Effects of Myopia and Glaucoma on the Neural Canal and Lamina Cribrosa Using Optical Coherence Tomography : Journal of Glaucoma

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Advances in Glaucoma: Original Studies

Effects of Myopia and Glaucoma on the Neural Canal and Lamina Cribrosa Using Optical Coherence Tomography

Lee, Sieun PhD*,†; Heisler, Morgan PhD*; Ratra, Dhanashree MS, DNB, FRCSEd; Ratra, Vineet DNB, FRCSEd; Mackenzie, Paul J. MD, PhD§; Sarunic, Marinko V. PhD*; Beg, Mirza Faisal PhD*

Author Information
Journal of Glaucoma 32(1):p 48-56, January 2023. | DOI: 10.1097/IJG.0000000000002107
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Abstract

Glaucoma is a leading cause of blindness in the world and a multi-factorial group of diseases involving progressive damage to the retinal ganglion cells and axons, resulting in irrevocable vision loss. Although the etiology and mechanism of glaucoma are not yet fully understood, elevated intraocular pressure (IOP) is an important risk factor and treatment target. In experimental and clinical studies,1–3 lamina cribrosa (LC) in the optic nerve head (ONH) has been shown as the main site of retinal ganglion cells axonal damage in early glaucoma; the IOP-related deformation, remodeling, and mechanical failure of the ONH connective tissues are proposed as the defining pathophysiology of the disease.4–6 These alterations include posterior laminar deformation,7,8 scleral canal expansion,8,9 posterior migration of anterior laminar insertion (ALI),10,11 laminar thickness change,7,12 and posterior bowing of the peripapillary sclera.2 The biomechanical paradigm suggests that the response of an individual ONH to a given level of IOP depends on its structural factors, affecting the disease susceptibility, occurrence, and progression.

In myopia, the eye elongates in the anterior-posterior (axial) direction, causing poor focus in distance vision. The myopic elongation, particularly in high myopia, affects the ONH structure.13–17 In the standard glaucoma examination of the ONH and peripapillary region using ophthalmoscopy and optical coherence tomography (OCT), myopia can confound the assessment with shallow cupping, pallor in the neuroretinal rim, and retinal nerve fiber layer thinning.18–20 Furthermore, high myopia has been associated with increased susceptibility to glaucoma in several population-based studies.21–23 These findings suggest that myopic deformation of the ONH structure may affect the biomechanism of glaucoma development and progression.

OCT has now become a standard technology in ophthalmic clinics, providing high resolution and cross-sectional 3D images of the retina. Compared with a conventional spectral domain OCT, a swept-source OCT (SS-OCT) with a 1060-nm wavelength source allows for visualization of deeper structures in the ONH. Using SS-OCT, we have previously published on the morphologic characteristics of the ONH and peripapillary region in myopic normal and glaucomatous subjects.24–26 We showed that axial length was a significant factor in the shape of Bruch’s membrane opening (BMO) and the degree of posterior bowing of the peripapillary BM. In the present retrospective pilot study, we extend the investigation to the prelaminar neural canal between BMO and ALI and anterior lamina cribrosa morphology in healthy and glaucomatous myopic subjects to further examine the structural effects of axial length and glaucoma in the ONH.

MATERIALS AND METHODS

Participants

The study was conducted in accordance with the Declaration of Helsinki and approved by the institutional research ethics boards of Simon Fraser University and University of British Columbia (UBC). Myopic participants with and without glaucoma were included after a full clinical examination by a fellowship-trained glaucoma specialist (P.J.M.), including dilated stereoscopic imaging, IOP measurement using Goldmann applanation tonometer, and reproducible Humphrey SITA-Standard white-on-white visual field. Myopic participants were identified as those with an axial length of 2 mm or longer.25 Axial length was measured using Zeiss IOLMaster (Carl Zeiss Meditec, Jena, Germany). We note that throughout the study, from participant recruitment to data collection and analysis, only axial length and not refractive error was considered as a measure of myopic severity. This was because the study concerns the structure and biomechanics of the optic nerve head in myopia and glaucoma, and axial length is a more direct measure of structural elongation from myopia than visual acuity.

The glaucomatous eyes included in the study met the following criteria: i) evidence of optic disk neural rim loss on clinical examination; ii) evidence of peripapillary NFL loss on spectral domain optical coherence tomography (SD-OCT); iii) glaucomatous visual field defect with an abnormal pattern SD (P<05); iv) stable SD-OCT, visual field, and optic disk clinical examination for 6 or more months. The glaucoma patients received regular treatment by a single glaucoma specialist (P.J.M.). The nonglaucomatous eyes included in the study showed no evidence of retinal or optic nerve pathology. From both groups, eyes were excluded based on the following criteria: i) retinal diseases or optic neuropathy other than primary open angle glaucoma, including myopic degeneration; ii) IOP lower than 10 mm Hg or greater than 20 mm Hg; iii) ocular media opacities; iv) any surgery-related complication that the investigators determined inappropriate for the study.

Image Acquisition and Processing

The participants were imaged at the Eye Care Centre, Vancouver General Hospital, using a custom swept-source optical coherence tomography (SS-OCT) system with a 1060-nm light source, built by Biomedical Optics Research Group at Simon Fraser University.25,27 The system had 100 KHz A-scan rate and 1.6 second imaging time with improved visualization of deeper ONH structures compared with conventional 800-nm range commercial OCT systems. The acquired volumetric images consisted of 400 B-scans with voxel dimension of 1024×400. The axial resolution was 2.8 µm and the lateral resolution was 11 to 20 µm, depending on the axial length of the eye. Axial motion correction and bounded variance smoothing was applied to improve the image quality.

Segmentation

Bruch’s membrane (BM), BMO, ALI, and anterior lamina cribrosa surface (ALCS) were segmented (Fig. 1A). BM was segmented automatically using a 3D graph-cut based method,25 and the result was examined and corrected for segmentation errors by trained raters. BMO, ALI, and ALCS were segmented manually using Amira (Thermo Fisher Scientific, MA) on 80 radial slices extracted from the OCT volume, intersecting at the approximate centre of BMO and equidistanced at 2.25 degrees.

F1
FIGURE 1:
Optic nerve head shape parameterization. A, Bruch’s membrane (red curve), Bruch’s membrane opening, red dot), prelaminar neural canal (yellow curve), ALIP (blue dots), and ALCS (pink dot). Bruch’s membrane is identified as the posterior boundary of the retina proper (bottom boundary of hyper-reflective retinal pigment epithelium). BMO is identified as the termination point of Bruch’s membrane at the optic nerve head. PNC is defined as a geometric approximation of the connective tissue passage through which the retinal ganglion cell axons pass between BMO and lamina cribrosa. ALIPs are identified as where the anterior surface of the lamina cribrosa meets the neural canal. ALCS is identified as the anterior boundary of lamina cribrosa, visible as a hyper-reflective structure that traverses the neural canal. B, BMO and ALIP centroids (white dot) and major and minor axes (white dotted line). C, PNC height (h), width (w), length (l), and angle (θ). D, ALCS depth (magenta arrows), ALIP centroid (white dot), ALCS deepest point (white asterisk), and off-center distance (white line). ALCS indicates anterior lamina cribrosa surface; ALIP, anterior laminar insertion points; BMO, Bruch’s membrane opening; PNC, Prelaminar neural canal.

Shape Parameterization

The prelaminar region was approximated as an oblique cylinder, open at the top by BMO, and closed at the bottom by ALCS, outlined by ALI. Parameters were defined to characterize the geometry of the cylinder and grouped into BMO and ALI parameters, prelaminar neural canal parameters, and ALCS parameters. BM plane was used as the reference, computed by principal component analysis on BM points at 2 mm away from BMO.

BMO and ALI

BMO and ALI were modeled as ellipses and measured for their sizes, lateral elongation, axial nonplanarity, and distance from BM (Fig. 1B). For geometrical analysis of BMO, an ellipse was fitted to the 160 segmented BMO points by computing the best-fit plane using principal component analysis and fitting an ellipse to the projection of the points on the plane using the minimum squared error criterion. The area, location of the centroid, and the major and minor axes were obtained from the BMO ellipse. BMO lateral elongation was characterized by eccentricity (ratio of the major and minor axes) and direction in the enface plane (angle between the BMO ellipse major axis and superior-inferior axis). BMO nonplanarity was calculated as the mean normal distance of the segmented BMO points to its own best-fit plane. This was also normalized to relative nonplanarity by dividing BMO nonplanarity by BMO area. BMO distance from BM was measured as the normal distance between the BM plane and BMO centroid. Same parameters were computed for ALI. The ellipse fitting approach mitigates the effects of heavy blood vessel shadowing in the ONH region and the resulting difficulty in segmenting BMO or ALI points in some slices.

Prelaminar Neural Canal

Prelaminar neural canal was measured for the dimension (length, height, and width) and direction (axial and lateral angles), and the difference between the anterior and posterior ends (expansion, bowing, and twist) as follows (Fig. 1C). First, canal axis was defined as the vector between the BMO centroid and ALIP centroid. Canal length was defined as the length of the vector, and the height and width as the lengths of the axial and lateral components of the vector. Canal angle was measured as the angle between the canal axis and the vertical (axial) axis of the image, and the enface canal direction was measured as the angle between the lateral component of the canal axis and the superior-inferior axis. The differences between the BMO and ALIP areas (posterior expansion), eccentricities, nonplanarity, and major axes (twist) were also measured.

ALCS

ALCS was measured for the degree of surface cupping (depth, curvature) and off-centeredness of the deepest point (Fig. 1D). The parameters were measured for the manual ALCS segmentation points and their least square-fit quadratic polynomial surface.

Mean ALCS depths were computed as the average normal distances from the ALI plane to the segmented points and to the fitted surface on a 0.01 mm grid. The mean depth was also normalized by dividing by the ALI area. For the fitted surface, mean curvature and the relative enface position of the ALCS minimum (defined as the deepest point on the surface) to the ALI centroid were measured.

Statistical Analysis

The nonglaucomatous and glaucomatous groups were compared using generalized estimation equation analysis, accounting for the inter-eye correlation and including age and axial length in the model to adjust for any confounding. The effects of age and axial length in the nonglaucomatous group and the effects of age, axial length, and visual field mean deviation (MD) in the glaucomatous group on the shape parameters were evaluated using a mixed effect model, with a random subject effect for the inter-eye correlation. SPSS 24 (IBM Corp. Released 2016. IBM, Armonk, NY) and SAS (SAS Institute Inc., Cary, NC) were used for the analysis.

RESULTS

The characteristics of the study population are listed in Table 1. There was a significant difference in the age and visual field mean deviation (MD) between the nonglaucomatous and glaucomatous groups.

TABLE 1 - Participant Summary Number of Subjects, Number of Eyes, and mean±SD (minimum–maximum) Age, Axial Length, and Visual Field Index (Mean Deviation) of Nonglaucomatous and Glaucomatous Participants
Nonglaucomatous Glaucomatous P
Number of Subjects 19 (10 females) 38 (15 females)
Number of Eyes 38 63
Age 37.3±13.9 (20–61) 61.2±12.5 (30–84) <0.001
Axial Length (mm) 25.1±1.42 (23.1–28.42) 25.9±1.78 (22.5–31.28)
Mean deviation (dB) −0.91±1.00 (−0.06–0.97) −11.9±8.82 (−33.6–0.83) <0.001

The mean results for BMO, ALI, prelaminar neural canal (PNC) and ALCS for nonglaucomatous and glaucomatous eyes are shown in Table 2.

TABLE 2 - Mean Measurements of Bruch’s Membrane Opening (BMO), Anterior Laminar Insertion Point (ALI) Ellipse, Prelaminar Neural canal (PNC), and Anterior Laminar Surface (ALCS) for Healthy and Glaucomatous eyes
Non-glaucomatous Glaucomatous P
BMO
 Area (mm2) 2.29±0.83 2.26±0.62
 Eccentricity 1.13±0.09 1.14±0.07
 Nonplanarity (µm) 8.18±3.51 9.67±3.73 0.026
 Centroid distance from BM (mm) 0.116±0.055 0.137±0.042
 Axis angle (°) 64.7±20.2 77.9±20.3
ALI
 Area (mm2) 2.97±0.83 2.86±0.67
 Eccentricity 1.13±0.05 1.15±0.08 0.037
 Nonplanarity (µm) 25.5±7.56 28.7±10.1
 Centroid distance from BM (mm) 0.395±0.059 0.447±0.132
 Axis angle (°) 66.4±24.2 87.1±47.1 0.029
PNC
 Canal height (mm) 0.247±0.061 0.194±0.059
 Canal width (mm) 0.275±0.186 0.391±0.246
 Canal length (mm) 0.394±0.175 0.480±0.224
Canal angle (°) 43.2±18.9 54.4±21.0
 BMO-ALI angle (°) 74.5±27.4 73.4±14.6
ALCS
 ALCS depth (mm, seg points) 0.109±0.046 0.143±0.048 <0.001*
 Relative ALCS depth (mm-1, seg points) 0.040±0.023 0.050±0.019 0.003
 ALCS depth (mm) (fitted surface) 0.096±0.043 0.131±0.050 <0.001*
 ALCS mean principal curvature (mm-1) 0.325±0.164 0.381±0.112 0.001
 ALCS minimum-ALI centroid Dist. (%) 6.51±3.68 7.10±3.30
*P<0.001.

Significant P-values (<.05) from the general linear models of the measurements with age and axial length (AL) as predictors for nonglaucomatous eyes and with age, AL, and visual field index (MD) are shown in Table 3.

TABLE 3 - Significant P-values from General Linear Models of Bruch’s Membrane Opening (BMO), Anterior Laminar Insertion (ALI), Prelaminar Neural canal (PNC), and Anterior Laminar Surface (ALCS) Measurements with Age, Axial Length (AL), and Visual Field Index (MD) as Predictors of Nonglaucomatous and Glaucomatous Eyes. Red Indicates the Predictor was Negatively Associated with the Variable
Non-glaucomatous Glaucomatous
Age AL Age AL MD
BMO
 Area (mm2) 0.008* 0.003*
 Eccentricity 0.010 0.018
 Nonplanarity (µm) 00.039
 Centroid distance from BM (mm) 0.018 0.004
 Axis angle (°) 0.009*
ALI
 Area (mm2) 0.014 0.011
 Eccentricity
 Nonplanarity (µm)
 Centroid distance from BM (mm) 0.030 <0.001*
 Axis angle (°)
PNC
 Canal height (mm) 0.004*
 Canal width (mm) <0.001* 0.025
 Canal length (mm) <0.001* 0.025
 Canal angle (°) <0.001*
 BMO-ALI angle (°) 0.036
ALCS
 ALCS depth (mm, points) 0.037 0.002*
 Relative ALCS depth (mm-1, points) 0.011 0.005* <0.001*
 ALCS depth (mm) (fitted surface) 0.047
 ALCS mean principal curvature (mm-1) 0.002*
 ALCS minimum-ALI centroid Dist. (%)
*P<0.001.

Bruch’s Membrane Opening and Anterior Laminar Insertion

BMO area and eccentricity were not significantly different between the nonglaucomatous and glaucomatous eyes (Table 2), but the longer axial length was associated with a larger and more elliptical BMO in both groups (Table 3). Compared with BMO, ALI area was larger and similarly associated with longer axial length in both nonglaucomatous and glaucomatous eyes (Table 3).

BMO and ALI nonplanarity is visualized for a representative eye in Figure 2. On the right side, the normal distance of the BMO and ALI points are plotted in reference to their own best-fit planes, starting from the temporal axis and progressing in the clockwise direction. The plot shows BMO and ALI shape in the axial direction, with nasal-temporal ends being the most anterior and inferior-superior ends being the most posterior. The enface views on the left side of the figure show the points anterior (green) and posterior (red) to the reference planes. The enface images also demonstrate the long ends of the BMO and ALI being more anterior than the short ends. The nonplanarity in ALI was in general greater than in BMO, following a similar pattern but with some rotation in the enface axis angle. Figure 3 shows the BMO and ALI nonplanarity plotted for all eyes in nonglaucomatous and glaucomatous groups. Between the 2 groups, BMO nonplanarity was significantly greater in the glaucoma eyes (Table 2) and associated with glaucoma severity (Table 3).

F2
FIGURE 2:
BMO and ALI nonplanarity Right: The normal distance of the BMO and ALI point their own best-fit planes are plotted, starting from the temporal axis and progressing in the clockwise direction. The plot shows BMO and ALI shape in the axial direction, with nasal-temporal ends being the most anterior and inferior-superior ends being the most posterior. Left: The enface views show the points anterior (green) and posterior (red) to the reference planes. The enface images also demonstrate the long ends of the BMO and ALI being more anterior than the short ends. The nonplanarity in ALI is in general greater than in BMO, following a similar pattern but with some rotation in the enface axis angle.ALI indicates anterior laminar insertion; BMO, Bruch’s membrane opening.
F3
FIGURE 3:
Bruch’s membrane opening (BMO) points (top) and anterior laminar insertion points (bottom) in reference to the best-fit plane for nonglaucomatous and glaucomatous eyes. Each point represents a manual segmentation point and each color represents measurements from an individual eye. Between the 2 groups, BMO nonplanarity was significantly greater in the glaucoma eyes and associated with glaucoma severity. BMO indicates Bruch’s membrane opening.

The distance of the BMO centroid from BM plane in the posterior direction, which can be contributed by both deformation and displacement of BMO, was negatively associated with axial length in nonglaucomatous eyes and positively associated with glaucoma severity in glaucomatous eyes (Table 3). The distance of the ALI centroid from BM plane was significantly greater in the glaucomatous eyes (Table 2), and positively associated with both axial length and glaucoma severity (Table 3).

Table 4A shows the frequency of BMO axis direction, grouped in 6 sectors with equal angles with reference to superior (S), inferior (I), nasal (N), and temporal (T) orientations. In both groups, BMO axis most frequently lay in the nasal-superior-nasal to nasal sectors. This directionality corresponds with the BMO bowing, and shows that BMO tends to be the most anterior on its longest ends (NSN-TIT to N-T) and most posterior on its shortest ends (IIN-SST to S-I). More BMO axes were in the nasal-temporal sectors for the glaucomatous eyes. BMO axis direction was associated with increased axial length (Table 3), suggesting BMO axis rotation is influenced by both myopia and glaucoma, and BMO nonplanarity and axis rotation may be related to glaucoma.

TABLE 4 - Frequencies of A) Bruch’s Membrane Opening (BMO) axis Directions, B) Anterior Laminar Insertion (ALI) Axis Directions, C) BMO-to-ALI Direction, and D) Anterior Laminar Surface Minimum Location
A. BMO Axial Direction S-I SSN-IIT NSN-TIT N-T NIN-STS IIN-SST
 Nonglaucomatous (n=38) 2 8 16 10 1 1
 Glaucomatous (n=63) 2 8 18 26 6 3
B. ALI Axial direction S-I SSN-IIT NSN-TIT N-T NIN-STS IIN-SST
 Nonglaucomatous (n=38) 2 4 18 12 1 1
 Glaucomatous (n=63) 9 8 13 18 7 9
C. BMO-to-ALI direction S SN N IN I IT T ST
 Nonglaucomatous (n=38) 1 11 18 1 0 3 1 3
 Glaucomatous (n=63) 3 18 34 1 1 2 0 4
D. ALS minimum location S SN N IN I IT T ST
 Nonglaucomatous (n=38) 7 15 7 1 2 3 4 2
 Glaucomatous (n=63) 17 27 8 0 2 0 4 8

Table 4B shows the frequency of ALI axis direction. As in BMO, the ALI axis also mainly lies in the nasal-superior-nasal to nasal sectors, corresponding to the ALI nonplanarity pattern. There was overall greater variability in the ALI axis of glaucomatous eyes and a larger mean axis angle (Table 2).

Prelaminar Neural Canal

In the nonglaucomatous eyes, prelaminar neural canal (PNC) was longer and more skewed with longer axial length. In the glaucomatous eyes, longer axial length was associated with a more skewed canal, and greater glaucoma severity was associated with a longer canal, likely because of the posterior cupping and displacement of ALI. Glaucoma severity was also associated with a decrease in the BMO-ALIP axis angle difference (Table 3), possibly reflecting the apparent glaucomatous rotation of BMO axis angle toward the nasal-temporal axis (Table 4A). Table 4C shows the frequency of BMO-to-ALI direction.

Anterior Laminar Surface

Anterior laminar surface (ALCS) was significantly deeper in the glaucomatous eyes (Table 2) and ALCS depth positively correlated with glaucoma severity (Table 3). However, in both nonglaucomatous and glaucomatous eyes, axial length was negatively correlated with ALCS depth. In nonglaucomatous eyes, longer axial length was significantly associated with less ALCS curvature of the fitted surface.

Table 4D shows the frequency of the location of the ALCS surface minimum. In both groups, ALCS minimum was mainly located in the superior, superior-nasal, and nasal sectors, corresponding to the directions of BMO and ALI elongation and the prelaminar neural canal.

DISCUSSION

Development of myopia typically begins between age 6 and 14, and the progression stops or slows at the end of adolescence as the general physical growth ends.28,29 The axial elongation of the eye during this process affects the structure of the optic nerve head (ONH). On the other hand, most common adult glaucoma occurs in mid-to-late adulthood, with intraocular pressure (IOP)-related deformation and remodeling of the ONH playing a key role in the pathophysiology. Myopia has been associated with increased susceptibility to glaucoma in several population studies,21–23 and the relationship between myopia and glaucoma involves the myopic ONH structure, the response of the myopic ONH to aging and IOP elevation, and how these affect the onset and progression of glaucoma.

Literature on Myopia and Optic Nerve Head

Optic disk Early histologic studies found that optic disks were larger and more oval in highly myopic eyes.13,30 Recent in vivo studies showed increasing axial length was associated with oblique or skewed insertion of the optic nerve into the globe31 in fundus photography32,33 and 3D optical coherence tomography (OCT).17,34,35 The resulting rotation of the major axis of the optic disk in the enface plane (optic disk torsion) has been associated with the location of visual field defects in glaucoma patients.33,36 A caveat is that the usage of the terms such as optic disk tilt, ovality, torsion, and skew have varied across the literature, especially between studies based on 2D fundus photographs and those based on 3D OCT. The correlation between the 2D and 3D measurements for the supposedly same anatomic measurements has been shown to be limited.35,37

Lamina cribrosa and sclera Lamina cribrosa (LC) was found to be significantly thinner in highly myopic eyes than in non-highly myopic eyes in both glaucoma and control groups, resulting in a shorter distance between the intraocular space and cerebrospinal fluid space and increased translaminar pressure gradient.12 The same experiment also showed that among highly myopic eyes, the presence of glaucoma was associated with thinner LC than in non-highly myopic eyes. Biomedical models of the sclera further associated myopia with scleral thinning,38,39 tissue loss,39 failure at a lower load,38 and an increase in small-diameter collagen fibrils.39

Literature on Myopia and Glaucoma

Among glaucoma patients, high myopia was identified as a significant risk factor for subsequent visual field loss,40,41 and in examination of glaucomatous optic nerve fiber loss using color stereo optic disk photographs, optic nerve damage was shown to be more significant in highly myopic eyes than in non-highly myopic eyes.42

RNFL thickness OCT-based measurement of peripapillary retinal nerve fiber layer (RNFL) thickness, a key measurement of glaucoma severity, was also shown to be thinner in healthy myopic subjects.19,43,44 However, because of the myopic expansion of the optic disk and Bruch’s membrane opening, RNFL thickness measurements based on the distance from the centre of the optic disk may be located closer to the BMO for myopic subjects than nonmyopic subjects.

Our Study

Summary

In this paper, we presented a comprehensive 3D shape characterization and analysis of the anterior laminar region in myopic eyes with and without glaucoma using images from a custom swept-source optical coherence tomography (SS-OCT) system with a 1060-nm light source. The myopic eyes were identified as those with an axial length of 24 mm or greater. The degree of myopia was considered only based on the axial length, and there was no specific grouping of ‘moderate’ or ‘high’ myopia. BMO, ALI, PNC, and ALCS were segmented from the images and analyzed for their relationships with age, axial length, and glaucoma severity. The age-adjusted results showed that the glaucomatous eyes had more bowed and nasally rotated BMO and ALI, more horizontally skewed PNC, and deeper ALCS than the nonglaucomatous eyes. General linear model analysis showed that increased axial length was a significant factor across the anterior laminar region, most notably with a wider, longer, and more horizontally skewed neural canal and a decrease in the ALCS depth and curvature. Such 3D evaluation of the ONH enhances the understanding of the peri-laminar structures and anatomy and can be a complementary tool to the conventional methods of assessment of glaucomatous or suspected glaucomatous eyes.

Serial SD-OCT scans in experimental glaucoma showed that changes in the deeper structures such as the laminar and prelaminar tissues precede other obvious glaucomatous changes such as thinning of the RNFL.45 The age-adjusted results showed that the glaucomatous eyes had more bowed and nasally rotated BMO and ALI, more horizontally skewed PNC, and deeper ALCS than the nonglaucomatous eyes, which may be a result of the increased intraocular pressure. On the anatomic parameterization, the authors noted that the neural canal opening plane was a valid reference point for assessing and quantifying the ONH parameters. Although the whole neural canal along with the LC may shift posteriorly because of glaucoma, the centroid of the neural canal opening remains stable. Sigler et al46 found that prelaminar canal depth, when measured from the BMO to ALCS, was positively correlated with peripapillary choroidal thickness, and this should be considered in modeling. Our study did not explicitly look at the extent of contribution of the peripapillary choroidal thickness to the neural canal length of depth. However, studies have demonstrated choroidal thinning in myopia47; and this would mean that the neural canal lengthening we observed in the myopic eyes were despite any associated choroidal thinning. We also note that our ALCS depth and curvature were defined using only the anterior laminar insertion points and anterior lamina cribrosa surface, without referencing Bruch’s membrane or BMO, to more accurately capture the shape of the ALCS.

Intraocular pressure (IOP) was not considered in the study because our aim was to investigate the axial length and glaucoma-severity-related structural deformation of the ONH independent of the IOP levels or treatment. These structural changes would have developed over several years of stress and strain, of which the effects would be more consistently observed in the ONH morphology than any by IOP, a more transient factor. We additionally note that 1 of the inclusion criteria for the glaucomatous subjects was stable SD-OCT, visual field, and optic disk clinical examination for 6 or more months, and these subjects were under standard care by a single glaucoma specialist.

The study was a retrospective pilot study, and the sample size was not calculated beforehand. Statistical analysis was performed using generalized estimating equations and linear mixed effect models to include both the left and right eyes of the same subject while accounting for the correlation between the fellow eyes. Calculating the sample size or effect size in such models is nontrivial and complex and subject to ongoing research.48 We have, however examined the effect and sample sizes of the same data for simpler statistical analysis. As an example, in the comparison of the ONH shape parameters between the nonglaucomatous and glaucomatous groups in Table 2, we used generalized estimating equations and included 38 eyes from 19 nonglaucomatous subjects and 63 eyes from 38 glaucomatous subjects. For comparing 2 means at a power of 0.8 and alpha of 0.05 using 2-sampled t test, the required sample size ranged from 20 to 140, and Cohen’s d ranged from 0.3 to 0.75 for the results in Table 2. We have included 101 eyes from 57 subjects, and some of the less clear results (0.01<P<0.05) may be underpowered or have a small effect size, but the results with P<0.01 likely have sufficient sample size and medium to large effect size.

Myopia & Glaucoma’s Effects in the ONH Structure-Compare & Contrast

Our study showed that myopia and glaucoma both affect the ONH structure; however, we note that their underlying mechanisms are fundamentally different. In myopia, the enlarged BMO and ALI areas suggest that the myopic axial elongation of the eye expands the optic neural canal, with force acting mainly along the scleral wall. In glaucoma, the intraocular pressure acting on the ONH has some laminar component but compared with the myopic expansion, it acts more in the axial direction. This simplified model can be useful for interpreting the current result of the ALCS depth being negatively associated with axial length but positively associated with glaucoma severity. In myopia, the enlarging of the canal pulls the LC taut, decreasing its curvature. This model is in line with previous studies in which myopic LC and sclera were shown to be thinner than in nonmyopic eyes.12,38,39 In glaucoma, the biomechanical model includes posterior bowing or “caving in” of the LC, and in our study the glaucomatous eyes indeed had deeper ALCS. Increased visual field deviation was also associated with deeper ALCS.

Another parameter affected by both myopia and glaucoma was the enface angle of the BMO and ALI axes, which were more horizontal (closer to the temporal-nasal axis) with both greater axial length and glaucoma severity. A myopic mechanism of the phenomenon may be that the myopic expansion of the prelaminar region and in extension scleral opening occurs at a greater degree in the temporal-nasal direction than in the superior-inferior direction. A glaucomatous mechanism of the same phenomenon may be that the intraocular pressure affects LC with regional variation.

So why are Myopes More Susceptible to Glaucomatous Damage?

An implication of our study is that the posterior bowing of the LC as a structural parameter of glaucoma severity can be significantly confounded by myopia, and that the myopic LC that is pulled taut, shallower, and thinner than nonmyopic eyes may be more vulnerable to mechanical failure and axonal damage inside the LC, despite the reduced global curvature. Previously, in an idealized, analytical microstructural model of the ONH, scleral canal eccentricity, LC stiffness, LC thickness, and eye radius were found to be important determinants of the stress and strain in the LC.49 Sawada et al51 reported that an increased neural canal angle, which correlated with a longer axial length in our study and a recent study by Jeoung et al50 was associated with a higher number of temporal LC defects, which in turn spatially corresponded with visual field defects in open angle glaucoma patients with myopia. The authors posited that the myopic elongation of the globe may lead to stretching of the LC in the temporal periphery, causing localized strain in the LC pores that may become torn and become larger pores that are susceptible to glaucomatous strain. Such myopic stretching in the temporal direction can also explain the BMO elongation direction we observed in the current study, in which longer axial length was associated with more elongated BMO and more nasal-temporally (horizontally) oriented BMO enface axis.

Age has been reported as a factor in LC deformation. In glaucomatous eyes with the same functional loss, older eyes presented shallower LC52 and less LC deformation51 than in younger eyes. This is likely related to the age-related decrease in the mechanical compliance of LC.53 In our study, age was not a significant factor in the shape parameters in either the nonglaucomatous or glaucomatous groups. This may be attributed to the limited sample size and age distribution and the effects of myopia and glaucoma being larger than that of age. However, myopic stretching of LC can result in the reduction of LC compliance, similarly with aging. Considering that aging and high myopia are 2 key risk factors in glaucoma, we may conjecture that independent of the degree of glaucomatous global LC deformation (cupping), reduced LC compliance itself, either from aging and/or myopic stretching, may be an important causal factor in the IOP-related axonal damage in glaucoma.

This can further relate to the connection between myopia and normal tension or low-pressure glaucoma. Studies have demonstrated that the association between myopia and glaucoma was stronger at lower IOP levels than higher IOP levels,54 and Sigler et al46 observed wider horizontal neural canal opening in the low-pressure glaucoma group compared with the normal or primary open angle glaucoma groups. In our study, similar horizontal torsion (T-N axis) and directed expansion of BMO and ALI were observed with increased axial length. These findings suggest that myopia causes characteristic structural deformation in the optic neural canal region, and this may create a risk factor, especially for a certain subtype of glaucoma related to the deformation and lower IOP range.

Finally, we note that although age, elevated IOP, and myopia are key risk factors of glaucoma, the pathogenesis of glaucoma is complex and likely involves several interlinked mechanisms such that these factors alone do not fully describe an individual’s risk of developing or progressing in glaucoma. Iglesia et al55 found no association between polygenetic risks of myopia and POAG, and the comorbidity of the 2 is likely not influenced by common genetic variants. However, epidemiological and experimental studies have found various associations with glaucoma in ocular perfusion pressure and blood flow,56 cerebrospinal fluid pressure,57 and systemic factors such as diabetes and hypertension.56 The question of why one with high myopia and at an older age may not develop glaucoma or which factors may play a protective role thus warrants further investigation with consideration of the complex, multi-domain causal mechanisms of glaucoma.

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Keywords:

glaucoma; myopia; optic nerve head morphometrics; swept-source optical coherence tomography

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.