition MATERIALS AND METHODS system, scan angle, and axial length of the eye. Resulting voxel dimension was 2.7 lm in the axial direction and 12.5 to 20 lm Participants in the lateral direction. A full volumetric image was acquired in A total of 27 subjects were recruited for this study: five young 1.6 seconds. healthy controls (10 eyes, mean age ¼ 29.8 6 3.6 years), five Axial motion artifact was corrected using cross-correlation 35 older healthy controls (10 eyes, mean age ¼ 57.0 6 4.4), seven between adjacent frames. Three-dimensional bounded vari- 36 patients with unilateral glaucoma (14 eyes, mean age ¼ 57.2 6 ation smoothing was applied to reduce the effect of speckles 12.4), and 10 patients with bilateral open-angle glaucoma (19 while preserving and enhancing edges (Figs. 1a, 1b). eyes, mean age ¼ 55.7 6 12.6). Ethics review for this study was approved from Simon Fraser University (SFU) and from the Segmentation University of British Columbia (UBC). The study was conduct- ed in accordance with the guidelines of the Declaration of Inner limiting membrane (ILM), the posterior boundary of Helsinki, and informed consent form was obtained from each nerve fiber layer (NFL), Bruch’s membrane (BM), Bruch’s participant. membrane opening (BMO), and the choroid–sclera boundary All participants had axial lengths greater than 24 mm. A (CS boundary) were segmented for this study (Fig. 1c). The diagnosis of open-angle glaucoma was made clinically by a four surfaces (ILM, NFL, BM, and CS boundary) were fellowship-trained glaucoma specialist (PJM) based on full segmented automatically in 3D using a graph-cut algo- examination including dilated stereoscopic examination of the rithm.37–40 Briefly, a graph was constructed for each volume optic nerve, analysis of stereo disc photography, and typical by assigning a node to each voxel and creating arcs between reproducible Humphrey SITA-Standard white on white visual the nodes based on smoothness of target surfaces and distance field abnormality. No reference to OCT images was made for between the surfaces. We used intensity gradient in the axial the purposes of categorizing subjects for the study. Severity of direction as the cost function such that the minimum s-t cut of glaucomatous visual field loss was quantified by visual field the graph corresponded to smooth edges with strong intensity mean deviation (MD) values. Participant demographics are contrast. Inner limiting membrane and BM, which are imaged tabulated in Table 1 with individual subject information in with higher contrast, were segmented first, and then posterior Supplementary Table S1. NFL and CS boundaries were found by limiting the search region based on the ILM and BM segmentation. Maxflow 41 Acquisition and Preprocessing software (version 3.01, V. Kolmogorov) was used to compute the minimum cut. A custom 1060-nm swept-source OCT system, developed by The automated segmentation result was examined and Biomedical Optics Research Group at SFU, was used to image corrected by a trained research engineer (SXH) using a custom the optic nerve head (ONH).34 The OCT system included in- script in Amira (version 5.2; Visage Imaging, San Diego, CA,

FIGURE 1. Image processing and segmentation. A B-scan is shown (a) in the original form, (b) smoothed and edge-enhanced, and (c) segmented for inner limiting membrane (ILM, magenta), posterior boundary of retinal nerve ﬁber layer (NFL, purple), Bruch’s membrane (BM, green), Bruch’s membrane opening (BMO, red), and choroid–sclera boundary (CS boundary, blue). The CS boundary was deﬁned as the outermost boundary of the choroidal blood vessels, which was consistently visible in all volumes. In (d), the segmented structures are displayed in 3D. Although shown here in a B-scan, the smoothing and segmentation were performed in 3D, not frame by frame.

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FIGURE 2. Shape parameters. (a) An example B-scan. (b) Nerve fiber layer thickness was measured as the closest distance to ILM from each point on the posterior NFL boundary. (c) Bruch’s membrane reference plane was defined as the best-fit plane to BM points 2 mm away from the BMO center. (d) Bruch’s membrane opening depth was measured as the normal distance between the BM reference plane and BMO center. (e) Bruch’s membrane depth was measured as the normal distance between each point of BM and the BM reference plane. (f) Choroidal thickness was measured as the closest distance to BM from each point on the posterior choroid boundary. Although shown here in a B-scan, all parameters were defined and measured in the full 3D volume.

USA). Segmented surfaces were overlaid on the original grayscale from a plane, was measured as the mean of the normal distance image and viewed simultaneously in three separate orthogonal between the segmented BMO points and its best-fit plane. planes for better visualization of the structural boundaries For the BM shape parameters, BMO depth and BM depth, a obscured by blood vessel shadows. The rater was able to scroll BM reference plane45 was first established by selecting points back and forth through the volume in any one of the three on BM along a circle 2 mm from the center of the BMO and orientation views while the other two orthogonal views and fitting a plane with PCA. Bruch’s membrane opening depth was location pointers were slaved and updated accordingly. measured as the normal distance from the BMO center to the Bruch’s membrane opening was defined as the termination BM reference plane and reflects the posterior depth of BMO point of the high-reflectance BM/retinal pigment epithelium with respect to the BM reference plane. Bruch’s membrane (RPE) complex on the OCT image (Fig. 1c). This corresponds depth was defined as the normal distance from each pixel of to a pigmented and thus clinically identifiable structure, or a the BM surface to the BM reference plane. For statistical nonpigmented and thus clinically invisible structure.42,43 The analysis, BM depth was averaged over an elliptical annulus, BMO was segmented manually by a trained research engineer inwardly bounded at BMO and outwardly bounded at 1.75 mm (SXH) on 40 radial slices extracted from the volume, from BMO. Furthermore, BM depth was averaged in regional intersecting at the approximated center of the BMO and sectors as shown in Figure 3. Four elliptical annuli, with the spaced at a constant angle of 4.58. Radial slices were used instead of the original raster scans because ONH is a relatively radially symmetric structure, and the radial slices provide more consistent cross-sectional views of the BMO.44

Measurements Seven shape characteristics were defined and measured on the segmented ILM, NFL, BM, BMO, and CS boundary: NFL thickness, BMO area, BMO eccentricity, BMO planarity,45 BMO depth, BM depth, and choroidal thickness. The parameters are graphically described in Figure 2. Nerve fiber layer thickness was measured at each pixel of the posterior NFL surface as the closest distance to the ILM surface. The NFL within 0.25 mm from BMO was excluded because near and inside BMO, NFL changes into vertical fiber bundles. For statistical analysis, NFL thickness was averaged over an elliptical annulus, inwardly bounded at 0.25 mm from BMO and outwardly bounded at 1.75 mm from BMO. This provided a level of anatomical consistency in averaging measurements over multiple eyes with different image and BMO sizes. To quantify the BMO shape, an ellipse was fitted to the segmented BMO points by first finding the best-fit plane using 46 FIGURE 3. Sectorization. Elliptical annuli were drawn at 0.25, 0.75, principal component analysis (PCA) and fitting an ellipse to 1.25, and 1.75 mm from Bruch’s membrane opening (BMO). The the projection of the BMO points on the plane by least-squares annuli were divided into 608 angular sectors of superior (S), nasal (N), criterion. Bruch’s membrane opening area and BMO eccen- inferior (I), and temporal (T) and 308 angular sectors of superior-nasal tricity were calculated from the fitted ellipse. Bruch’s (SN), inferior-nasal (IN), inferior-temporal (IT), and superior-temporal membrane opening planarity, or how much the BMO deviates (ST).

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TABLE 2. Performance of the Automated Segmentation of Peripapillary Structures

ILM NFL BM CS Boundary

Corrected region, % 8.0 6 12.3 8.6 6 10.5 7.8 6 8.8 12.2 6 15.3 Mean amount of correction, pixels 28.6 6 31.0 7.6 6 12.2 7.4 6 13.4 18.6 6 12.5 Mean amount of correction, mm 0.077 6 0.084 0.020 6 0.033 0.020 6 0.036 0.050 6 0.033

innermost boundary of the BMO ellipse and consecutive subjects) and older eyes (all subjects age 50 or older, 18 boundaries at 0.25, 0.75, 1.25, and 1.75 mm from the BMO subjects). Lastly, multiple regression was performed on ellipse, were drawn. Elliptical annuli with fixed distances from intereye difference of the shape parameters with intereye the BMO ellipse were chosen over concentric circles centered difference of axial length and MD. at the BMO center because of considerable variability in size and eccentricity of BMO among individuals. The annuli were also divided into eight angular sectors: nasal, superior, RESULTS temporal, inferior (608 each) and superior-nasal, inferior-nasal, Out of 53 eyes, three eyes from two subjects were excluded inferior-temporal, and superior-temporal (308 each). Such from NFL and choroid analysis because the layer boundaries sectorization allowed generating comparable group means for could not be segmented with confidence, either automati- different regions (e.g., superior versus inferior, nasal versus cally or manually. Table 2 summarizes the performance of the temporal) as well as aggregating measurements of multiple eyes automated segmentation by (1) percentage of correction, without losing all regional information. calculated by dividing the number of corrected pixels by the Choroidal thickness was measured at each pixel of the total number of pixels (400 3 400 pixels), and (2) amount of posterior choroid boundary (CS boundary) as the closest correction, calculated by the difference between the distance to the BM surface. The choroid within 0.25 mm from automated segmentation and manual correction averaged BMO was excluded because choroid termination near sclera over all corrected pixels. Out of 202 automatically segment- canal was often unclear and indistinguishable. Similarly to BM ed surfaces, 10 surfaces (three ILM, two posterior NFL depth, for statistical analysis, choroidal thickness was averaged boundary, two BM, three CS boundary) from six volumes had in the elliptical annulus and regional sectors as described above. a manual correction rate greater than 50% and were categorized as unsuccessful. These cases were attributed to Analysis severe pathological deformation, image artifact, and poor image contrast. Subjects were divided into four groups: young normal (five Figure 4 illustrates the NFL thickness mapping for all subjects, 10 eyes, mean age ¼ 29.8 6 3.6 years), older normal subjects by group and demonstrates the characteristic hour- (five subjects, 10 eyes, mean age ¼ 57.0 6 4.4), glaucoma glass pattern of thicker NFL in superior and nasal regions suspect (seven subjects, seven eyes, mean age ¼ 57.2 6 12.4), relative to temporal and nasal regions. The accompanying and glaucoma (17 subjects, 26 eyes, mean age ¼ 55.7 6 12.6). scatter plot shows the distribution of mean NFL thickness, The suspect group consisted of the apparently normal 47,48 averaged over the region between 0.25 and 1.75 mm from contralateral eyes of the patients with unilateral glaucoma. BMO, between groups. As expected, NFL thickness decreases For all analysis and graphical presentation, left eyes were in the glaucomatous group. In multiple regression (Table 3), flipped horizontally into right-eye orientation. NFL thickness was significantly correlated with MD, and the Nerve fiber layer thickness, BM depth, and choroidal intereye difference in NFL thickness was significantly correlat- thickness were mapped on two-dimensional (2D) en face ed with the intereye difference in MD (Table 4). color maps. Bruch’s membrane depth and choroidal thickness Figure 5 illustrates the delineated BMO points overlaid on were further plotted in the regional sectors described in the the sum-voxel, en face view of the image volumes for all previous section. All seven shape characteristics (NFL thick- subjects. Red points indicate where the BMO is positioned ness, BMO area, BMO eccentricity, BMO planarity, BMO depth, posterior (into the page) to its plane (best-fit plane to all BMO BM depth, choroidal thickness) were scatter plotted and points), and green points indicate where the BMO is compared between groups and against age, axial length, and positioned anterior (out of the page) to the plane. The variable MD. For BM depth and choroidal thickness, regional sectors correspondence between the BMO, delineated from 3D OCT were also compared by averaging measurements in each sector image, and clinical disc margin can be seen. In Figure 6, three for all eyes in each group. Multiple linear regression was BMO shape parameters (area, eccentricity, mean planarity) are performed on the shape parameters against age, axial length, plotted by group and against age, axial length (AL), and MD. In and MD. For the regression, only the right eye of each subject multiple regression of the same parameters with age, AL, and was selected to avoid artificial reinforcement of a trend due to MD (Table 3), all three parameters of BMO area, eccentricity, intereye correlation. Outliers were excluded from the regres- and planarity were significantly correlated with AL. sion by a threshold of two standard deviations. IBM SPSS Figure 7 illustrates BM depth with respect to the BM Statistics Version 19 (IBM Corp., Armonk, NY, USA) was used reference plane at every point across the whole BM for each to perform multiple linear regression on each of the seven subject. Warm colors, or positive distance values, indicate dependent variables against the three independent variables, as that the BM surface is posterior to the reference plane; cool the following equation: colors, or negative distance values, indicate that the BM surface is anterior to the reference plane. In Figure 8, BMO Shape parameter e g BMO area ð : :; Þ depth and mean BM depth are plotted by group and against ¼ a þ b1 Age þ b2 Axial length þ b3 Mean deviation: age, AL, and MD. Bruch’s membrane opening depth captures ð1Þ the degree of posterior deviation of BM at BMO. A larger BMO depth reflects a greater degree of steepness between from the Regression was performed with all eyes and repeated for BM reference plane and BMO. Mean BM depth is the mean of two subsets: normal eyes (young normal and older normal, 10 the absolute BM depth value, averaged over the region

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FIGURE 4. Peripapillary retinal nerve ﬁber layer (NFL) thickness. All thickness color maps are in scale and right-eye orientation. The region within 0.25 mm from Bruch’s membrane opening (BMO) was excluded. The graph plots the NFL thickness averaged over the region between 0.25 and 1.75 mm from BMO, with outliers in each group marked by red circles.

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TABLE 3. Multiple Regression Analyses of Shape Parameters With Age, Axial Length, and Mean Deviation (MD): Mean Nerve Fiber Layer Thickness, BMO Area, BMO Eccentricity, BMO Planarity, BMO Depth, Mean BM Depth, and Mean Choroidal Thickness

Part Correlation Coefﬁcients (P Value)

nR F(Sig.) Age AL MD

Mean nerve fiber layer thickness All data 25 0.92 38.55 (<0.001) - - 0.89 (<0.001) Normal, YN, and ON ------Age-matched, 50þ 16 0.86 11.95 (0.001) - - 0.75 (<0.000) BMO area All data 25 0.71 7.18 (0.002) 0.34 (0.038) 0.69 (<0.001) - Normal, YN, and ON 10 0.86 5.47 (0.038) - 0.83 (0.008) - Age-matched, 50þ 16 0.78 6.13 (0.009) 0.45 (0.030) 0.59 (0.007) - BMO eccentricity All data 26 0.59 3.94 (0.022) - 0.42 (0.025) - Normal, YN, and ON 10 0.80 3.54 (0.088) - 0.59 (0.053) - Age-matched, 50þ ------BMO planarity All data 25 0.69 6.70 (0.002) - 0.40 (0.019) - Normal, YN, and ON ------Age-matched, 50þ ------BMO depth All data ------Normal, YN, and ON ------Age-matched, 50þ ------Mean BM depth All data ------Normal, YN, and ON ------Age-matched, 50þ 16 0.67 3.30 (0.058) - 0.62 (0.014) 0.49 (0.040) Mean choroidal thickness All data 24 0.75 8.82 (0.001) 0.59 (0.001) - - Normal, YN, and ON 10 0.84 4.92 (0.047) 0.81 (0.010) - - Age-matched, 50þ 16 0.76 5.59 (0.012) 0.56 (0.011) 0.45 (0.034) - Sig., signiﬁcance; YN, young normal; ON, older normal.

between BMO and 1.75 mm from BMO, and reflects the Figure 9 presents the sectoral analysis of BM depth with degree to which the overall BM shape deviates from a plane. A sectors divided by both radial distance from BMO and angular larger mean BM depth indicates a less planar BM, while a sectors. In Figure 9A, BM depth is shown averaged in each smaller mean BM depth indicates a flatter BM. In multiple sector across each group. A greater overall BM depth, regression of BMO depth and mean BM depth with age, AL, indicating a greater degree of global deviation from a plane, and MD (Table 3), some correlation existed between BM can be seen in the older normal and glaucomatous groups depth and AL and MD. More significant correlations were compared with the young normal group. In Figures 9B and 9C, observed between the intereye difference of BMO depth and BM depth is plotted by angular sectors only, starting from intereye MD difference, and also between the intereye temporal and proceeding clockwise to inferior-temporal difference in mean BM depth and intereye MD difference. region. In Figure 9B, all BM depth points in the same angular

TABLE 4. Multiple Regression Analyses of Intereye Difference in Shape Parameters With Intereye Difference in Axial Length and Mean Deviation (n ¼ 26)

Part Correlation Coefﬁcients (P Value)

R2 F (Sig. F) AL—IED MD—IED

NFL thickness—IED 0.83 21.5 (<0.001) - 0.745 (<0.001) BMO area—IED - - - - BMO eccentricity—IED - - - - BMO plane error—IED - - - - BMO depth—IED 0.61 5.98 (0.009) - 0.610 (0.003) BM bowing—IED 0.56 4.90 (0.018) - 0.554 (0.006) Choroidal thickness—IED - - - - IED, intereye difference.

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FIGURE 5. Bruch’s membrane opening disc margin correspondence and planarity of BMO. Bruch’s membrane opening points overlaid on en face images generated by summing the 3D OCT volumes in the axial direction. Red points indicate where the BMO is posterior (into the page) to reference plane, and green points indicate where the BMO is anterior (out of the page) to the reference plane.

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FIGURE 6. Bruch’s membrane opening shape measurements. (A) Bruch’s membrane opening area, (B) BMO eccentricity, and (C) mean BMO planarity, distributed by (i) group and versus (ii) age, (iii) axial length, and (iv) MD. Outliers in each group are marked by red circles in plots (i).

sectors were averaged, each sector extending from BMO to difference in the degree of glaucoma and axial length with the 1.75 mm from BMO. In Figure 9C, only the BM depth points intereye difference in the shape parameters, thus controlling between BMO and 0.25 mm from BMO were averaged by for large intersubject differences. We found that the dimension angular sectors. In both cases, BM depth is smaller in young and shape of BMO tended to change with axial length but not normal eyes compared to older normal and glaucomatous eyes, with age or degree of glaucoma. Peripapillary BM position was with a general pattern of smaller BM depth in the nasal region. associated with distance from BMO such that BM was more Figure 10 illustrates choroidal thickness at every point posterior closer to BMO. Large variability in BM depth was across the whole choroid for each subject. Compared to NFL noted between subjects; but within subjects, our analysis thickness or BM depth, there is a larger individual variability in revealed an association between degree of glaucoma and BM the magnitude and spatial pattern of choroidal thickness. There depth. Finally, choroidal thickness appeared to decrease with is, however, visible similarity between fellow eyes. The young normal group generally exhibited thicker choroid. age but not with the presence of glaucoma. In Figure 11, mean choroidal thickness, averaged over the In displaying images in en face view and NFL thickness, BM region between 0.25 and 1.75 mm from BMO, is plotted by depth, and choroid thickness color maps, we chose to use the group and against age, AL, and MD. In multiple regression with same size scale for all images rather than scaling the images to age, AL, and MD (Table 3), choroidal thickness was signiﬁcantly the same presentation size. Differences in scan size were due correlated with age, and within the age-matched group (50þ), to the axial length differences between the eyes, and a also with axial length. common scale allowed a truer, in-scale visual comparison, Figure 12 presents the sectoral analysis of choroidal including that of varying BMO size and level of BM stiffness thickness, similarly to Figure 9 for BM depth. In Figure 12, all among the subjects. groups display the thickest choroid in the superior or superior- In the sectoral analysis, the sectors were divided by angles nasal sector and the thinnest choroid in the inferior sector. measured with reference to the acquired image frame. A more anatomically consistent approach would be using the axis between the center of the BMO and fovea (foveal–BMO axis), DISCUSSION which aligns with the direction of the nerve ﬁber bundles.49 It In this study we have examined RNFL thickness, BMO shape, has been shown that there is intrasubject and intersubject BM planarity, and choroidal thickness in myopic subjects both variability in the correspondence between the acquired image with and without glaucoma. Most patients had asymmetric frame and the foveal–BMO axis43,50; using the foveal–BMO axis glaucoma, which allowed us to also compare the intereye in future studies will reduce the effect of individual variability

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FIGURE 7. Peripapillary BM depth. All depth maps are in scale and right-eye orientation. The BM depth is measured with respect to the BM reference plane at each point on BM.

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FIGURE 8. Bruch’s membrane opening and mean BM depth measurements. (A) Bruch’s membrane opening depth and (B) mean BM depth distributed by (i) group and versus (ii) age, (iii) axial length, and (iv) MD (C). Intereye differences of BMO depth and BM depth are also plotted versus intereye MD difference. Outliers in each group are marked by red circles in plots (i).

FIGURE 9. Bruch’s membrane depth sectoral analysis. (A) Sectorized group averages of Bruch’s membrane (BM) surface depth. The color in each sector indicates the mean absolute magnitude of the normal distance between BM and its ﬁtted plane. Elliptical annuli are drawn at 0.25, 0.75, 1.25, and 1.75 mm from Bruch’s membrane opening (BMO). The annuli are divided into 608 angular sectors of superior (S), nasal (N), inferior (I), and temporal (T), and 308 angular sectors of superior-nasal (SN), inferior-nasal (IN), inferior-temporal (IT), and superior-temporal (ST). (B) Average BM depth by angular sector for the whole BM surface. (C) Average BM depth by angular sector for the inner annulus only (0–0.25 mm distance from BMO).

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FIGURE 10. Peripapillary choroidal thickness. All thickness color maps are in scale and right-eye orientation. The region inside and within 0.25 mm from Bruch’s membrane opening (BMO) was excluded.

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FIGURE 11. Choroidal thickness measurements. Choroidal thickness distributed by (i) group, and versus (ii) age, (iii) axial length, and (iv) MD.

and result in more anatomically equivalent and comparable laminar position, decreased contrast of neuroretinal rim sectors across multiple individuals. tissues, and peripapillary degenerative changes can make The eyes that were grouped as ‘‘suspect’’ in this study were preperimetric glaucoma detection more difficult. Optical the normal-appearing fellow eyes of subjects with glaucoma. coherence tomograpy imaging of the NFL can be particularly No reference to OCT imaging was made during diagnosis. beneficial in these patients. Outliers in the dataset were included in the scatter plots but As expected, we observed decreasing NFL thickness in excluded from the multivariate regression analyses. The most subjects with glaucoma and significant negative correlations extreme example was a glaucomatous eye with axial length of between NFL thickness and severity of glaucoma quantified by 31.3 mm, which was also a full millimeter longer than that of MD (Fig. 4; Table 3). These findings agree with a large body of its fellow (glaucomatous) eye. At such extreme axial lengths of research on NFL in glaucoma51–54 and provided an internal pathologic myopia, different mechanisms may be at play than control for imaging, segmentation, and analysis method in our generally seen in the rest of the dataset. With the exception of study. Among the studies on NFL thickness of normal myopic this eye, our axial lengths were between 24 and 30 mm, and subjects, Bendschneider et al.54 and Budenz et al.55 found the results are applicable only to this range. significant correlations in NFL thickness with both age and axial length, whereas Leung et al.56 and Rauscher et al.57 Nerve Fiber Layer Thickness reported no correlation with age but with axial length. In age- matched studies, several groups24–26 reported significant In nonmyopic eyes, characteristic ONH features are more correlation between NFL thickness and axial length, while apparent. In myopic eyes, however, the myopic tilt, shallow the last saw large variability in the correlation depending on

FIGURE 12. Choroidal thickness sectoral analysis. (A) Sectorized peripapillary choroidal thickness. Elliptical annuli are drawn at 0.25, 0.75, 1.25, and 1.75 mm from Bruch’s membrane opening (BMO). The annuli are divided into 608 angular sectors of superior (S), nasal (N), inferior (I), and temporal (T), and 308 angular sectors of superior-nasal (SN), inferior-nasal (IN), inferior-temporal (IT), and superior-temporal (ST). (B) Average choroidal thickness by angular sector.

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the quadrant, with the inferior quadrant showing the highest relationship was seen between glaucoma severity (as measured correlation and the temporal quadrant showing the weakest by MD) and BMO shape, which agrees with previous correlation. Hoh et al.58 found no significant correlation studies.71,72 The change in BMO shape associated with longer between NFL thickness and axial length among 132 young axial length in this study may be a ramification of global males. Our measurement of NFL thickness was not correlated structural change in myopia, including elongation of the eye with age or axial length. The varying results of previous studies due to growth and remodeling mechanism driven by visual possibly indicate that age and axial length, compared to MD, error signal. are more subtle and easily confounded factors; and the small sample size and presence of glaucoma patients in this study Peripapillary Bruch’s Membrane Shape likely made it difficult to detect meaningful influence by age or axial length. All eyes showed increasing posterior deformation of BM with increasing proximity to BMO (Figs. 7, 9B). Within the same Bruch’s Membrane Opening Shape subject, there appeared to be a good intereye correspondence in the degree of posterior deformation. In BMO depth and We quantified BMO shape by three parameters: area, eccen- mean BM depth, no significant group difference was observed tricity, and planarity. Figure 5 illustrates the large variability in between the nonglaucomatous and glaucomatous eyes (Figs. BMO shape between myopic patients with and without 8A, 8A). However, a significant correlation existed between the glaucoma. The figure also demonstrates the large variability intereye differences of BMO depth and mean BM depth with in the correspondence between the clinical disc margin and the intereye MD difference (Fig. 8C; Table 4), suggesting that BMO between myopic patients, again with and without when intersubject variance is partitioned, greater BMO depth glaucoma. This supports an increasing body of evidence that and BM depth are associated with a greater degree of the clinical disc margin is clinically heterogeneous, even within glaucomatous damage. Similar change was also observed in a an individual eye,42,43,59–63 and suggests that similar issues also longitudinal study of experimental glaucoma in NHPs.45 These exist in myopes. data are illustrated in a sectoral analysis in Figure 9, which We observed larger BMO area with increasing axial length presents, with small but consistent associations with the (Fig. 6A; Table 3). This finding is not artifactual since the pixel presence of glaucoma, a visible BM depth increase with age. dimension was corrected for axial length, and it is consistent The statistical significance of the group mean difference with previous studies showing increasing disc area with between the young normal (n ¼ 5) and older normal subjects increasing axial length.64–66 We also noted a small but (n ¼ 5) was 0.084 with the right eyes and 0.037 with the left significant (P < 0.05) negative correlation between age and eyes, suggesting a relationship that would possibly be more BMO size. This may represent type I error in our population apparent with a larger dataset. Taken together, the results and needs to be further investigated. However, if confirmed, suggest that in the myopic subjects under study, despite the we speculate that this could reflect the presumed greater large intersubject variability in BM position, there is an compliance of younger tissues, resulting in outward expansion association of BM depth with age and a smaller but consistent of BMO as seen in nonhuman primate (NHP) experimental association with degree of glaucoma. Axial length was also glaucoma.3,67–69 Bruch’s membrane opening eccentricity correlated with BM depth among the older, age-matched increased with increasing axial length; that is, as axial length normal and glaucoma subset of the data. The exact shape and increased, the BMO tended away from a circular to a more regional pattern of this deviation requires further investigation elliptical shape (Fig. 6B; Table 3). Regarding the orientation of to analyze the slope, change of slope (bending/bowing), and the BMO ellipse, or the direction of its major axis, 61%, or 32 differences and similarities in the effect of myopia and effect of out of a total 52 BMOs, were oriented in the nasal-temporal glaucoma. We are currently using a combined surface and direction; 23%, or 12 BMOs, were oriented in the superior- volume registration technique to further characterize these nasal–inferior-temporal direction. Seven BMOs were oriented differences.73 in the superior-temporal–inferior-nasal direction, and only 1 The increase in BM depth may be a direct mechanical result BMO was oriented in the superior-inferior direction. This of increased IOP or a secondary deformation resulting from pattern can be seen in Figure 5. Bruch’s membrane opening tissue remodeling of deeper structures, such as the lamina planarity (by which we measure how much BMO deviates from cribrosa and peripapillary sclera, in a complex interplay of a plane) also appeared to increase slightly with axial length aging, myopia, and glaucoma. The peripapillary sclera was (Fig. 6C; Table 3). Bruch’s membrane opening planarity can be shown to become posteriorly deformed and displaced in early related to a small but consistent saddle configuration of BMO glaucomatous monkey ONH,17 and the peripapillary scleral we observed (Fig. 5). In this saddle configuration, BMO tended thickness near the scleral canal and optic nerve meninges was to be posteriorly displaced along its long axis and anteriorly shown to decrease significantly with increasing axial length.74 displaced along its short axis. Furthermore, BMO planarity was Posterior cupping of the lamina cribrosa (LC) and posterior indeed correlated with BMO eccentricity (Pearson correlation migration of the laminar insertion in the connective tissue ¼ 0.613, P ¼ 0.001), such that a more elliptical BMO was remodeling in response to elevated IOP in glaucoma14,17,75 correlated to more deviation from a plane. It should be noted may also influence posterior deformation of BM. Ocular this BMO saddling is small in magnitude (~0.03 mm on elongation and IOP both influence ONH remodeling, and it is average) relative to the length of BMO (~1 mm on average), an important challenge to understand the combined impact and BMO is still a relatively planar structure. We are unsure and mechanism, particularly in the context of higher glaucoma whether the BMO saddling is a feature unique to myopes, how susceptibility among people with advanced myopia. it reflects underlying stresses and strains on BM, or whether it Myopia, especially high myopia, has been a complicating corresponds to local variability in deep ONH morphology such factor in glaucoma in that it is associated with structural as the recently reported horizontal laminar ridge.70 We are changes in the peripapillary region. Optic disc area and area of currently analyzing the 3D morphology of BM in more detail in the peripapillary region with chorioretinal atrophy were a greater number of subjects and hope to investigate these correlated with degree of myopia along with disc elonga- questions in future studies. tion,64,76–80 and the LC was shown to be thinner in highly In summary, BMO appeared to become larger, more myopic eyes than in nonhighly myopic eyes.81 In highly elliptical, and less planar with increasing axial length. No myopic glaucomatous eyes, compared to nonhighly myopic

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glaucomatous eyes, optic disc area, elongation, cup length, and 2. Quigley HA, Addicks EM, Green WR, Maumenee AE. Optic peripapillary atrophy were significantly larger,32,33 LC was nerve damage in human glaucoma. II. The site of injury and thinner,81 and rim loss was greater.31 In our study of myopic susceptibility to damage. Arch Ophthalmol. 1981;99:635–649. glaucomatous subjects, we aimed to observe, in relation to 3. Bellezza AJ, Rintalan CJ, Thompson HW, Downs JC, Hart RT, myopia and glaucoma, not only the changes in RNFL but also Burgoyne CF. Deformation of the lamina cribrosa and anterior their effect on Bruch’s membrane and the opening. These are scleral canal wall in early experimental glaucoma. Invest relatively robust structures not directly subject to glaucoma- Ophthalmol Vis Sci. 2003;44:623–637. tous atrophy, and thus better indicators of mechanical or 4. Minckler DS, Bunt AH, Johanson GW. Orthograde and pressure-related deformation associated with both myopia and retrograde axoplasmic transport during acute ocular hyper- glaucoma. A recent study by Johnstone et al.82 suggests tension in the monkey. Invest Ophthalmol Vis Sci. 1977;16: posterior migration of BMO with age in relation to age-related 426–441. choroidal thinning. This questions the appropriateness of the 5. Quigley HA, Anderson DR. The dynamics and location of BMO as a reference structure in shape measurement. However, axonal transport blockade by acute intraocular pressure in establishing the reference plane in this study, we used BM elevation in primate optic nerve. Invest Ophthalmol Vis Sci. points 2 mm outward from the BMO centroid.45 A typical 1976;15:606–616. model of ONH deformation in glaucoma, originating from the 6. Cioffi GA. Ischemic model of optic nerve injury. 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The optic nerve head in glaucoma: role of increased age, and also with axial length among older, age- astrocytes in tissue remodeling. Prog Retin Eye Res. 2000;19: matched subjects (Table 3). Mean deviation was not a 297–321. significant factor in choroidal thickness. These results are in 10. Wang B, Nevins JE, Nadler Z, et al. In vivo lamina cribrosa agreement with several studies that have reported macular micro-architecture in healthy and glaucomatous eyes as 83 84 choroidal thinning with both age and high myopia. Maul et assessed by optical coherence tomography. Invest Ophthal- 85 al. found that peripapillary choroidal thickness was associ- mol Vis Sci. 2013;54:8270–8274. ated with age, axial length, central corneal thickness, and also 11. Roberts MD, Sigal IA, Liang Y, Burgoyne CF, Downs JC. diastolic ocular profusion pressure in glaucoma suspects and Changes in the biomechanical response of the optic nerve patients. In recent studies, choroidal thickness was not head in early experimental glaucoma. Invest Ophthalmol Vis 85–87 correlated with glaucomatous damage. In our sectoral Sci. 2010;51:5675–5684. analysis (Fig. 12), we observed a regional pattern of the 12. Roberts MD, Grau V, Grimm J, et al. Remodeling of the thickest choroid at superior or superior-nasal region and the connective tissue microarchitecture of the lamina cribrosa in thinnest in inferior region. early experimental glaucoma. Invest Ophthalmol Vis Sci. 2008;50:681–690. 13. Grytz R, Sigal IA, Ruberti JW, Meschke G, Downs JC. Lamina CONCLUSIONS cribrosa thickening in early glaucoma predicted by a We have demonstrated a computational pipeline for shape microstructure motivated growth and remodeling approach. analysis in normal and glaucomatous myopic eyes. We found Mech Mater. 2012;44:99–109. that in myopes with axial lengths between 24 and 30 mm, 14. Downs CJ, Roberts MD, Sigal IA. Glaucomatous cupping of the increasing axial length was associated with deviation from a lamina cribrosa: a review of the evidence for active circular, planar BMO, but BMO shape was not associated with progressive remodeling as a mechanism. Exp Eye Res. 2011; age or functional glaucomatous damage. Posterior deformation 93:133–140. of the peripapillary BM was seen in all myopes, although highly 15. Grytz R, Girkin CA, Libertiaux V, Downs JC. Perspectives on variable between subjects, and associated with the degree of biomechanical growth and remodeling mechanisms in glau- functional glaucomatous damage. coma. Mech Res Commun. 2012;42:92–106. 16. Downs JC, Suh JKF, Thomas KA, Bellezza AJ, Hart RT, Acknowledgments Burgoyne CF. Viscoelastic material properties of the peripapillary sclera in normal and early glaucoma monkey eyes. Invest Supported by Canadian Institutes of Health Research (CIHR), Ophthalmol Vis Sci. 2005;46:540–546. Natural Sciences and Engineering Research Council of Canada 17. Yang H, Downs JC, Girkin C, et al. 3-D histomorphometry of (NSERC), and Michael Smith Foundation for Health Research the normal and early glaucomatous monkey optic nerve head: (MSFHR). lamina cribrosa and peripapillary scleral position and thick- Disclosure: S. Lee, None; S.X. Han, None; M. Young, None; M.F. ness. Invest Ophthalmol Vis Sci. 2007;48:4597–4607. Beg, None; M.V. Sarunic, None; P.J. Mackenzie, None 18. Downs JC, Yang H, Girkin C, et al. Three-dimensional histomorphometry of the normal and early glaucomatous References monkey optic nerve head: neural canal and subarachnoid space architecture. Invest Ophthalmol Vis Sci. 2007;48:3195– 1. Quigley HA, Hohman RM, Addicks EM, Massof RW, Green WR. 3208. Morphological changes in the lamina cribrosa correlated with 19. Mitchell P, Hourihan F, Sandbach J, Wang JJ. The relationship neural loss in open-angle glaucoma. Am J Ophthalmol. 1983; between glaucoma and myopia. 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