OCT Optic Nerve Head Morphology in Myopia IV: Neural Canal Scleral Flange Remodeling in Highly Myopic Eyes

Anuwat Jiravarnsirikul; Hongli Yang; Jin Wook Jeoung; Seung Woo Hong; Jasmin Rezapour; Stuart Gardiner; Brad Fortune; Michaël JA Girard; Marcelo Nicolela; Linda Zangwill; Balwantray C Chauhan; Claude F Burgoyne

doi:10.1016/j.ajo.2024.01.023

. Author manuscript; available in PMC: 2025 May 1.

Published in final edited form as: Am J Ophthalmol. 2024 Feb 3;261:141–164. doi: 10.1016/j.ajo.2024.01.023

OCT Optic Nerve Head Morphology in Myopia IV: Neural Canal Scleral Flange Remodeling in Highly Myopic Eyes

Anuwat Jiravarnsirikul ^1,^2,^*, Hongli Yang ^1,^*, Jin Wook Jeoung ³, Seung Woo Hong ⁴, Jasmin Rezapour ^5,⁶, Stuart Gardiner ⁷, Brad Fortune ⁷, Michaël JA Girard ⁸, Marcelo Nicolela ⁹, Linda Zangwill ⁵, Balwantray C Chauhan ⁹, Claude F Burgoyne ¹

PMCID: PMC11031338 NIHMSID: NIHMS1964284 PMID: 38311154

Abstract

Purpose:

To compare the prevalence, location and magnitude of optic nerve head (ONH) OCT-detected, exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT) and exposed scleral flange (ESF) regions in 122 highly myopic (Hi-Myo) versus 362 non-highly myopic healthy (Non-Hi-Myo-Healthy) eyes.

Design:

Cross-sectional study

Methods:

After OCT radial B-scan, ONH imaging, Bruch’s membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented in each B-scan and projected to BMO reference plane. The direction and magnitude of BMO/ASCO offset and BMO/SFO offset as well as the location and magnitude of ENC, EOCBT and ESF regions, perineural canal (pNC) retinal nerve fiber layer thickness (RNFLT) and pNC choroidal thickness (CT) were calculated within 30° sectors relative to the Foveal-BMO (FoBMO) axis. Hi-ESF eyes were defined to be those with an ESF region ≥ 100 μms in at least one sector.

Results:

Hi-Myo eyes more frequently demonstrated Hi-ESF regions (87/122) than Non-Hi-myo-Healthy eyes (73/362) and contained significantly larger ENC, EOCBT, and ESF regions (p< 0.001) which were greatest in magnitude and prevalence within the inferior-temporal FoBMO sectors where Hi-Myo pNC-RNFLT and pNC-CT were thinnest. BMO/ASCO offset and the BMO/SFO offset were both significantly increased (p< 0.001) in the Hi-Myo eyes, with the latter demonstrating a greater increase.

Conclusions:

ENC region tissue remodeling that includes the scleral flange is enhanced in Hi-Myo compared to Non-Hi-Myo-Healthy eyes. Longitudinal studies are necessary to determine whether the presence of an ENC region influences ONH susceptibility to aging and/or glaucoma.

INTRODUCTION

The global prevalence of myopia is increasing with more than 5 billion individuals predicted to be “myopic” by the year 2050 of which 938 million will be “highly myopic”.¹ In myopia², elongation of the eye and/or refractive error changes are accompanied by structural alterations to the choroid, sclera, retina and optic nerve head (ONH) tissues that are referred to by clinical disc margin based terminology such as “optic disc” “tilt”, “torsion” and “peripapillary” “atrophy”.^3–6 These clinical terms, combined with refractive error and axial length, are used both to define myopia and assess its progression¹. Until recently^7–13 there have been no OCT parameterization strategies based entirely on OCT-detected anatomic landmarks to quantify and stage the morphologic character of myopic ONH structural alteration in a given eye. In their absence, the field has only recently begun to build an OCT-based conceptual framework for parameterizing longitudinal “myopic” ONH remodeling.^13–16

In recent publications,^11,12 we have introduced OCT-defined, ONH neural canal and peri-neural canal (pNC) tissue terminology (Figure 1) to identify and distinguish OCT ONH terminology, (which we argue should be based on OCT-detected anatomic landmarks) from the clinical terms “optic disc” and “peripapillary” because these terms, being based on clinical photographic and clinical biomicroscopic assignment of the clinical disc margin, have no consistent OCT-detectable anatomic foundation in the human eye.^17,18 Having no consistent anatomic foundation, the clinical disc margin is inconsistently assigned by clinicians^18–20 (Supplemental Figure 1). Because the clinical disc margin is commonly used in the definitions of “optic disc tilt” and “torsion” as well as the clinical “gamma” and “delta” zones, its use has also contributed to the lack of anatomically consistent OCT definitions for these terms.^3–6,21,22

We have previously defined^23,24 the ONH anatomically and morphologically (Figures 1 and 2 and Supplemental Figure 1) to include the tissues within the neural canal and those immediately adjacent to it.^11,12,23 The ONH tissues thus include not just the retinal ganglion cell (RGC) axons, their associated glia and vasculature and the lamina cribrosa (within the neural canal), but also the scleral flange^23–26, the pNC-sclera, choroid and retina, the immediate retrolaminar orbital optic nerve, the dural and pial sheath insertions and the medial portion of the inferior oblique muscle insertion (Supplemental Figure 1).

Figure 2. — (A1 – C1) Three OCT-radial B-scan from three representative eyes (FDA165 (A1) top, FDA261 (B1) middle, and Hi-Myo-GL-29, (C1) bottom). (A2 - C2) The scleral flange histologically refers to the peri-neural canal (pNC) sclera that is “central “or “internal” to the dural sheath insertion. The dural sheath adds substantial thickness to the outer layers of the posterior sclera. The potential thinness of the scleral flange relative to the adjacent posterior sclera may have important biomechanical implications on the flow of blood within the posterior ciliary arteries which pass through the scleral flange to achieve the juxta canalicular choroid as well as the lamina cribrosa. The anterior scleral canal opening (ASCO) is histologically defined to be the projection of the anterior scleral flange surface through the choroidal border tissues (CBT). The posterior scleral canal opening has been described histologically and using 3D histomorphometry (see Introduction) but is not consistently visualized in OCT imaging and is shown here for representation purposes only. For this study the scleral flange opening (SFO) was manually segmented either “geometrically” when identifiable (Panels B2 and C2, see Methods) or, when not geometrically identifiable, estimated visually by projecting the anterior laminar surface through the neural canal wall (Panel A2, see methods). (A3 – C3) Existing BMO and ASCO segmentations in combination with the segmented SFO points were used to define the externally oblique CBT (EOCBT) and Exposed Scleral Flange (ESF) which were parameterized within BMO reference plane as shown in Figure 5.

We define the neural canal to be the connective tissue pathway through the choroid and sclera through which the RGC axons achieve the orbital optic nerve (Figures 1 and 2 and Supplemental Figure 1).^{7,10,12,23,27} The pre-scleral neural canal extends from Bruch’s membrane opening, (BMO), through the anterior scleral canal opening, (ASCO) (Figure 1). It consists of the choroidal border tissues (CBT) which are known histologically as the border tissues of Elschnig.^27–29 The scleral portion of the neural canal extends from the ASCO through the scleral flange opening (SFO), (when present - see Methods and Figures 1–4), ending at the posterior scleral canal opening (PSCO) which can be identified histologically^23,30 but is, at present, only inconsistently visualized by OCT (Figure 2).

Figure 4. — (A1-F1) OCT prelaminar neural canal anatomy. (A2-F2) OCT B-scans from the locations denoted by a green line in panels A1-F1. (A3-F3) OCT ENC region anatomic landmarks. (A4-F4) Pertinent ENC region and EOCBT and ESF sub-region segmentations. We define an EOCBT region to be internal to BMO extending to the ASCO which defines the CBT insertion into the scleral flange. We define an ESF region to extend from the ASCO to the SFO and to be devoid of overlying choroid and/or Bruch’s membrane. (A1-A4) Study eye FDA124 does not demonstrate an ENC region because the CBTs are internally oblique in all ONH segments. ((A1)-(C4)) Panels A - C show three non-highly myopic eyes with their increasing ENC regions by radial and sectoral extent. The ENC region of each eye contains both EOCBT and ESF sub-regions. ((D1)-(F4)) Panel D - F show three highly myopic eyes with their increasing ENC regions by radial and sectoral extent, in which the ESF and/or EOCBT region is even further elongated. All eyes are shown in right eye orientation.

In previous 3D-histomorphometric monkey studies,^23,24 we defined the scleral flange to be the portion of the pNC-sclera that was “internal” to the PSCO (Figure 2.) In separate histologic studies in post-mortem human eyes,^25,26 Jonas defined the scleral flange to be the portion of the pNC-sclera that was “central “or “internal” to the dural sheath insertion. These independent definitions suggest two independent mechanisms of scleral flange development that may be synergistic. First, scleral flange morphology is influenced by transverse neural canal enlargement within the sclera, as has been previously reported in both monkey, (quantitatively)^23,24,31 and human (through qualitative inspection)^30,32,33 eyes. Second, scleral flange morphology is influenced by the insertion of the dural sheath into the pNC sclera which adds substantial thickness to the posterior sclera peripheral to the flange.^25,26

In our recent study,¹² we manually segmented BMO, the ASCO and the OCT-determined scleral flange opening (SFO), (when present), in 362 non-highly myopic healthy eyes, so as to report the prevalence, magnitude and Foveal-BMO (FoBMO) location of a new, OCT-defined, ONH region - the “exposed neural canal” (ENC) region (Figure 3). In that study we defined the ENC region to consist of two neural canal wall sub regions, an externally oblique choroidal border tissue (EOCBT) region and/or an exposed scleral flange (ESF) region (Figures 3 and 4). To our knowledge, that study was the first to detect and parameterize the ONH scleral flange tissues using OCT. Its findings included the substantial prevalence and magnitude of “myopic-appearing” ENC regions in non-highly myopic eyes, their common presence in the inferior temporal sectors and the inverse correlation between the FoBMO location of the ESF region and pNC-choroidal thickness (pNC-CT) within individual eyes.

Figure 3. — (A) Pre-scleral and scleral flange neural canal anatomy projected onto the fundus photo of study eye Hi-Myo-GL-29, (also shown in Figure 1). Here the OCT ENC region is longest temporally, and extends from Bruch’s membrane opening (BMO–red dots) to the scleral flange opening (SFO-yellow dots). OCT landmarks are shown relative to the Foveal-to-BMO centroid (FoBMO) axis and 12 FoBMO 30° sectors (sectoral acronyms defined below). (B) Here the EOCBT region (BMO peripheral to the ASCO) is shown in translucent green), and the adjacent crescent of ESF is shown in translucent magenta (also on the left of Panel D). (C) OCT-radial B-scan from the location depicted by the green line in Panel B. (D) The scleral flange histologically refers to the region of the pNC-sclera that is internal to the insertion of the dural sheath.^23–26 Because, the dural sheath is not consistently visualized in OCT B-scans, the outer boundary of the scleral flange can not (yet) be consistently determined by OCT. We hypothesize that EOCBT and ESF regions are a manifestation of neural canal remodeling that is required when BMO enlarges and/or shifts temporally relative to the ASCO and SFO (when present). IOCBT - internally oblique choroidal border tissues (BMO central to the ASCO) (right side of Panel C); FoBMO 30° sectoral acronyms (Panel A): S-superior; SN-superior-nasal; NS-nasal-superior; N-nasal; NI-nasal-inferior; IN-inferior-nasal; I-Inferior; IT-Inferior-temporal; TI-temporal-inferior; T-temporal; TS-temporal-superior; ST-superior-temporal.

Based on those findings, we proposed that imaging the scleral flange cross-sectionally and longitudinally through the full spectrum of myopia is important for the following reasons. First, from the standpoint of ONH biomechanics,^34–38 the scleral flange likely contains the juxta-canalicular collagen and elastin ring,^39–43 the vascular circle of Zinn-Haller^44–47 as well as the penetrating branches of the posterior ciliary arteries which pass through it to supply the pNC choroid, the laminar beam and retrolaminar septal capillaries.⁴⁴ It is also likely that the scleral flange tissues include the laminar beam insertions into the pNC collagen and elastin ring and directly experience IOP and cerebrospinal fluid (CSF) mechanical loading that produce substantial stress and strain. This loading may be pathophysiologic depending upon scleral flange geometry, material properties and the homeostatic reserves of the involved tissues.^34,48–50 The scleral flange tissues may also directly experience the effects of eye-movement-induced fluctuations in dural sheath insertion loading.^51–57 Finally, in highly myopic eyes, Jonas has histologically described thinning and stretching of the scleral flange tissues which likely contribute to or underlie myopic staphylomatous degeneration of the pNC sclera.⁵⁸

To the best of our knowledge, while a previous longitudinal study clearly described compatible scleral flange and CBT changes in its figures,¹³ the purpose of this study was to use OCT to identify and parameterize the scleral flange contribution to ONH neural canal remodeling in highly myopic eyes. The aim of the current study was to extend our assessment of the ENC region and sub-regions to highly myopic (Hi-Myo) eyes so as to compare the prevalence, FoBMO sectoral location, and magnitude of the ENC region and sub-regions to the non-highly myopic healthy (Non-Hi-Myo-Healthy) eyes of our previous report.¹² While comparisons between Hi-Myo eyes with (Hi-Myo-GL eyes) and without glaucomatous visual field loss (Hi-Myo-Healthy eyes) were not a primary goal of this study, we also determined if the prevalence and magnitude of ENC regions and sub-regions were increased within the Hi-Myo-GL versus the Hi-Myo-Healthy eyes.

Methods

Definitions, Conventions and Quantification Software.

(Figures 1–4) Supplemental Table 1 and 2 define the OCT terminology and acronyms, respectively, used in this study. Figures 1–4 provide illustrations and explanations of the anatomic terms associated with the OCT neural canal and scleral flange.^11,12 Figure 4 illustrates OCT examples of ENC regions and sub-regions within representative Non-Hi-Myo-Healthy and Hi-Myo eyes of this study. For analysis and presentation, all left eye data have been converted to right eye configuration, unless otherwise indicated. The quantification of all parameters was carried out using Matlab R2016a (version 9.0.0.341360; The MathWorks, Natick, MA).

Study subjects and eyes.

This study adhered to the declaration of Helsinki for research involving human participants and was approved by the institutional review board of each participating institution. All participants provided written informed consent. Data for the 122 Hi-Myo eyes came from two Cohorts: n=69 eyes of 69 subjects from ongoing studies at the Eye Care Centre, Queen Elizabeth II Health Sciences Centre, Halifax,^59,60 and n=53 eyes of 53 subjects from the “Diagnostic Innovations in Glaucoma Study” (DIGS), at the University of California, San Diego (UCSD)^61,62. For both Cohorts, Hi-Myo inclusion criteria included: best-corrected visual acuity ≥ 20/40; spherical equivalent of ≤ −6 diopters or an axial length of ≥ 26.5 mm; astigmatism less than 4 diopters; absence of degenerative myopic changes in the macula; and absence retinal or optic nerve diseases, except for glaucoma.

The criteria for Hi-Myo-GL and Hi-Myo-Healthy classification in each cohort have been previously described.^59,61,62 For the Halifax Hi-Myo cohort, a consensus diagnosis was reached among three glaucoma subspecialists who independently reviewed the visual fields and optic disc photographs of all participants - masked from additional demographic or clinical details. Out of 74 Hi-Myo eyes meeting screening criteria, 5 eyes were excluded due to poor OCT imaging quality, leaving a final sample of 69 Hi-Myo study eyes (38 Hi-Myo-Healthy eyes and 31 Hi-Myo-GL eyes). For the UCSD cohort, glaucoma was established based on the presence of photograph-based glaucomatous optic disc damage and the presence of corresponding glaucomatous visual field loss.^61–63 For the UCSD cohort, 53 highly myopic eyes (26 Hi-Myo-Healthy eyes and 27 Hi-Myo-GL eyes) were enrolled.

Details regarding the 362 Non-Hi-Myo-Healthy eyes have been previously reported.¹² Subject age ranged from 18 to 90 years old; inclusion criteria included: no history of glaucoma; IOP ≤ 21mmHg; best corrected visual acuity ≥ 20/40; refraction less than ±6.00 diopter sphere and ±2.00 diopter cylinder; and Glaucoma Hemifield Test and Mean Deviation (MD) within normal limits. Exclusion criteria included: unusable stereo photographs or inadequate OCT image quality (scan quality score < 20); clinically abnormal optic disc appearance; any intraocular surgery (except uncomplicated cataract surgery); and any vitreous, retinal, choroidal or neuro-ophthalmological disease.

OCT Image Acquisition and Segmentation.

Spectral domain OCT (Spectralis, Heidelberg Engineering GmbH, Heidelberg, Germany, software version Heyex 1.9.10.0) was utilized to capture images of the ONH, pNC-RNFL, and macula. Prior to image acquisition, refractive correction and keratometry values were entered for each eye. The fovea was manually identified and marked in a live B-scan, followed by centering the imaging field on the ONH. Two BMO points in two perpendicular ONH radial B-scans were identified to establish the eye-specific FoBMO axis, which served as the reference for acquiring all OCT B-scans.^64–66 The complete ONH imaging pattern included 24 radial B-scans, spaced 15° apart, with each B-scan containing 768 A-scans, centered on BMO and obtained in Enhanced Depth Imaging mode⁶⁷ with an average of 25 repetitions each.

Our strategy for OCT ONH image manual segmentation has been described previously, and was used to segment all of the Hi-Myo-Healthy as well as the Halifax Hi-Myo eyes.^10,11 Segmented landmarks included: the internal limiting membrane (ILM); posterior surface of the RNFL, posterior surface of the Bruch’s membrane/retinal pigment epithelium complex, BMO, neural canal wall, anterior scleral surface, and the ASCO (segmented on each side of the canal by visually projecting the plane of the peripapillary anterior scleral surface through the neural canal wall and marking their intersection).

For the recently added UCSD Hi-Myo eyes, raw OCT volumes were imported into our custom 3D visualization and segmentation software (ATL 3D Suite) which now automatically segments the same targets in each radial B-scan using deep learning algorithms employing a modified U-net framework developed by our collaborative research group. For all B-scans, and for all OCT targets, the automated segmentations were reviewed and manually corrected when necessary by a single operator (AJ). Therefore, manual inspection and correction of all segmentations was the final common segmentation strategy for all OCT data sets in this study, as has been previously described. ^7,8,68,69

In eyes with an ESF region, the SFO,¹² was anatomically defined to be the transition between the anterior and internal surfaces of the scleral flange (Figure 2). It was manually segmented “geometrically” (Figure 2, Panels B2 and C2) when the transition from the “anterior” to the “internal” scleral flange surfaces (Figure 2, Panel C2), was acute enough to be visually identified. In eyes where the transition was not visually discernible (see Discussion), the operator “estimated” the SFO by visually projecting the anterior laminar surface through the neural canal wall (Figure 2, Panel A2). In all instances, and for all segmentations, the operator was able to inspect adjacent B-scans on either side of the B-scan in question to inform their final SFO segmentation choice within a given B-scan.

Sectoral ENC, EOCBT and ESF Measurements (Figure 5).

For each eye, segmented BMO, ASCO and SFO points along with BMO centroid (the centroid of the segmented BMO points) were projected to the BMO reference plane (Figure 5A – 5D) for re-sampled measurement within 30° sectors (Figure 5E). BMO, ASCO and SFO B splines were then plotted within the BMO reference plane. Within each sector, four equally-spaced re-sampling lines were used to measure the radial extent (magnitude) of the EOCBT, ESF and ENC (the sum of the two) regions (Figure 5E). Data from these four measurements of each region were then averaged. Data from sectors with less than 2 measurements were not included (i.e., the region was treated as not present (0 magnitude) in that sector. For a given eye, the definition for the presence of an EOCBT or ESF region (alone or together constituting an ENC region) – required the presence of that region in 2 contiguous FoBMO sectors.

While BMO demarcates the peripheral extent of the EOCBT in most sectors of most eyes (Figures 1 - 4), in those sectors in which BM extends beyond (or “overhangs”) the CBT, (causing BMO to be “central” to the CBT insertion into BM after projection to the BMO reference plane), the CBT BM insertion (CBT-BMI) was used to define the peripheral extent of the EOCBT region. See our previous report¹² for a detailed explanation.

BMO, ASCO, SFO and Neural Canal Minimum Cross-Sectional Area (NCMCA) Size and Shape Measurements (Figure 6).

Using a best-fit ellipse within their respective, reference planes, BMO, ASCO and SFO size and shape (ovality index) were evaluated, as previously described.¹² We have previously defined the SFO to consist of 48 points (two per each radial B-scan – as for BMO and ASCO), which included the SFO points at each radial location when present and the ASCO points at the radial locations where an SFO point was not present. In that description¹² we used the term “SFO/ASCO Conjugate Opening” for this group of points to communicate its conjugate SFO and ASCO origin. In the present report we simplify this to “SFO” both for conceptual reasons, (see Discussion), and to improve clarity.

NCMCA (Figure 6 and Supplemental Figure 2)⁷ estimates the smallest opening that the RGC axons pass through as they move through the pre-scleral neural canal. As previously described,^7,10 NCMCA was determined in a plane perpendicular to the neural canal axis after projecting BMO and ASCO points onto the plane and identifying the overlapping area between the two projections. The size and ovality index of NCMCA was computed within the projection plane, using the methods described for BMO, the ASCO and the SFO, above.

BMO/ASCO Offset Magnitude. (Figure 7 - left).

As previously described,¹² a plane was fitted to the 48 BMO and ASCO points, satisfying a least mean square error restraint.^70,71 The BMO and ASCO coordinates were then projected onto the BMO reference plane. Subsequently, a best-fit ellipse was fitted to calculate the centroids of both the BMO and ASCO.^70,71 The magnitude of BMO/ASCO offset was established by projecting the vector connecting the ASCO and BMO centroids to the BMO reference plane (the BMO/ASCO centroid vector), and transposing it from the projected ASCO centroid to the BMO centroid.

BMO/SFO Offset Magnitude (Figure 7 - right).

Because we hypothesize that the SFO is the “original” (i.e., “post-embryonic” ) entrance to the scleral portion of the neural canal,¹² (see Discussion), we predict that BMO/SFO offset will be a more robust surrogate measure of myopic neural canal remodeling than BMO/ASCO offset, (above), in eyes that demonstrate a substantial ESF region (such as the Hi-Myo eyes of this study). The magnitude of BMO/SFO offset was established by projecting the vector connecting the SFO and BMO centroids to the BMO reference plane (the BMO/SFO centroid vector) and then transposing it from the Projected SFO centroid to the BMO centroid.

Neural Canal Obliqueness.

As previously described,^7,10 neural canal obliqueness was defined by the angle between the neural canal axis vector (defined by the BMO/ASCO centroid vector as described above) and the vector perpendicular to the BMO plane, originating at the BMO centroid.

BMO Minimum Rim Width (BMO-MRW), pNC-Retinal Nerve Fiber Layer Thickness (pNC-RNFLT) and pNC Choroidal Thickness (pNC-CT).

Global and FoBMO 30° BMO-MRW and pNC-RNFLT data were generated as previously described.^12,64 pNC-CT measurements in FoBMO 30⁰ sectors were generated from the 24 radial B-scans, as previously described^8,11,12,69 (Supplemental Figure 3). pNC-CT data at the 100, 300, 500 and 700 μm measurement points were represented in microns and as their age-corrected, normative range percentile for each FoBMO sector of each study eye.

Subdivision of Study eyes into Hi-ESF and Non-Hi-ESF subgroups.

In order to test the hypothesis that the Non-Hi-Myo and Hi-Myo eyes with the largest ESF regions would exhibit distinct features related to neural canal remodeling, we defined Hi-ESF eyes to be those demonstrating at least one FoBMO sector with an ESF region ≥ 100 μms in length. We then compared Hi-ESF eyes to Non-Hi-ESF eyes in a series of subsequent analyses.

Inter-observer reproducibility.

The inter-observer reproducibility of ASCO and SFO segmentation was evaluated to determine its impact on the parameters EOCBT and ESF length. This assessment was conducted using manual segmentations performed by the two independent operators (AJ and XJ) on the same 20 OCT data sets. In the 48 radial OCT B-scan images from the same 20 reproducibility study eyes, both operators independently marked the ASCO and SFO (when present). Subsequently, EOCBT and ESF length were calculated for each sector of each reproducibility study eye based on the ASCO and SFO marked by each respective observer.

Statistical Analysis.

All statistical analyses were performed with R Studio (version 2022.12.0+353 - The R Foundation for Statistical Computing, Vienna, Austria). Descriptive statistics included the mean and standard deviation for continuous variables and proportions for categorical variables. The t-test, Wilcoxon rank sum test (continuous variable) or Chi-square test (dichotomous variable) were used to compare characteristics between groups. Intra-class correlation coefficients (ICC) between observers for EOCBT and ESF length were calculated using a two-way mixed model for agreement. Ocular and demographic effects on the OCT ENC, EOCBT and the ESF regions were assessed using univariable and multivariable linear regression, ensuring the variance inflation factor remained below 5 to avoid excessive multicollinearity.

Multiple Comparisons.

For all analyses, we report comparisons with p < 0.05 as significant but emphasize those that achieved significance using a more stringent criteria for type I error correction (Holm-Bonferroni).⁷²

Results

Study Subjects and Eyes.

Three hundred sixty-two Non-Hi-Myo-Healthy eyes of 362 subjects and 122 Hi-Myo eyes of 122 subjects were studied. Demographic and ocular data for all subjects and eyes are reported in Tables 1–6.

Table 1.

Demographic and Ocular Characteristics of the Study Participants and Non-Highly Myopic Healthy (Non-Hi-Myo-Healthy) versus Highly Myopic (Hi-Myo) Eyes.

	Non-Hi-Myo-Healthy Eyes (n=362)			Hi-Myo Eyes (n=122)

	All Eyes (n=362)	Non-Hi-ESF Eyes (n=289)	Hi-ESF Eyes (n=73)	All Eyes (n=122)	Non-Hi-ESF Eyes (n=35)	Hi-ESF Eyes (n=87)
Female Gender (n (%))	202 (55.8)	165 (57.1)	37 (50.7)	58 (47.5)	17 (48.6)	41 (47.1)
Left Eye (n (%))	181 (50.0)	147 (50.9)	34 (46.6)	58 (47.5)	17 (48.6)	41 (47.1)
Age (year ± SD, (range))	50.6 ± 17.5 (19.8 to 90.3)	50.3 ± 17.7 (19.8 to 90.3)	52.0 ± 16.9 (20.3 to 84.3)	58.6 ± 15.0^*** (26.0 to 87.8)	56.8 ± 17.1 (26.0 to 84.1)	59.4 ± 14.1^** (27.0 to 87.8)
Axial Length (mm ± SD, (range))	23.74 ± 0.95 (21.41 to 26.44)	23.64 ± 0.88 (21.41 to 26.44)	24.15 ± 1.11^††† (21.96 to 26.29)	26.98 ± 1.00^*** (24.84 to 30.74)	26.97 ± 1.04^*** (24.84 to 29.74)	26.98 ± 0.99^*** (24.86 to 30.74)
Spherical Equivalent (diopter ± SD, (range))	−0.47 ± 1.82 (−6.00 to 5.375)	−0.24 ± 1.53 (−5.75 to 5.375)	−1.38 ± 2.48^††† (−6.00 to 4.125)	−5.90 ± 2.80^*** (−12.75 to 0.75)	−6.20 ± 2.42^*** (−11.00 to −0.375)	−5.78 ± 2.95^*** (−12.75 to 0.75)
IOP (mmHg ± SD, (range))	14.5 ± 2.7 (7.0 to 21.0)	14.6 ± 2.7 (9.0 to 21.0)	14.2 ± 2.6 (7.0 to 21.0)	15.2 ± 4.2 (2.0 to 32.0)	14.5 ± 3.7 (7.0 to 24.0)	15.5 ± 4.3 (2.0 to 32.0)
CCT (μm ± SD, (range))	555.3 ± 32.6 (390.0 to 658.4)	553.6 ± 33.7 (390.0 to 658.4)	562.1 ± 26.8 (507.0 to 655.0)	544.0 ± 41.1^** (425.3 to 629.3)	532.5 ± 39.9^** (449.0 to 617.3)	548.5 ± 40.9 (425.3 to 629.3)

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Data for each group are reported for “All Eyes” as well as for “Hi-ESF and for “Non-Hi-ESF” sub-groups (Hi-ESF eyes were defined to be those eyes in which the magnitude of the ESF subregion was ≥ 100 μm in at least one ONH sector – (see Methods). Within the Hi-Myo eyes (Right Panel), data in bold red with asterisks are significantly different from the Non-Hi-Myo value (Left Panel) for the same sub-group and remain significant using a Holm-Bonferonni correction for multiple comparisons

^***

(p < 0.001

^**

p < 0.01

p < 0.05, t test or Chisquare test). Within the Hi-ESF column of both groups, obelisks denote data that are significantly different from the Non-Hi-ESF eyes of the same group and remain significant using a Holm-Bonferonni correction for multiple comparisons

^†††

(p < 0.001

^††

p < 0.01

^†

p < 0.05, (t test or Chi-square test)).

Table 6.

Mean Exposed Neural Canal (ENC) Parameters for the Highly Myopic Healthy (Hi-Myo-Healthy) and Highly Myopic Glaucoma (Hi-Myo-GL) Eyes.

	Hi-Myo Eyes (n=122)

	Hi-Myo-Healthy Eyes (n=64)			Hi-Myo-GL Eyes (n=58)

	All Eyes (n=64)	Non-Hi-ESF Eyes (n=17)	Hi-ESF Eyes (n=47)	All Eyes (n=58)	Non-Hi-ESF Eyes (n=18)	Hi-ESF Eyes (n=40)
ENC (μm ± SD, (range))	174.21 ± 110.20 (19.04 to 560.64)	87.20 ± 39.15 (19.04 to 169.18)	205.69 ± 110.85^††† (56.56 to 560.64)	148.55 ± 98.47 (0.84 to 463.08)	69.89 ± 72.73 (0.84 to 268.66)	183.94 ± 87.90^††† (51.56 to 463.08)
EOCBT (μm ± SD, (range))	114.09 ± 72.66 (7.98 to 423.34)	74.22 ± 36.05 (19.04 to 147.08)	128.52 ± 77.32^†† (7.98 to 423.34)	92.78 ± 68.15 (0.84 to 258.46)	57.53 ± 67.06^* (0.84 to 254.44)	108.65 ± 63.21^††† (23.98 to 258.46)
ESF (μm ± SD, (range))	60.12 ± 53.99 (0.00 to 259.70)	12.99 ± 11.54 (0.00 to 39.33)	77.17 ± 53.18^††† (18.29 to 259.70)	55.76 ± 59.16 (0.00 to 317.37)	12.36 ± 11.54 (0.00 to 35.86)	75.30 ± 61.62^†††(24.21 to 317.37)

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Within the Hi-Myo eyes (Right Panel), data in bold red with asterisks are significantly different from the Non-Hi-Myo value (Left Panel) for the same sub-group

^***

(p < 0.001

^**

p < 0.01

p < 0.05, (Wilcoxon rank sum test). Within the Hi-ESF column of both groups, obelisks denote data that are significantly different from the Non-Hi-ESF eyes of the same group

^†††

(p < 0.001

^††

p < 0.01

^†

p < 0.05, (Wilcoxon rank sum test).

Inter-observer ASCO and SFO Segmentation Reproducibility.

Segmentation reproducibility for all OCT anatomic landmarks of this report have been previously reported in both Non-Hi-Myo-Healthy and Hi-Myo-eyes.^{7,8,10,12,64,68,69} SFO reproducibility in the Non-Hi-Myo-Healthy eyes of this study was excellent in a recent report.¹² Within the Hi-Myo eyes of the present report, ICC values for the EOCBT region length, (i.e., BMO and ASCO segmentation) for all 12 FoBMO sectors ranged from 0.995–0.999. ICC values for the ESF region (i.e., for ASCO and SFO segmentation) ranged from 0.950 to 0.995 (Supplemental Table 3). However, for the FoBMO sectors in which an ESF region appeared in only one of the reproducibility eyes or did not exist in any eyes, ICC values were not available.

Ocular and demographic differences between the Non-Hi-Myo-Healthy and Hi-Myo eyes (Tables 1–3).

Table 3.

Mean Exposed Neural Canal Parameters by Group.

	Non-Hi-Myo-Healthy Eyes (n=362)			Hi-Myo Eyes (n=122)

	All Eyes (n=362)	Non-Hi-ESF Eyes (n=289)	Hi-ESF Eyes (n=73)	All Eyes (n=122)	Non-Hi-ESF Eyes (n=35)	Hi-ESF Eyes (n=87)
ENC (μm ± SD, (range))	30.61 ± 52.27 (0.00 to 379.36)	11.16 ± 18.84 (0.00 to 133.29)	107.57 ± 68.98^††† (28.32 to 379.36)	162.01 ± 105.15^*** (0.83 to 560.64)	78.30 ± 58.68^*** (0.83 to 268.66)	195.69 ± 100.97^***,^††† (51.56 to 560.64)
EOCBT (μm ± SD, (range))	14.75 ± 24.99 (0.00 to 145.71)	6.67 ± 12.92 (0.00 to 104.56)	46.71 ± 34.12^††† (4.71 to 145.71)	103.96 ± 71.07^*** (0.83 to 423.34)	65.63 ± 54.14^*** (0.83 to 254.44)	119.38 ± 71.48^***,^††† (7.98 to 423.34)
ESF (μm ± SD, (range))	16.18 ± 30.95 (0.00 to 263.98)	4.72 ± 7.94 (0.00 to 36.94)	61.52 ± 44.04^††† (14.56 to 263.98)	58.05 ± 56.31^*** (0.00 to 317.37)	12.67 ± 11.37^*** (0.00 to 39.33)	76.31 ± 56.88^*,^††† (18.29 to 317.37)

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^***

(p < 0.001

^**

p < 0.01

p < 0.05, Wilcoxon rank sum test). Within the Hi-ESF column of both groups, obelisks denote data that are significantly different from the Non-Hi-ESF eyes of the same group

^†††

(p < 0.001

^††

p < 0.01

^†

p < 0.05, Wilcoxon rank sum test).

Compared to Non-Hi-Myo-Healthy eyes, Hi-Myo eyes demonstrated significantly older age, longer axial length, greater myopic spherical equivalent, thinner CCT, thinner global BMO-MRW, thinner global pNC-RNFLT, larger BMO area, greater BMO/ASCO area ratio, smaller NCMCA, greater NCMCA ovality and SFO ovality, greater BMO/ASCO offset magnitude, greater BMO/SFO offset magnitude, greater neural canal obliqueness and thinner global proportional pNC-CT at all measurement points (Tables 1 and 2). The mean length of the ENC, EOCBT and ESF regions was profoundly greater in the Hi-Myo compared to the Non-Hi-Myo-Healthy eyes (Table 3).

Table 2.

Mean OCT Neuroretinal Rim, Perineural Canal Retinal Nerve Fiber Layer Thickness (pNC-RNFLT), Neural Canal, and Perineural Canal Choroidal Thickness (pNC-CT) Parameter Values by Group.

	Non-Hi-Myo-Healthy Eyes (n=362)			Hi-Myo Eyes (n=122)

	All Eyes (n=362)	Non-Hi-ESF Eyes (n=289)	Hi-ESF Eyes (n=73)	All Eyes (n=122)	Non-Hi-ESF Eyes (n=35)	Hi-ESF Eyes (n=87)
Global BMO-MRW (μm ± SD, (range))	333.1 ± 60.0 (190.0 to 558.3)	334.6 ± 60.4 (190.0 to 558.3)	327.3 ± 58.7 (213.6 to 510.4)	235.7 ± 81.1^*** (96.6 to 414.6)	239.3 ± 100.1^*** (107.0 to 414.6)	234.3 ± 72.8^*** (96.6 to 397.0)
Global pNC-RNFLT (12 degree) (μm ± SD, (range))	98.1 ± 10.1 (73.0 to 133.3)	99.2 ± 9.9 (75.9 to 133.3)	93.4 ± 9.3^††† (73.0 to 118.3)	76.2 ± 18.6^*** (43.3 to 116.5)	77.0 ± 19.7^*** (46.2 to 116.5)	75.9 ± 18.2^*** (43.3 to 116.3)
BMO area (mm² ± SD, (range))	1.83 ± 0.38 (1.05 to 3.46)	1.79 ± 0.37 (1.05 to 3.46)	1.98 ± 0.42^††† (1.20 to 3.15)	2.32 ± 0.80^*** (1.07 to 5.42)	2.04 ± 0.57 (1.07 to 3.98)	2.44 ± 0.85^***,^†† (1.22 to 5.42)
ASCO area (mm² ± SD, (range))	2.23 ± 0.43 (1.24 to 3.97)	2.24 ± 0.44 (1.24 to 3.97)	2.20 ± 0.42 (1.27 to 3.43)	2.37 ± 0.74 (0.89 to 5.21)	2.29 ± 0.64 (1.24 to 4.13)	2.41 ± 0.77 (0.89 to 5.21)
BMO/ASCO area ratio (± SD, (range))	0.83 ± 0.11 (0.55 to 1.21)	0.81 ± 0.09 (0.55 to 1.12)	0.91 ± 0.11^††† (0.66 to 1.21)	0.99 ± 0.20^*** (0.59 to 1.99)	0.91 ± 0.16^*** (0.66 to 1.48)	1.03 ± 0.21^***,^††† (0.59 to 1.99)
SFO area (mm² ± SD, (range))	2.16 ± 0.43 (1.09 to 3.90)	2.21 ± 0.44 (1.19 to 3.90)	1.97 ± 0.36^††† (1.09 to 2.98)	2.16 ± 0.66 (0.82 to 4.30)	2.24 ± 0.65 (1.24 to 4.13)	2.13 ± 0.66 (0.82 to 4.30)
NCMCA (mm² ± SD, (range))	1.33 ± 0.42 (0.40 to 2.57)	1.40 ± 0.38 (0.55 to 2.57)	1.06 ± 0.44^††† (0.40 to 2.29)	0.86 ± 0.50^*** (0.24 to 3.19)	1.10 ± 0.59^** (0.32 to 2.66)	0.77 ± 0.43^*** (0.24 to 3.19)
BMO ovality index (± SD, (range))	1.12 ± 0.07 (1.00 to 1.36)	1.13 ± 0.07 (1.00 to 1.36)	1.11 ± 0.05 (1.01 to 1.25)	1.12 ± 0.08 (1.01 to 1.36)	1.13 ± 0.08 (1.01 to 1.31)	1.12 ± 0.08 (1.01 to 1.36)
ASCO ovality index (± SD, (range))	1.12 ± 0.06 (1.00 to 1.37)	1.12 ± 0.07 (1.00 to 1.37)	1.11 ± 0.05 (1.03 to 1.24)	1.14 ± 0.08 (1.00 to 1.40)	1.16 ± 0.10 (1.00 to 1.36)	1.13 ± 0.08 (1.01 to 1.40)
SFO ovality index (± SD, (range))	1.13 ± 0.07 (1.01 to 1.41)	1.13 ± 0.07 (1.01 to 1.39)	1.16 ± 0.09 (1.01 to 1.41)	1.19 ± 0.12^*** (0.94 to 1.63)	1.17 ± 0.10 (1.00 to 1.35)	1.19 ± 0.13 (0.94 to 1.63)
NCMCA ovality index (± SD, (range))	1.54 ± 0.57 (1.01 to 4.49)	1.39 ± 0.34 (1.01 to 2.90)	2.14 ± 0.84^††† (1.09 to 4.49)	2.78 ± 1.04^*** (1.11 to 6.52)	2.15 ± 0.88^*** (1.11 to 4.84)	3.04 ± 0.99^***,^††† (1.12 to 6.52)
BMO / ASCO offset magnitude (μm ± SD, (range))	89.76 ± 62.34 (4.00 to 402.00)	72.60 ± 42.40 (4.00 to 220.00)	157.71 ± 80.29^††† (16.00 to 402.00)	253.22 ± 129.09^*** (23.00 to 724.00)	159.86 ± 100.29^*** (23.00 to 506.00)	290.78 ± 120.39^***,^††† (42.00 to 724.00)
BMO / SFO offset magnitude (μm ± SD, (range))	108.68 ± 86.38 (4.00 to 484.00)	78.67 ± 48.38 (4.00 to 264.00)	227.48 ± 100.61^††† (70.00 to 484.00)	317.34 ± 163.23^*** (29.00 to 938.00)	175.17 ± 106.74^*** (29.00 to 524.00)	374.54 ± 146.45^***,^††† (84.00 to 938.00)
Neural Canal Obliqueness (degree ± SD, (range))	39.73 ± 16.83 (2.00 to 76.00)	35.81 ± 14.77 (2.00 to 70.00)	55.23 ± 15.55^††† (11.00 to 76.00)	65.30 ± 13.65^*** (16.00 to 83.00)	55.37 ± 17.02^*** (16.00 to 80.00)	69.30 ± 9.56^***,^††† (16.00 to 83.00)
Global pNC-CT 100 (μm ± SD, (range))	108.85 ± 26.23 (45.00 to 194.00)	109.13 ± 26.31 (45.00 to 194.00)	106.81 ± 25.90 (65.00 to 175.00)	98.69 ± 29.20^*** (34.45 to 189.58)	96.30 ± 28.28 (34.45 to 150.88)	99.65 ± 29.67 (43.44 to 189.58)
Global pNC-CT 300 (μm ± SD, (range))	129.32 ± 37.46 (37.00 to 244.00)	131.06 ± 37.38 (37.00 to 244.00)	121.94 ± 37.21 (62.00 to 220.00)	101.32 ± 30.14^*** (35.08 to 169.35)	104.62 ± 31.76^*** (35.08 to 154.37)	99.99 ± 29.56^*** (40.17 to 169.35)
Global pNC-CT 700 (μm ± SD, (range))	156.49 ± 53.92 (36.00 to 296.00)	160.17 ± 54.16 (36.00 to 296.00)	141.65 ± 50.64 (57.00 to 273.00)	103.67 ± 33.46^*** (38.24 to 184.56)	114.30 ± 40.09^*** (39.95 to 184.56)	99.39 ± 29.58^*** (38.24 to 182.45)
Global pNC-CT 1100 (μm ± SD, (range))	172.51 ± 62.39 (40.00 to 341.00)	177.38 ± 62.62 (40.00 to 341.00)	151.52 ± 57.24^†† (58.00 to 285.00)	104.78 ± 36.89^*** (35.22 to 192.43)	119.16 ± 45.01^*** (43.28 to 192.43)	98.99 ± 31.55^*** (35.22 to 186.07)

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Data for each group are reported for “All Eyes” as well as for “Hi-ESF and for “Non-Hi-ESF” sub-groups. Hi-ESF eyes were defined to be those eyes in which the magnitude of the ESF subregion was ≥ 100 μm in at least one ONH sector – (see Methods). Within the Hi-Myo eyes (Right Panel), data in bold red with asterisks are significantly different from the Non-Hi-Myo value (Left Panel) for the same sub-group and remain significant using a Holm-Bonferonni correction for multiple comparisons

^***

(p < 0.001

^**

p < 0.01

p < 0.05, t test). Within the Hi-ESF column of both groups, obelisks denote data that are significantly different from the Non-Hi-ESF eyes of the same group and Page 40 remain significant using a Holm-Bonferonni correction for multiple comparisons

^†††

(p < 0.001

^††

p < 0.01

^†

p < 0.05, t test).

ENC region sectoral magnitude is greatest and pNC-RNFLT and pNC-CT are thinnest in the inferior-temporal sectors of both the Hi-Myo and Non-Hi-Myo-Healthy eyes (Figure 8).

Figure 8. — Within both the Non-Hi-Myo-Healthy and Hi-Myo eyes, sectoral data for each data type (ENC,EOCBT, ESF, pNC-RNFLT and pNC-CT), is the mean of the sectoral values from all n=362, or n=122 eyes, respectively. For this analysis, eye-specific sectoral values for sectors in which there was no ENC, no EOCBT, no ESF region, no pNC-RNFLT or no pNC-CT were treated as zero (0). All 30° sectoral data are in right eye orientation (upper left panel, see Figure 3 legend for the sectoral acronym definitions). See Supplemental Figure 4 for pNC-CT measurement data at the 100, 700 and 1100 um measurement points which confirm the inferior temporal thinning shown in the pNC-CT 300 data included above.

The longer sectoral length of the ENC regions and the thinner sectoral thickness of pNC-RNFLT and pNC-CT in the Hi-Myo versus the Non-Hi-Myo-Healthy eyes are also most pronounced within the inferior-temporal sectors. Supplemental Figure 4 reports FoBMO sectoral mean pNC-CT data at all four pNC-CT measurement points that is consistent with the pNC-CT at the 300 μm measurement point (pNC-CT 300) data shown in Figure 8.

Differences between the Hi-Myo Hi-ESF versus the Non-Hi-Myo-Healthy Hi-ESF eyes (Tables 1–3).

Compared to Non-Hi-Myo-Healthy Hi-ESF eyes, the Hi-Myo Hi-ESF eyes demonstrated significantly older age, longer axial length, greater myopic spherical equivalent, thinner global BMO-MRW, thinner pNC-RNFLT, greater BMO area, BMO/ASCO area ratio, smaller NCMCA, greater NCMCA ovality, greater BMO/ASCO offset magnitude, greater BMO/SFO offset magnitude, greater neural canal obliqueness, thinner pNC-CT at the 300,700 and 1100 μm measurement points and greater ENC, EOCBT and ESF region length.

Ocular and demographic differences between Hi-Myo-Healthy and Hi-Myo-GL eyes (Tables 4 – 6).

Table 4.

Demographic and Ocular Characteristics of the Study Participants for the Highly Myopic Healthy (Hi-Myo-Healthy) and Highly Myopic Glaucomatous (Hi-Myo-GL) Eyes.

	Hi-Myo Eyes (n=122)

	Hi-Myo-Healthy Eyes (n=64)			Hi-Myo-GL Eyes (n=58)

	All Eyes (n=64)	Non-Hi-ESF Eyes (n=17)	Hi-ESF Eyes (n=47)	All Eyes (n=58)	Non-Hi-ESF Eyes (n=18)	Hi-ESF Eyes (n=40)
Female Gender (n (%))	34 (53.1)	7 (41.2)	27 (57.5)	24 (43.4)	10 (55.6)	14 (35.0)
Left Eye (n (%))	34 (53.1)	7 (41.2)	27 (57.5)	24 (43.4)	10 (55.6)	14 (35.0)
Age (year ± SD, (range))	50.9 ± 13.6 (26.0 to 79.2)	44.2 ± 12.5 (26.0 to 65.7)	53.3 ± 13.3 (27.0 to 79.2)	67.2 ± 11.5^*** (41.3 to 87.8)	68.7 ± 11.5^*** (50.0 to 84.1)	66.5 ± 11.5^*** (41.3 to 87.8)
Axial Length (mm ± SD, (range))	26.76 ± 0.90 (24.84 to 29.69)	26.70 ± 0.97 (24.84 to 28.14)	26.78 ± 0.89 (25.12 to 29.69)	27.22 ± 1.05 (24.86 to 30.74)	27.22 ± 1.06 (26.16 to 29.74)	27.22 ± 1.07 (24.86 to 30.74)
Spherical Equivalent (diopter ± SD, (range))	−7.04 ± 2.32 (−12.75 to 0.00)	−7.49 ± 1.54 (−11.00 to 6.13)	−6.87 ± 2.54 (−12.75 to 0.00)	−4.67 ± 2.78^*** (−8.38 to 0.75)	−4.99 ± 2.51^** (−7.50 to −0.38)	−4.52 ± 2.91^*** (−8.38 to 0.75)
IOP (mmHg ± SD, (range))	16.0 ± 3.6 (8.5 to 26.0)	15.4 ± 3.9 (8.5 to 24.0)	16.3 ± 3.4 (10.0 to 26.0)	14.3 ± 4.6 (2.0 to 32.0)	13.6 ± 3.4 (7.0 to 20.0)	14.5 ± 5.1 (2.0 to 32.0)
CCT (μm ± SD, (range))	549.8 ± 39.2 (457.0 to 629.3)	529.6 ± 35.4 (457.0 to 602.7)	556.9 ± 38.4 (475.0 to 629.3)	537.2 ± 42.6 (425.3 to 617.3)	535.5 ± 45.2 (449.0 to 617.3)	537.9 ± 42.1 (425.3 to 607.0)
Mean deviation (dB ± SD, (range))	−1.00 ± 1.52 (−5.43 to 1.86)	−1.00 ± 1.65 (−4.21 to 1.86)	−1.00 ± 1.49 (−5.43 to 1.61)	−9.19 ± 6.08^*** (−23.27 to −0.46)	−7.12 ± 4.99^*** (−16.98 to 0.46)	−10.13 ± 6.35^*** (−23.27 to −0.63)

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^***

(p < 0.001

^**

p < 0.01

p < 0.05, t test or Chi-square test). Within the Hi-ESF column of both groups, obelisks denote data that are significantly different from the Non-Hi-ESF eyes of the same group and remain significant using a Holm-Bonferonni correction for multiple comparisons

^†††

p < 0.001

^††

p < 0.01

^†

p < 0.05, (t test or Chi-square test)).

The 58 Hi-Myo-GL eyes demonstrated significantly older age, less myopic spherical equivalent and greater visual field loss (MD) than the 64 Hi-Myo-Healthy eyes. Among all global OCT structural parameters, only BMO-MRW (decreased), pNC-RNFLT (decreased) and pNC-CT100 (decreased) achieved significance. The ENC, EOCBT and ESF regions, specifically, were substantially decreased in length in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes (Table 6), though these differences did not achieve significance. Among the Hi-Myo-GL eyes, while visual field loss was greater in the Hi-ESF compared to the Non-Hi-ESF eyes, this difference did not achieve significance.

ENC region sectoral magnitude as well as pNC-RNFLT and pNC-CT are decreased in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes (Figure 9).

Against expectation, while in both groups the inferior temporal sectors demonstrate the highest ENC regional magnitudes and the thinnest pNC-RNFLT and pNC-CT, the sectoral magnitudes of each ENC region and sub-region were decreased rather than increased in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes (see Discussion). As expected, pNC-RNFLT and pNC-CT were both thinner in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes. Supplemental Figure 5 reports FoBMO sectoral mean pNC-CT data at all four pNC-CT measurement points that is consistent with the pNC-CT-300 data shown in Figure 9.

Ocular and Demographic Factors associated with the ENC, EOCBT and ESF regions of the Hi-Myo eyes (Table 7).

Table 7.

Univariable and multivariable associations with the magnitude of an OCT Exposed Neural Canal (ENC), Externally Oblique Choroidal Border Tissue (EOCBT) and Exposed Scleral Flange (ESF) region, (respectively), among Highly Myopic Eyes (n=122).

	Highly Myopic Eyes (n=122)

	Univariable (β)			Multivariable (β)

	ENC	EOCBT	ESF	ENC	EOCBT	ESF
Female Gender	28.58 (P=0.134)	19.71 (P=0.127)	8.87 (P=0.387)
Left Eye	−28.81 (P=0.131)	−24.15 (P=0.061)	−4.66 (P=0.650)
Age	0.78 (P=0.224)	0.45 (P=0.300)	0.33 (P=0.337)
Axial Length	9.14 (P=0.341)	−1.90 (P=0.770)	11.03 (P=0.030)
Spherical Equivalent	−3.40 (P=0.343)	−0.72 (P=0.766)	−2.68 (P=0.162)
IOP	3.65 (P=0.132)	2.20 (P=0.180)	1.45 (P=0.267)
CCT (10 μm increase)	9.75 (P<0.001)	5.61 (P<0.001)	4.14 (P=0.002)
Mean deviation	1.47 (P=0.364)	1.50 (P=0.171)	−0.02 (P=0.978)
Global BMO-MRW	0.13 (P=0.292)	0.15 (P=0.067)	−0.02 (P=0.739)
Global pNC-RNFLT	0.81 (P=0.117)	0.55 (P=0.116)	0.26 (P=0.346)
BMO area (0.1mm² increase)	5.91 (P<0.001)	2.88 (P<0.001)	3.03 (P<0.001)
ASCO area (0.1mm² increase)	1.65 (P=0.204)	−0.61 (P=0.487)	2.27 (P<0.001)
BMO/ASCO area ratio	300.39 (P<0.001)	235.86 (P<0.001)	64.52 (P=0.010)	176.83 (P<0.001)	174.69 (P<0.001)
SFO area (0.1mm² increase)	−1.14 (P=0.436)	−1.46 (P=0.136)	0.33 (P=0.676)
NCMCA (0.1mm² increase)	−4.92 (P=0.009)	−3.54 (P=0.005)	−1.38 (P=0.175)
BMO ovality index	−127.70 (P=0.294)	−14.84 (P=0.857)	−112.82 (P=0.082)
ASCO ovality index	−5.87 (P=0.960)	75.45 (P=0.334)	−81.33 (P=0.188)			−141.92 (P=0.002)
SFO ovality index	325.78 (P<0.001)	176.15 (P<0.001)	149.63 (P<0.001)	185.80 (P<0.001)	67.51 (P=0.041)	159.01 (P<0.001)
NCMCA ovality index	46.38 (P<0.001)	28.08 (P<0.001)	18.30 (P<0.001)			−18.45 (P<0.001)
BMO / ASCO offset magnitude (100 μιπ increase)	58.88 (P<0.001)	35.01 (P<0.001)	23.87 (P<0.001)	47.84 (P<0.001)	25.46 (P<0.001)
BMO / SFO offset magnitude (100 μιπ increase)	51.97 (P<0.001)	25.55 (P<0.001)	26.42 (P<0.001)			31.53 (P<0.001)
Neural Canal Obliqueness	3.26 (P<0.001)	1.83 (P<0.001)	1.43 (P<0.001)
Global pNC-CT 300	0.40 (P=0.204)	0.15 (P=0.495)	0.26 (P=0.130)

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Within this analysis, data for each eye and each ENC region includes the sectoral values for that region in all 12 sectors - with sectoral values in which there is no ENC, no EOCBT or no ESF, (respectively) being treated as zero (0).

Within the multivariable analysis, both the ENC region and the EOCBT sub-region were positively associated with BMO/ASCO area ratio, SFO ovality index, and BMO/ASCO offset magnitude. The ESF region was negatively associated with ASCO ovality and NCMCA ovality and positively associated with SFO ovality and BMO/SFO offset magnitude.

Discussion

In this study we used OCT to manually segment the SFO, a recently described,¹² deep ONH neural canal anatomic landmark, to characterize the prevalence, FoBMO sectoral location and magnitude of the ONH ENC regions in highly myopic eyes. Our findings suggest how the ENC regions, in being exposed neural canal are not the result of “atrophy” so much as remodeling^5,21,22 and in being defined to be within the neural canal are not peri-neural canal and therefore are not “peripapillary”. In this, our study illustrates how traditional optic disc terminology is inconsistent with OCT ONH neural canal anatomy in both non-highly myopic and highly myopic eyes. It additionally lays the foundation for future studies that will extend our OCT ONH parameterization strategies^7,8,10–12 to include topographically-correspondent, OCT anatomically-defined, pNC-choroidal (“beta”)^59,69 and pNC-retinal pigment epithelial (“alpha”)⁷³ forms of pNC atrophy and/or degeneration.

The Hi-Myo eyes of this study demonstrated significantly larger ENC, EOCBT, and ESF regions than the Non-Hi-Myo-Healthy eyes, and these regions were largest in sectoral prevalence and magnitude within the inferior-temporal sectors, where both pNC-RNFLT and pNC-CT were also proportionally thinnest. While both BMO/ASCO offset and BMO/SFO offset were larger in the Hi-Myo eyes, the BMO/SFO offset was notably larger in magnitude compared to BMO/ASCO offset. Finally, within the Hi-Myo eyes, the magnitude of an ESF region was negatively associated with ASCO ovality and NCMCA ovality and positively associated with SFO ovality as well as BMO/SFO offset magnitude, suggesting that neural canal shape change is a component of myopic neural canal remodeling that may influence or be the result of ESF creation and expansion.

Taken together with our previous reports,^{7,8,10–12,64,69} the Non-Hi-Myo-Healthy and Hi-Myo eyes demonstrate a continuum of “myopic” neural canal remodeling and pNC choroidal and RNFL degeneration that increased through the range of axial length (21.4 to 30.7 mm) and “myopic” spherical equivalent (+5.375 to −12.50 D) studied. However, our data also make clear that while myopic ONH neural canal remodeling generally increased with axial length, neither spherical equivalent nor axial length were significantly associated with any of the ENC region parameters within a multivariable analysis of the Hi-Myo eyes. This finding supports the suggestion^11,12 that axial length and spherical equivalent are poor surrogates for parameterizing the neural canal structural alterations of myopia as defined by the parameters of this report.

To further clarify these findings, we performed additional univariable and multivariable association studies in “All Study” eyes (Supplemental Table 4, n=484 eyes spanning the full spectrum of axial length and spherical equivalent) and “All Hi-ESF eyes (Supplemental Figure 5, n=160 eyes also spanning the full spectrum of both parameters). The associations for each group of eyes, and for each ENC region, are summarized in Table 8. Within each group of eyes, and for each ENC region, the single most consistent predictor of region magnitude was SFO ovality index which was a significant predictor for each region in all three groups of eyes. Axial length did not achieve significance for any region in any analysis group. Spherical equivalent predicted EOCBT region magnitude within the data from all study eyes, only. However, as would be expected morphologically, (Figure 10), BMO/ASCO offset magnitude consistently predicted the magnitude of the ENC region (except for the “All Study Eye” analysis) and EOCBT region. Likewise, BMO/SFO offset magnitude predicted the magnitude of the ESF region within all three groups of eyes. These data, taken together, further support the notion that myopic neural canal remodeling, as described by the parameters of this report, is a continuum that can be present at all levels of axial length and refractive error, and that cross-sectional and longitudinal measures of SFO ovality, BMO/ASCO offset and BMO/SFO offset may provide insight into its presence and progression.

Table 8.

Significant Multivariable associations with the magnitude of an OCT Exposed Neural Canal (ENC) Region (Left), Externally Oblique Choroidal Border Tissue (EOCBT) Region (Middle) and Exposed Scleral Flange (ESF) Region (Right), (respectively), among All Study Eyes (n=484); All Hi-ESF Eyes (n=160) and All Hi-Myo Eyes (n=122).

	ENC			EOCBT			ESF

	All Eyes	Hi-ESF	Hi-Myo	All Eyes	Hi-ESF	Hi-Myo	All Eyes	Hi-ESF	Hi-Myo
Age				0.14 (P=0.037)
Spherical Equivalent				−1.70 (P<0.001)
BMO area (0.1mm² increase)		10.03 (P<0.001)					2.61 (P<0.001)
ASCO area (0.1mm² increase)		−7.81 (P<0.001)
BMO/ASCO area ratio	245.65 (P<0.001)		176.83 (P<0.001)	151.62 (P<0.001)	202.84 (P<0.001)	174.69 (P<0.001)
SFO area (0.1mm² increase)							−2.14 (P<0.001)
BMO ovality index	−157.04 (P<0.001)						−57.23 (P<0.001)
ASCO ovality index									−141.92 (P=0.002)
SFO ovality index	151.86 (P<0.001)	195.70 (P<0.001)	185.80 (P<0.001)	39.14 (P=0.003)	61.42 (P=0.003)	67.51 (P=0.041)	62.00 (P<0.001)	86.34 (P<0.001)	159.01 (P<0.001)
NCMCA ovality index	40.26 (P<0.001)								−18.45 (P<0.001)
BMO / ASCO offset (100 μm increase)		44.07 (P<0.001)	47.84 (P<0.001)	28.07 (P<0.001)	30.16 (P<0.001)	25.46 (P<0.001)
BMO / SFO offset (100 μm increase)							17.99 (P<0.001)	31.70 (P<0.001)	31.53 (P<0.001)
Neural Canal Obliqueness	0.87 (P<0.001)							−1.30 (P<0.001)
Global pNC-CT 300	0.27 (P<0.001)

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Within this analysis, data for each eye and each ENC, EOCBT or ESF region include the sectoral values for that region in all 12 sectors - with sectoral values in which there is no ENC, no EOCBT or no ESF, (respectively) being treated as zero (0). Taken together these data strongly suggest that axial length and spherical equivalent are poor surrogates for predicting the magnitude and regional composition of myopic neural canal structural remodeling as described by the parameters of this report. Likewise, the single parameter SFO ovality index was associated with the magnitude of each ENC region, (and strongly associated with the ESF region), in all three groups of Study eyes. (Variables with no significant correlations included: Female Gender, Left Eye, Axial length, Intraocular Pressure, Central Corneal Thickness, Mean deviation, Global BMO-MRW, Global pNC-RNFLT and Neural Canal Minimum Cross-sectional Area. See Table 7 and Supplemental Tables 4 and 5 for the expanded Univariable and Multivariable association data that are summarized herein).

Figure 10. — (Left Panel) The existing exposed neural canal (ENC) region from the 48 year old Hi-Myo-GL-29 example eye from Figure 4 is used to create a “Proposed Longitudinal Change” scenario (Left Middle Panels - top-to-bottom) in which CBT “externalization” and “insertion migration” away from the post-embryonic ASCO creates an ESF region and a geometrically identifiable SFO that is separate from the ASCO. However, an “Alternative Longitudinal Change” scenario (Right Middle Panels – top-to-bottom) can be imagined, in which the CBT is externalized and elongates progressively without losing its insertion into the original “synonymous” ASCO/SFO point. (Right Panel) Had CBT elongation alone occurred, the expected composition of the ENC region would consist entirely of an EOCBT region only – without creating an ESF region. (Reprinted with edits from Hong et al, AJO, 2023).¹²

In this regard, we have proposed¹¹ that a goal of myopic eye OCT imaging should be to primarily detect and parameterize ONH and posterior pole myopic structural abnormality in a topographically correspondent fashion with only modest regard for the spherical equivalent or axial length at which they occur. We predict that cross-sectional^10–12 and longitudinal^13–16 studies through the development and progression of myopic structural alteration utilizing a wide range of topographically correspondent ONH and posterior pole parameters^{7,8,10–12,64,68,69,74,75} will eventually lead to strategies for staging the character (i.e., sectoral location, extent and radial magnitude) of myopic structural abnormality¹¹ in a given eye.

To date, the scleral flange has been described within histologic sections of highly myopic eyes^{21,25,58,73,76,77} but neither it, nor the SFO (as an opening), have been identified and parameterized in highly myopic eyes using OCT-detected anatomic landmarks.¹³ While the clinical “gamma” and “delta” zones are sometimes schematically depicted as including the scleral flange,^13,73 they are at present defined based on the clinical disc margin which has no consistent OCT anatomic foundation. As such, we are not aware of a study that has used OCT-detected anatomic landmarks to define and parameterize the either the “gamma” and ‘delta” zones or the SFO as well as the ENC regions in highly myopic eyes.

In the present report, similar to our use of the terms “BMO” and “ASCO”, we use the term SFO both as an OCT anatomic landmark within individual radial OCT B-scans and to name an anatomic opening which, in the case of the SFO, consists of the SFO points at each radial B-scan location when present and the ASCO points at the radial locations where an SFO point is not identifiable. In our original description of the SFO as an opening,¹² we used the term “SFO/ASCO Conjugate opening” to communicate its conjugate SFO and ASCO point origin. In this report we have simplified the term to SFO for clarity and now propose that in any cross-sectional OCT images of post-embryonic eyes, (i.e., at any post-embryonic point in life at which the eye is imaged), at radial ONH locations where an SFO point can be identified separate from an ASCO point, the SFO point is the “original” (i.e., “post-embryonic development” or “pre-myopic neural canal remodeling”) entrance to the scleral flange portion of the neural canal.¹² (Figure 11). Likewise, the SFO as an opening, represents the “entrance” to the scleral flange portion of the neural canal at the end of neural canal embryonic development, (though its size, shape and planarity may also have been altered by postembryonic remodeling).¹² In this same construct, the ASCO, as detected in the same images, represents the “entrance” to the scleral flange portion of the neural canal after whatever post-embryonic remodeling of the CBT (Figure 10)¹³ has occurred.

Figure 11. — **(A1 – B1)** Neural canal landmarks segmented within a representative Hi-Myo-Healthy (A1) and Hi-Myo-GL (B1) eye. (A2-B2) Radial B-scans denoted by the green lines in Panels (A1) and (B1) (N-Nasal; T-Temporal). (A3-B3) Bruch’s Membrane Opening (BMO), Anterior Scleral Canal Opening (ASCO) and Scleral Flange Opening (SFO) segmented in the Temporal portion of each B-scan. (A4-B4) While not measured in this study, we have previously reported that pNC-SB is increased in a subset of the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes of this study.¹¹ In a manuscript in preparation, we will measure both NCSFB and “running length” (rather than) “projected length” measures of each ENC region in an expanded group of Hi-Myo-GL versus Hi-Myo-Healthy eyes. We predict that NCSFB will be significantly increased as will “running length” measures of the ESF region in the Hi-Myo-GL versus the Hi-Myo-Healthy eyes.

It is in this context, that we propose that the morphologic differences between SFO and ASCO openings in a given eye provide insight into the post-embryonic neural canal remodeling that has occurred in that eye. Figure 10, (modified from our previous report),¹² uses the Hi-Myo-GL-29 eye from Figure 4 to create a “Proposed Longitudinal Change” scenario in which CBT “externalization” and “insertion migration” away from the “embryonic” entrance to the scleral flange portion of the neural canal creates an ESF region as well as an ASCO point that is separate from a geometrically identifiable SFO point. Figure 10 also includes a second, “Alternative Longitudinal Change” scenario, in which the CBT become externalized and then elongate progressively without losing their insertion into the post-embryonic ASCO point creating an ENC region that consists entirely of EOCBT. We propose that longitudinal studies of young eyes undergoing myopic remodeling¹³ will demonstrate both forms of ONH neural canal remodeling at all levels of myopia. In fact, two longitudinal OCT studies have described similar phenomena without using similar terminology.^12,13,78

We,^7,10–12 and others,⁷⁹ have previously emphasized the importance of the inferior temporal shift of BMO relative to ASCO (assessed by our parameter BMO/ASCO offset) as a contributing mechanism of pre-scleral, (i.e., CBT), myopic neural canal remodeling in eyes undergoing axial elongation. However, in eyes with an ESF region, if the SFO, as an opening, is the post-embryonic entrance to the scleral flange portion of the neural canal, then it is reasonable to consider that the offset of BMO should be measured relative to the SFO to best assess its effects on ENC overall and on the ESF region in particular. We thus reported both BMO/ASCO and BMO/SFO offset, and as expected, found that BMO/SFO offset was substantially larger in both the Non-Hi-Myo and Hi-Myo eyes. In addition, again as expected, within the multivariable analysis among the Hi-Myo eyes, BMO/ASCO offset significantly influenced the ENC region overall and the EOCBT region, but not the ESF region, whereas BMO/SFO offset had significant effects on the ESF region only.

The fact that the ENC region sectoral magnitudes were smaller rather than larger in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes directly counters our hypothesis that ENC region remodeling, especially ESF remodeling, may increase ONH sectoral susceptibility to glaucoma. While in both groups of eyes the inferior temporal sectors demonstrated the highest ENC regional magnitudes and the thinnest pNC-RNFLT and pNC-CT, the sectoral magnitudes of each ENC region and sub-region were decreased rather than increased in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes. However, two additional clarifications are necessary to better understand this finding.

First, longitudinal studies in at risk eyes that include a topographically- correspondent characterization of all forms of ONH myopic structural abnormality,^{7,8,10–12,64,68,69,74} may be necessary to most sensitively detect whether the FoBMO sectoral susceptibility to aging and glaucoma in a given eye is influenced by the character of an ENC region. Second, in further analyzing our images, we recognized 3 limitations of our method, that may have contributed to the underestimation of the “actual” (i.e., running distance) of the ENC regions in the Hi-Myo-GL eyes. Figure 11 illustrates how increased peri-neural canal scleral bowing (pNC-SB) and increased neural canal scleral flange bowing (neither of which having been reported in this study) in the Hi-Myo-GL eyes may have increased the “axial” orientation of the scleral flange and in so doing reduced the “transverse extent” of the exposed neural canal (ENC) regions in the Hi-Myo-GL eyes. Thus, if the Hi-Myo-GL eyes demonstrate greater outward bowing of the pNC-scleral and scleral flange, our method of “projection” to the BMO reference plane would reduce their “projected length” within the BMO reference plane.

We have previously reported that pNC-SB is greater in the Halifax subset of the Hi-Myo-GL eyes (see methods) compared to the Halifax Hi-Myo-Healthy eyes of this study.¹¹ In a manuscript in preparation, we will measure both neural canal scleral flange bowing (Supplemental Figure 6)¹¹ and “running length” (rather than) “projected length” measures of each ENC region in an expanded group of Hi-Myo-GL versus Hi-Myo-Healthy eyes. We predict that neural canal scleral flange bowing will be significantly increased as will “running length” measures of the ESF region in the Hi-Myo-GL versus Hi-Myo-Healthy eyes.

Limitations.

We have extensively discussed the limitations of our methods in previous publications.^7,8,10–12 Unlike BMO, which can be anatomically identified using histology^80,81 and OCT^27,70,81, we identify the ASCO by visually projecting the anterior scleral surface through the neural canal wall. Previous studies^10,68 have demonstrated excellent inter-operator reproducibility of ASCO area. While we believe that the SFO can be identified as an anatomic landmark using OCT in most B-scans in which it is present, remodeling of the scleral flange, including changes in its primary shape and fusion with the pial sheath and laminar beam insertions²¹, can present challenges to accurately locating the SFO. Despite these challenges, we found excellent reproducibility in the identification of the SFO in the Non-Hi-Myo-Healthy eyes of our recent study¹² as well as the Hi-Myo eyes of the present report.

Finally, the implementation of our OCT ENC region landmarks and parameters in clinical practice will face delays due to the manual segmentation required for identifying the necessary anatomical targets. However, we are actively collaborating with multiple laboratories to create automated segmentation algorithms that will facilitate this transition. In these regards, an additional large group of eyes will be available to us and others as a product of the Glaucoma/Myopia OCT Phenotyping Consortium (www.gmopconsortium.org).¹¹

Summary.

Our study, employing recently described¹² OCT-detected, neural canal landmarks found that OCT ENC region tissue remodeling that includes the scleral flange is greater in the Hi-Myo compared to the Non-Hi-Myo-Healthy eyes. Longitudinal studies are now necessary to determine whether the presence of an ENC region influences longitudinal ONH susceptibility to aging and/or glaucoma and whether these susceptibilities are more pronounced in highly myopic eyes.

Supplementary Material

1. Supplemental Figure 1. Paradigm Change from the clinical examination of the optic disc to the clinical evaluation of the optic nerve head (ONH) tissues using OCT.

(Left) Pre-sacrifice color photo of a non-human primate (NHP) Control eye in acquired-image-frame (AIF) orientation (see below); (N – nasal; T- temporal; S – superior; I – inferior). The clinical terms “optic disc”, “papilla”, and “peripapillary” are based on the clinical disc margin which lacks a consistent histologic or OCT-detectable anatomic foundation.^17,18 The clinical disc margin is therefore inconsistently assigned by clinicians¹⁹ (note open versus closed white dots) which undermines the anatomic foundation for concepts such as optic disc “size”, “shape”, “tilt” and “torsion”. (Center) Vitreal (lower) and retrobulbar (upper) views of an 8 mm trephined NHP ONH tissue specimen. Note the dramatic increase in the size of the retrobulbar nerve and dural sheath insertions relative to the size of the clinical “disc”. We define the ONH anatomically and morphologically to include the tissues within the neural canal and those immediately adjacent to it, namely, the peri-neural canal (pNC) retina, choroid, and sclera (Figures 1 and 3) as well as the immediate retrobulbar orbital optic nerve (Right). (Right) We propose that the ONH tissues biomechanically and physiologically include the dural sheath, the pNC portion of the inferior oblique extraocular muscle (EOM) insertion, the posterior ciliary artery insertions (via the dural sheath – not shown), as well as the pNC scleral collagen ring, (not shown) and contained vascular circle of Zinn-Haller, (also not shown). (S – superior; N – nasal; I – inferior; T – temporal clinical orientation assigned without anatomic justification on the basis of the AIF (blue –outline). (Reprinted with minor edits from Burgoyne et al, AJO, 2023).¹¹

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2. Supplemental Figure 2. Neural canal minimum cross-sectional area (NCMCA) estimates the smallest opening through which the RGC axons pass as they leave the eye.

It is calculated within a plane that is perpendicular to the neural canal axis (the neural canal perpendicular plane) and is here depicted for a representative study eye (FDA287). (Top Left Panel) Segmented BMO (red) and ASCO (blue) points along with their centroids and the neural canal axis (green) that connects them are shown relative to the Fovea to BMO centroid (FoBMO) axis on the infrared image obtained at the time of OCT imaging. Note that the eye has been rotated so that the FoBMO axis is horizontal to the image frame for representation purposes. (Top Right Panel) Same structures (BMO and ASCO are now B-spline fitted curves after projection of each point to its respective reference plane), projected onto a colocalized clinical photograph. (Middle Panel) The NCMCA is calculated by generating a neural canal perpendicular plane (right), projecting the BMO and ASCO points onto it and quantifying the area that is common to both projections (bright green, lower right middle panel). (Lower Left Panel) The relative size and shape of BMO, ASCO and the NCMCA as projected to the Neural Canal Axis Perpindicular plane are shown, (the neural canal axis is now depicted as a dot because the visualization or projection plane is within the paper this figure is printed on and the axis is perpendicular to it), (Lower Right Panel) The actual sizes of each opening are plotted within the BMO reference plane, (rather than projected to it) for comparison purposes. The position of BMO is accurate, but the positions of ASCO and NCMCA are approximated so as to maintain an accurate depiction of their size and shape.(Reprinted with minor edits from Hong et al, AJO, 2023).¹²

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3. Supplemental Figure 3. Measurement of perineural canal choroidal thickness (pNC-CT) at six distances (measured in microns) from the anterior scleral canal opening (ASCO) within the ASCO reference plane.

Within the 3D point cloud of segmented points from each OCT ONH data set, Bruch’s membrane and the anterior scleral surface points were interpolated using b-splines. pNC-CT was assessed in microns at six distances (vertical blue dotted lines) from the ASCO, measured within the ASCO reference plane, (horizontal blue dotted line). Each measurement distance was projected from the ASCO to the anterior sclera surface (yellow dots). At each anterior scleral measurement point pNC-CT was defined by the minimum distance to the posterior surface of Bruch’s membrane (red arrows) (pNC-CT 100, pNC-CT 300, pNC-CT 500, pNC-CT 700, pNC-CT 900, and pNC-CT 1100, respectively). To simplify data presentation, we concentrate on pNC-CT at the 300, 700 and 1100 μm measurement points (where they approximate the measurement of pNC-SS. This strategy does not measure choroidal thickness between the pNC-CT 100 measurement point and BMO (transparent red). This region of the choroid can be the site of extensive neural canal remodeling and choroidal thinning and/or atrophy in myopic eyes. (Reprinted with minor edits from Burgoyne et al, AJO, 2023).¹¹

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4. Supplemental Figure 4. Mean (± standard deviation) FoBMO 30° sectoral pNC-CT at the 100 μm, (far left), 300 μm, (middle left), 700 μm, (middle right) and 1100 μm (far right) measurement points for all Non-Highly Myopic Healthy Control Eyes (n=362) (upper row) and all Highly Myopic eyes (n=122) (bottom row).

Within both the Non-Hi-Myo-Healthy and Hi-Myo eyes, sectoral data is the mean of the sectoral values from all n=362, or n=140 eyes, respectively. For this analysis, eye-specific sectoral values for sectors in which there was no pNC-CT were treated as zero (0). All 30° sectoral data are in right eye orientation (upper left panel, see Figure 3 legend for the sectoral acronym definitions).

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5. Supplemental Figure 5. Mean (± standard deviation) FoBMO 30° sectoral pNC-CT at the 100 μm, (far left), 300 μm, (middle left), 700 μm, (middle right) and 1100 μm (far right) measurement points for Highly Myopic Healthy Eyes (n=64) (upper row) and Highly Myopic Glaucomatous Eyes (n=58) (bottom row).

Within both the Hi-Myo-Healthy and Hi-Myo-GL eyes, sectoral data is the mean of the sectoral values from all n=362, or n=140 eyes, respectively. For this analysis, eye-specific sectoral values for sectors in which there was no pNC-CT were treated as zero (0). All 30° sectoral data are in right eye orientation (upper left panel, see Figure 3 legend for the sectoral acronym definitions).

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6. Supplemental Figure 6. ONH neural canal scleral flange remodeling includes “externalization” and “bowing” that underlie myopic ONH staphylomatous degeneration and can be parameterized using OCT parameters complimentary to pNC-SS (manuscripts in preparation).

(A1 – C1, left) Representative OCT B-scans from representative non-highly myopic (A1 – top), (B1 – middle) and highly myopic (C1 - bottom) eyes. (A2 - C2) Because the internal boundaries of the depicted tissues are anatomically continuous, the internal boundaries shown are representative. The anterior scleral canal opening (ASCO) is defined to be the projection of the anterior pNC scleral surface through the choroidal border tissues. The scleral flange is histologically defined to be the pNC sclera that is “internal” or “medial” to the dural sheath insertion. Current OCT parameterization of the pNC scleral flange (commonly referred to as the “gamma” region) employs a projection of the clinical disc margin rather than segmentation of the OCT-detected scleral flange opening (SFO, yellow circle) to define its innermost margin. When there is a region of exposed scleral flange tissue internal to the ASCO, the SFO can be manually segmented either “geometrically” when identifiable (Panels B2 and C2) or “estimated” by visually projecting the anterior laminar surface through the neural canal wall (Panel A2). (A3 – C3) The slope of the anterior scleral flange surface (between the ASCO and SFO) can be calculated in a manner that is separate from, but complimentary to, the pNC-scleral bowing (SB)-scleral slope(SS) parameter. (Reprinted with minor edits from Burgoyne et al, AJO, 2023).¹¹

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Table 5.

Mean OCT Neuroretinal Rim, Perineural Canal Retinal Nerve Fiber Layer Thickness (pNC-RNFLT), Neural Canal, and Perineural Canal Choroidal Thickness (pNC-CT) Parameter Values of Study Participants for the Highly Myopic Healthy (Hi-Myo-Healthy) and Highly Myopic Glaucomatous (Hi-Myo-GL) Eyes.

	Hi-Myo Eyes (n=122)

	Hi-Myo-Healthy Eyes (n=64)			Hi-Myo-GL Eyes (n=58)

	All Eyes (n=64)	Non-Hi-ESF Eyes (n=17)	Hi-ESF Eyes (n=47)	All Eyes (n=58)	Non-Hi-ESF Eyes (n=18)	Hi-ESF Eyes (n=40)
Global BMO-MRW (μm ± SD, (range))	292.1 ± 63.8 (175.7 to 414.6)	320.4 ± 69.1 (194.8 to 414.6)	281.9 ± 59.2 (175.7 to 397.0)	173.5 ± 44.5^*** (96.6 to 302.3)	162.8 ± 52.7^*** (107.0 to 302.3)	178.3 ± 40.1^*** (96.6 to 270.0)
Global pNC-RNFLT (12 degree) (μm ± SD, (range))	87.8 ± 14.9 (55.3 to 116.5)	91.1 ± 15.7 (55.3 to 116.5)	86.6 ± 14.6 (62.4 to 116.3)	63.5 ± 13.1^*** (43.3 to 103.2)	63.6 ± 12.5^*** (46.2 to 96.0)	63.4 ± 13.5^*** (43.3 to 103.2)
BMO area (mm² ± SD, (range))	2.39 ± 0.78 (1.14 to 4.32)	2.00 ± 0.41 (1.14 to 2.69)	2.53 ± 0.84^** (1.22 to 4.32)	2.25 ± 0.82 (1.07 to 5.42)	2.08 ± 0.70 (1.07 to 3.98)	2.34 ± 0.86 (1.32 to 5.42)
ASCO area (mm² ± SD, (range))	2.44 ± 0.70 (0.89 to 3.81)	2.32 ± 0.57 (1.24 to 3.52)	2.48 ± 0.74 (0.89 to 3.81)	2.29 ± 0.78 (1.23 to 5.21)	2.25 ± 0.71 (1.28 to 4.13)	2.31 ± 0.81 (1.23 to 5.21)
BMO/ASCO area ratio (± SD, (range))	1.00 ± 0.23 (0.59 to 1.99)	0.88 ± 0.14 (0.66 to 1.22)	1.04 ± 0.24^** (0.59 to 1.99)	0.99 ± 0.17 (0.69 to 1.55)	0.93 ± 0.17 (0.75 to 1.49)	1.02 ± 0.17 (0.69 to 1.55)
SFO area (mm² ± SD, (range))	2.23 ± 0.64 (0.82 to 3.66)	2.27 ± 0.59 (1.24 to 3.52)	2.22 ± 0.66 (0.82 to 3.66)	2.08 ± 0.68 (1.03 to 4.30)	2.21 ± 0.72 (1.25 to 4.13)	2.03 ± 0.66 (1.03 to 4.30)
NCMCA (mm² ± SD, (range))	0.85 ± 0.45 (0.26 to 2.35)	1.09 ± 0.57 (0.32 to 2.18)	0.76 ± 0.36 (0.26 to 2.35)	0.88 ± 0.56 (0.24 to 3.19)	1.10 ± 0.63 (0.42 to 2.66)	0.77 ± 0.50 (0.24 to 3.19)
BMO ovality index (± SD, (range))	1.13 ± 0.09 (1.01 to 1.36)	1.13 ± 0.08 (1.01 to 1.31)	1.13 ± 0.09 (1.01 to 1.36)	1.11 ± 0.07 (1.01 to 1.28)	1.13 ± 0.09 (1.01 to 1.28)	1.10 ± 0.06 (1.02 to 1.25)
ASCO ovality index (± SD, (range))	1.14 ± 0.09 (1.01 to 1.40)	1.15 ± 0.10 (1.02 to 1.30)	1.13 ± 0.08 (1.01 to 1.40)	1.13 ± 0.08 (1.00 to 1.36)	1.16 ± 0.10 (1.00 to 1.36)	1.12 ± 0.07 (1.01 to 1.28)
SFO ovality index (± SD, (range))	1.19 ± 0.12 (1.01 to 1.63)	1.17 ± 0.11 (1.04 to 1.34)	1.19 ± 0.13 (1.01 to 1.63)	1.18 ± 0.12 (0.94 to 1.57)	1.17 ± 0.10 (1.00 to 1.35)	1.19 ± 0.12 (0.94 to 1.57)
NCMCA ovality index (± SD, (range))	2.86 ± 1.03 (1.11 to 6.09)	2.24 ± 1.10 (1.11 to 4.84)	3.08 ± 0.91 (1.74 to 6.09)	2.71 ± 1.06 (1.12 to 6.52)	2.06 ± 0.61 (1.12 to 3.04)	2.99 ± 1.09^*** (1.12 to 6.52)
BMO / ASCO offset magnitude (μm ± SD, (range))	284.55 ± 140.12 (23.00 to 724.00)	176.59 ± 113.79 (23.00 to 506.00)	323.60 ± 128.53^*** (60.00 to 724.00)	218.66 ± 106.57 (29.00 to 509.00)	144.06 ± 85.94 (29.00 to 310.00)	252.23 ± 98.25^*** (42.00 to 509.00)
BMO / SFO offset magnitude (μm ± SD, (range))	348.31 ± 175.33 (31.00 to 938.00)	192.47 ± 119.81 (31.00 to 524.00)	404.68 ± 157.75^*** (84.00 to 938.00)	283.17 ± 142.54 (29.00 to 697.00)	158.83 ± 93.24 (29.00 to 322.00)	339.13 ± 124.74^*** (129.00 to 697.00)
Neural Canal Obliqueness (degree ± SD, (range))	66.02 ± 12.67 (16.00 to 83.00)	54.77 ± 17.28 (16.00 to 80.00)	70.09 ± 7.23^** (47.00 to 83.00)	64.52 ± 14.73 (16.00 to 81.00)	55.94 ± 17.24 (19.00 to 74.00)	68.38 ± 11.76 (16.00 to 81.00)
Global pNC-CT 100 (μm ± SD, (range))	106.31 ± 25.54 (55.89 to 163.86)	107.84 ± 23.10 (69.07 to 150.88)	105.76 ± 26.59 (55.89 to 163.86)	90.27 ± 30.85^** (34.45 to 189.58)	85.40 ± 28.95 (34.45 to 126.96)	92.46 ± 31.78 (43.44 to 189.58)
Page 42 Global pNC-CT 300 (μm ± SD, (range))	108.08 ± 28.73 (48.31 to 169.35)	114.67 ± 27.81 (62.94 to 154.37)	105.70 ± 28.97 (48.31 to 169.35)	93.85 ± 30.14 (35.08 to 163.88)	95.12 ± 33.05 (35.08 to 144.21)	93.27 ± 29.17 (40.17 to 163.88)
Global pNC-CT 700 (μm ± SD, (range))	110.69 ± 33.66 (46.67 to 184.56)	127.01 ± 36.67 (50.48 to 184.56)	104.79 ± 29.50 (46.67 to 182.45)	95.92 ± 31.74 (38.24 to 171.73)	102.30 ± 37.68 (39.95 to 171.73)	93.05 ± 28.74 (38.24 to 168.77)
Global pNC-CT 1100 (μm ± SD, (range))	112.12 ± 37.66 (50.33 to 192.43)	133.41 ± 46.89 (50.33 to 192.43)	104.42 ± 30.82 (54.70 to 186.07)	96.68 ± 34.55 (35.22 to 185.45)	105.71 ± 39.86 (43.28 to 185.45)	92.61 ± 31.58 (35.22 to 176.14)

Open in a new tab

Data for each group are reported for “All Eyes” as well as for “Hi-ESF and for “Non-Hi-ESF” sub-groups (Hi-ESF eyes defined to be those eyes in which the magnitude of the ESF subregion was ≥ 100 μm in at least one ONH sector – (see Methods). Within the Hi-Myo eyes (Right Panel), data in bold red with red asterisks are significantly different from the Non-Hi-Myo value (Left Panel) for the same sub-group and remain significant using a Holm-Bonferonni correction for multiple comparisons

^***

(p < 0.001

^**

p < 0.01

p < 0.05, t test). Within the Hi-ESF column of both groups, black asterisks denote data that are significantly different from the Non-Hi-ESF eyes of the same group and remain significant using a Holm-Bonferonni correction for multiple comparisons

^***

(p < 0.001

^**

p < 0.01

p < 0.05, t test).

Taxonomy topics.

Optic Nerve Head, Neural Canal, Glaucoma, 3D Imaging, Optical Coherence Tomography, Imaging Anatomy, Bruch’ Membrane Opening, Anterior Scleral Canal Opening, Myopia, Scleral Flange, Dural Sheath, Scleral Flange Opening; Glaucoma; Myopia;

Acknowledgements/Disclosure

a. Funding/ Support:

NIH/NEI R01-EY021281; Legacy Good Samaritan Foundation; Heidelberg Engineering, GmbH, Heidelberg, Germany; German Research Foundation (RE4155/1–1)

b. Financial Disclosure:

A. Jiravarnsirikul: None. H. Yang: None. JW. Jeoung: None. SW. Hong: None. J. Rezapour: None. S. Gardiner: Nonfinancial support – Heidelberg Engineering. B. Fortune: Financial support - Legacy Good Samaritan Foundation, Inotek Pharmaceuticals. M. Girard: Financial support - Abyss Processing Pte Ltd. M. Nicolela: None. L. Zangwill: None. B. C. Chauhan: Financial support - Heidelberg Engineering. C. F. Burgoyne: Financial support - NIH/NEI R01EY021281, Legacy Good Samaritan Foundation, Heidelberg Engineering.

* The above listed sponsors/funding organizations had no role in the design, conduct, analysis or reporting of this research.

c. Other Acknowledgments

Anuwat Jiravarnsirikul and Hongli Yang contributed equally to this work.

Abbreviations/Acronyms:

ASCO: anterior sclera canal opening
BM: Bruch’s Membrane
BMO: Bruch’s membrane opening
CBT: Choroidal Border Tissues – previously referred to by their histologic name (“Border tissues of Elschnig”)
CCT: central corneal thickness
CDM: clinical disc margin
CSF: Cerebrospinal Fluid
DIGS: Diagnostic Innovations in Glaucoma Study
ENC: exposed Neural Canal
EOCBT: Externally Oblique CBT
ESF: Exposed Scleral Flange
FDA: Food and Drug Administration
FoBMO: Foveal-BMO
GHT: Glaucoma Hemifield Test
Hi-ESF: Study Eyes in which the ESF region is ≥ 100 μms in at least one sector
Hi-Myo: Highly myopic eyes
Hi-Myo-Healthy: Highly myopic healthy eyes
Hi-Myo-GL: Highly myopic eyes with glaucoma
IOCBT: Internally Oblique Choroidal Border Tissues
IOP: Intraocular pressure
MD: Mean Deviation
MRW: Minimum Rim Width
NC: Neural Canal
NCMCA: Neural Canal Minimum Cross-Sectional Area
NCSFB: neural canal scleral flange bowing
Non-Hi-ESF: Study eyes in which the ESF region is < 100 μms in all sectors
Non-Hi-Myo-Healthy: Non-highly myopic healthy eyes
PSCO: Posterior Scleral Canal Opening (Not segmented in this study)
OCT: optical coherence tomography
ONH: optic nerve head
pNC: perineural canal
pNC-CT: perineural canal choroidal thickness
pNC-SB: perineural canal scleral bowing
RNFL: retinal nerve fiber layer
RNFLT: RNFL thickness
RPE: Retinal Pigment Epithelium
Sector: ONH FoBMO 30° (clock-hour) sectors (see Figure 2, Panel (A))
SFO: Scleral Flange Opening
SD: standard deviation
SE: spherical equivalent
UCSD: University of California, San Diego

Footnotes

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1. Supplemental Figure 1. Paradigm Change from the clinical examination of the optic disc to the clinical evaluation of the optic nerve head (ONH) tissues using OCT.

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2. Supplemental Figure 2. Neural canal minimum cross-sectional area (NCMCA) estimates the smallest opening through which the RGC axons pass as they leave the eye.

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NIHMS1964284-supplement-10.docx^{(100.5KB, docx)}

NIHMS1964284-supplement-11.docx^{(102.7KB, docx)}

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OCT Optic Nerve Head Morphology in Myopia IV: Neural Canal Scleral Flange Remodeling in Highly Myopic Eyes

Anuwat Jiravarnsirikul, MD

Hongli Yang, PhD

Jin Wook Jeoung, MD, PhD

Seung Woo Hong, MD, PhD

Jasmin Rezapour, MD

Stuart Gardiner, PhD

Brad Fortune, OD, PhD

Michaël JA Girard, PhD

Marcelo Nicolela, MD, PhD

Linda Zangwill, PhD

Balwantray C Chauhan, PhD

Claude F Burgoyne, MD

Abstract

Purpose:

Design:

Methods:

Results:

Conclusions:

INTRODUCTION

Figure 1. OCT-detected anatomy defines the ONH neural canal and peri-neural canal (pNC) regions and tissues.

Figure 2. OCT neural canal and scleral flange anatomy, morphologic relationships, and scleral flange opening (SFO) segmentation.

Figure 4. OCT exposed neural canal (ENC) region anatomy and segmentation in representative Non-Highly Myopic and Highly Myopic Eyes.

Figure 3. OCT-detected exposed neural canal (ENC) morphology (A) includes externally oblique choroidal border tissue (EOCBT) and/or exposed scleral flange (ESF) (B, C and D) regions.

Methods

Definitions, Conventions and Quantification Software.

Study subjects and eyes.

OCT Image Acquisition and Segmentation.

Sectoral ENC, EOCBT and ESF Measurements (Figure 5).

Figure 5. OCT Scleral Flange Opening Segmentation, Scleral Flange Surfaces, Neural Canal Wall Regions and Exposed Neural Canal Region and Sub-Region parameterization within Bruch’s Membrane Opening (BMO) reference plane.

BMO, ASCO, SFO and Neural Canal Minimum Cross-Sectional Area (NCMCA) Size and Shape Measurements (Figure 6).

Figure 6. The size and shape of three neural canal openings as well as the Neural Canal Minimum Cross-Sectional Area (NCMCA) in a representative study eye.

BMO/ASCO Offset Magnitude. (Figure 7 - left).

Figure 7. BMO/ASCO Offset Magnitude (Left) versus BMO/SFO Offset Magnitude (Right) in the representative Hi-Myo (Hi-MYO-GL-29) eye from Figures 1–6.

BMO/SFO Offset Magnitude (Figure 7 - right).

Neural Canal Obliqueness.

BMO Minimum Rim Width (BMO-MRW), pNC-Retinal Nerve Fiber Layer Thickness (pNC-RNFLT) and pNC Choroidal Thickness (pNC-CT).

Subdivision of Study eyes into Hi-ESF and Non-Hi-ESF subgroups.

Inter-observer reproducibility.

Statistical Analysis.

Multiple Comparisons.

Results

Study Subjects and Eyes.

Table 1.

Table 6.

Inter-observer ASCO and SFO Segmentation Reproducibility.

Ocular and demographic differences between the Non-Hi-Myo-Healthy and Hi-Myo eyes (Tables 1–3).

Table 3.

Table 2.

ENC region sectoral magnitude is greatest and pNC-RNFLT and pNC-CT are thinnest in the inferior-temporal sectors of both the Hi-Myo and Non-Hi-Myo-Healthy eyes (Figure 8).

Differences between the Hi-Myo Hi-ESF versus the Non-Hi-Myo-Healthy Hi-ESF eyes (Tables 1–3).

Ocular and demographic differences between Hi-Myo-Healthy and Hi-Myo-GL eyes (Tables 4 – 6).

Table 4.

ENC region sectoral magnitude as well as pNC-RNFLT and pNC-CT are decreased in the Hi-Myo-GL compared to the Hi-Myo-Healthy eyes (Figure 9).

Ocular and Demographic Factors associated with the ENC, EOCBT and ESF regions of the Hi-Myo eyes (Table 7).

Table 7.

Discussion

Table 8.

Limitations.

Summary.

Supplementary Material

Table 5.

Taxonomy topics.

Acknowledgements/Disclosure

Abbreviations/Acronyms:

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

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