Abstract
Purpose
The parapapillary gamma zone is a hallmark structural change of the optic nerve head (ONH) in pathological myopia and is closely linked to axial elongation. Cross-sectional studies suggest strong correlations between gamma zone and axial length (AL), but longitudinal data characterizing gamma zone progression and its impact on AL are scarce.
Methods
In this 10-year prospective study, 205 participants with bilateral high myopia (spherical equivalent ≤ −6.0 diopter [D]) from the Zhongshan High Myopia cohort were followed. A novel swept-source optical coherence tomography (SS-OCT)-based algorithm was developed for automated three-dimensional quantification of Bruch's membrane opening (BMO) displacement and gamma zone parameters, including area, angular extent, maximal radial extent, and spatial distribution. Associations among BMO and gamma zone metrics and myopia progression (AL, spherical equivalent, and AL change rate) were analyzed using linear and nonlinear regression.
Results
The study included 205 individuals (mean age = 14.84 ±2 .26 years). In multivariate analysis, a larger area of BMO (mean = 3.65 ± 1.06 mm²) was associated with greater AL (P = 0.039) and inversely related with spherical equivalent (SE; P = 0.001). The gamma zone area (mean = 1.71 ± 2.20 mm²) was significantly correlated with AL (P < 0.001) and SE (P = 0.003) after adjusting for confounders. The gamma zone area was used to stratify the participants into four quartiles (Q1–Q4). Quartile Q4 showed a markedly greater rate of AL change than each of the lower quartiles (P < 0.0001), which remained evident even after Q1 to Q3 were merged.
Conclusions
Progressive gamma zone enlargement is strongly associated with axial elongation in high myopia. Once the gamma zone exceeds a critical area threshold, the AL accelerates rapidly, likely reflecting compromised biomechanical counterforce from Bruch's membrane (BM). Longitudinal gamma zone monitoring may provide a valuable prognostic marker for identifying eyes at risk of accelerated and potentially irreversible myopic progression.
Keywords: parapapillary gamma zone, axial elongation, high myopia, Bruch's membrane opening (BMO), swept-source optical coherence tomography (SS-OCT)
Myopia has reached pandemic proportions worldwide, with prevalence rates exceeding 80% among adolescents, particularly in East Asia.1–4 Pathological myopia, characterized by excessive axial elongation, induces profound histological remodeling of the choroid, sclera, retina, and optic nerve head (ONH). These structural alterations underlie the characteristic features of myopic eyes, including optic disc tilt, torsion, and peripapillary atrophy,5,6 which are closely associated with myopic maculopathy and high-myopia–related glaucomatous or glaucoma-like optic neuropathy.7,8 Understanding the biomechanical processes driving axial elongation is therefore critical for developing effective strategies for prevention and intervention.
Anatomically, the ONH canal can be divided into three layers: the opening in Bruch's membrane (BM) as the innermost layer, the choroidal opening as the intermediate layer, and the opening in the peripapillary scleral flange as the outermost layer.9 Both BM and the peripapillary scleral flange have distinct anatomic apertures, the Bruch's membrane opening (BMO) and the anterior scleral canal opening (ASCO), respectively.10 Experimental and imaging studies suggest that BM undergoes active expansion during myopization, primarily at equatorial and retro-equatorial regions, while maintaining the macular architecture.11–14 This enlargement of BM leads to secondary thinning of the scleral and choroidal tissues, particularly at the posterior pole, reflecting a passive redistribution of existing tissue rather than true volumetric expansion.15 As the posterior pole moves backward, the BMO shifts toward the fovea, whereas the deeper ASCO remains relatively stationary.16–18 The resulting spatial misalignment between these layers gives rise to the parapapillary gamma zone on the temporal side of the optic disc, characterized by the absence of both BM and the retinal pigment epithelium (RPE).17–19 Correspondingly, the border tissue of Elschnig assumes an externally oblique configuration temporally and an internally oblique configuration nasally.19
Previous studies have demonstrated a close relationship between the gamma zone and axial elongation.13 The increase in the fovea–disc distance during myopic progression is primarily attributed to the enlargement of the gamma zone.20,21 Population-based data further indicate that, unlike the β-zone, the γ-zone is strongly correlated with axial length (AL) rather than age.17 Moreover, eyes with steeper peripapillary scleral angles exhibit greater AL and a larger γ-zone, supporting the notion that the gamma zone reflects localized posterior deformation of the peripapillary sclera.22
Despite these insights, most existing evidence is derived from cross-sectional investigations, leaving the longitudinal dynamics between gamma zone development and axial elongation largely unexplored, particularly in highly myopic populations. To address this gap, we developed an automated, optical coherence tomography (OCT)-based three-dimensional algorithm for precise quantification of BMO displacement and gamma zone morphology. Using longitudinal imaging data from highly myopic eyes, this study aimed to characterize the temporal evolution of the gamma zone and its components, to determine the relationship between gamma zone progression and axial elongation rate, and to elucidate the potential biomechanical mechanisms underlying posterior pole deformation in myopia.
Methods
Participants
Participants were drawn from the Zhongshan High Myopia Cohort (ZHMC, ISRCTN56368396), an ongoing longitudinal study whose methodology has been described previously. Briefly, between November 2011 and October 2012, individuals with bilateral high myopia were recruited from the Zhongshan Ophthalmic Center (ZOC), Sun Yat-Sen University, Guangzhou, China. The study adhered to the tenets of the Declaration of Helsinki and received approval from the Institutional Ethics Committee of ZOC. Written informed consent was obtained from all adult participants and from the legal guardians of pediatric subjects.
Eligible participants were aged 7 to 70 years and exhibited bilateral high myopia, defined as a spherical equivalent of ≤ −6.00 diopters (D). Exclusion criteria included: secondary myopia; history of intraocular surgery, ocular trauma, or any myopia-control intervention; ocular or systemic disorders that could affect ONH morphology or preclude visualization of BMO margins; significant media opacity (e.g, dense corneal opacity) precluding fundus imaging; and poor-quality OCT images, defined as incomplete BMO margin or ASCO demarcation spanning ≥90 degrees. Ultimately, 8 participants were excluded because they did not meet the eligibility criteria, and 205 eligible participants were included in the final analysis.
Ophthalmic Examinations
All participants underwent a comprehensive ophthalmic examination, including visual acuity testing, ocular biometry, cycloplegic refraction, Goldmann applanation tonometry, slit-lamp biomicroscopy, and color fundus photography (Canon CX-1; Canon, Tokyo, Japan). After baseline evaluation, participants were scheduled for follow-up examinations over a 10-year period. All demographic characteristics and clinical data, including SFCT, MMD category, BMO shift parameters, and gamma zone parameters, were measured at baseline. AL and spherical equivalent (SE) were measured longitudinally during the 10-year follow-up period, and the values obtained at the final follow-up were used in the regression analyses. AL change rate was calculated based on the interval between the baseline and final follow-up examinations.
Visual function was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR E charts (Precision Vision, Villa Park, IL, USA), recording both uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA). Before cycloplegia, ocular biometry parameters, including AL, corneal curvature (CC), lens thickness (LT), and anterior chamber depth (ACD) were measured with optical low-coherence reflectometry (Lenstar LS-900; Haag-Streit AG, Switzerland). For eyes exceeding the device's upper measurement limit (AL ≥ 32.0 mm), AL was reassessed using partial coherence interferometry (IOLMaster; Carl Zeiss Meditec, Jena, Germany). SE was measured under cycloplegic conditions using an autorefractor (Topcon KR-8800; Topcon, Tokyo, Japan). All measurements were obtained using calibrated clinical instruments according to the manufacturers’ protocols.
Retinal photography was performed after pharmacologic dilation with 45 degrees disc-centered and macular-centered protocols. Autofluorescence imaging (500/640 nm exciter/barrier filters) was also acquired to visualize the optic nerve–macula interface. Myopic maculopathy was graded using fundus photographs according to the International Photographic Classification and Grading System for Myopic Maculopathy (META-PM classification).23 The categories included C0, no myopic retinal degenerative lesions; C1, tessellated fundus; C2, diffuse chorioretinal atrophy; C3, patchy chorioretinal atrophy; and C4, macular atrophy. Swept-source optical coherence tomography (SS-OCT; Triton, Topcon, Tokyo, Japan) was performed for all participants. Macular imaging was acquired using the radial scan protocol, providing high-resolution maps of retinal thickness and the ganglion cell complex. ONH assessment used 6-mm 3-dimensional disc and nerve head mapping combined with 9-mm radial scanning protocols to capture detailed ONH morphology.
Certified ophthalmologists identified the presence of gamma zone and measured its width along each radial scan. The gamma zone was defined as ≥100 µm of BM termination before reaching the optic disc border, quantified as the distance between the BM termination and the disc border delineated by the interface between the lamina cribrosa and the peripapillary scleral flange, equivalent to the peripapillary border tissue of the peripapillary scleral flange.24 This ≥100 µm threshold was adopted because a smaller BM–disc border gap may be difficult to distinguish from measurement noise, segmentation variability, or subtle anatomic irregularities on OCT images, whereas this cutoff provides a more conservative and reproducible criterion for identifying true BM absence in the peripapillary region.
The circumferential gamma zone was defined as the gamma zone extending across multiple contiguous radial OCT scans around the optic disc, rather than being confined to a single focal sector. In contrast, the focal gamma zone was localized to a single sector and was categorized according to the quadrant of maximal width (temporal, inferior, nasal, or superior). Post-processing included adaptive compensation algorithms to reduce vascular shadowing and enhance delineation of the lamina cribrosa and anterior scleral surfaces.25 Quantitative measurements were performed using customized MATLAB software (MathWorks, Natick, MA, USA).
BMO Shift and Gamma Zone Quantification
A novel OCT-based algorithm was developed to enable automated three-dimensional quantification of BMO displacement and gamma zone morphology (Supplementary File S1). The analytic framework is illustrated in Figure 1. Morphometric parameters included BMO area, ASCO area, and inter-structural displacement indices, such as angular extent, deviation angle, center shift distance, and shift direction.
Figure 1.
Automated OCT-based quantification of BMO displacement and gamma zone parameters. (A) OCT image illustrating the nasal and temporal endpoints of BMO (red points) and ASCO (blue points). Bruch's membrane (BM; yellow line) and the anterior scleral surface (green line) are demarcated for structural reference. (B) BMO and ASCO are outlined in red and blue, respectively. The gamma zone (gray-shaded area) represents the spatial mismatch between BMO and ASCO. The OCT scan is divided into 24 radial sectors to represent superior, inferior, nasal, and temporal quadrants. Maximal radial gamma zone distance is defined as the largest width in any quadrant, reflecting the maximal misalignment between BMO and ASCO. Circumferential angular extent is defined as the angle between intersections of BMO and ASCO. (C) Angular extent is defined as the circumferential angle spanning the gamma zone between the two intersection points of the BMO and ASCO outlines. Maximal radial extent is defined as the greatest radial distance between BMO and ASCO among all measured sectors, representing the maximum local width of the gamma zone. (D) Center shift distance is calculated by projecting the centroid vector connecting BMO and ASCO centroids within the BMO reference plane. Deviation angle represents the angle formed between the diameter lines of BMO and ASCO. OCT, optical coherence tomography; BM, Bruch's membrane; BMO, Bruch's membrane opening; gamma zone, gamma parapapillary atrophy; ASCO, anterior scleral canal opening.
The BMO area was measured using the San Diego Automated Layer Segmentation Algorithm (SALSA).26 Details of the algorithm and its validation have been published previously.26,27 ASCO corresponds to the anterior opening of the peripapillary scleral flange. The ASCO area was estimated from the ratio of ASCO to BMO fitting ellipse areas (see Fig. 1A). Angular extent represented the angular offset between diameter lines intersecting the BMO and ASCO centroids, whereas the center shift distance was defined by the vector connecting the two centroids projected within the BMO reference plane (see Fig. 1D). The deviation angle described the angular difference between the respective diameter lines of BMO and ASCO.
Gamma zone was defined as the exposed border tissue between the BMO and the clinical optic disc margin (see Fig. 1B), which was identified on OCT images as the interface between the lamina cribrosa and the peripapillary scleral flange, corresponding to the peripapillary border tissue. The parameters of interest included the gamma zone area, maximal radial extent, and circumferential angular extent (see Fig. 1C). Maximal radial extent was defined as the greatest width measured across one of four quadrants (temporal, superior, nasal, or inferior), representing the largest local misalignment between BMO and ASCO. The spatial distribution of the maximal gamma zone extent was recorded according to clock hours: clockwise for right eyes and counterclockwise for left eyes. Spatial sectors were categorized as inferotemporal (7–8 o'clock), horizontal temporal (9 o'clock), and others, corresponding to the retinotopic projection of the visual field onto the disc.
Statistical Analysis
Categorical variables were summarized as frequencies and percentages, whereas continuous variables were presented as medians with interquartile ranges (IQRs). Demographic and clinical characteristics were compared across groups using Student's t-tests for continuous variables and χ² tests with Bonferroni correction for categorical variables. The relationship between the gamma zone area and the rate of axial elongation was assessed using locally estimated scatterplot smoothing (LOESS) regression for nonparametric curve fitting. Through a data-driven procedure, we evaluated span values of 0.3, 0.5, 0.75, and 1.0, and selected span = 0.75 degrees because it minimized the fitting error based on cross-validation. Univariate linear regression analyses were first performed to examine the associations of BMO shift parameters and gamma zone parameters with AL and SE. Variables that were statistically significant in the univariate analyses, together with variables considered clinically relevant or potentially associated with AL or SE based on prior literature, were subsequently entered into the multivariable linear regression models. Collinearity among independent variables was evaluated through correlation analysis before multivariable modeling. Associations between the gamma zone area and AL change rate were visualized using violin plots. Regression results are reported as β coefficients with corresponding 95% confidence intervals (CIs). Statistical significance was defined as P ≤ 0.05. Analyses were conducted using R software (version 4.3.2; R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline Characteristics
A total of 205 participants were included in the present study (Table 1). The mean age was 14.84 ± 2.26 years, with 96 (46.8%) male subjects and 109 (53.2%) female subjects. The mean age of myopia onset was 6.47 ± 2.76 years. Clinically, the mean AL was 27.39 ± 1.35 mm, and the mean SE was −10.23 ± 2.53 D. Mean intraocular pressure, central corneal thickness, and subfoveal choroidal thickness (SFCT) were 16.17 ± 2.11 µm, 545.85 ± 31.66 µm, and 167.07 ± 59.98 µm, respectively.
Table 1.
Baseline Characteristics of the Included Participants
| Characteristics | Overall | Group 1 | Group 2 | Group 3 | P Value |
|---|---|---|---|---|---|
| Demographic data | |||||
| Participants, n | 205 | 88 | 62 | 55 | |
| Age, y | 14.84 (2.26) | 14.82 (2.40) | 14.76 (2.14) | 14.96 (2.18) | 0.888 |
| Sex | 0.001 | ||||
| M, n (%) | 96 (46.8) | 30 (34.1) | 30 (48.4) | 36 (65.5) | |
| F, n (%) | 109 (53.2) | 58 (65.9) | 32 (51.6) | 19 (34.5) | |
| Age of myopia onset, y | 6.47 (2.76) | 6.99 (3.01) | 6.61 (2.38) | 5.46 (2.50) | 0.006 |
| Clinical data | |||||
| Axial length, mm | 27.39 (1.35) | 26.24 (0.58) | 27.52 (0.28) | 29.11 (1.00) | <0.001 |
| Spherical equivalence, D | −10.23 (2.53) | −8.80 (1.35) | −10.11 (1.82) | −12.66 (2.86) | <0.001 |
| IOP, mm Hg | 545.85 (31.66) | 544.98 (34.24) | 545.26 (28.75) | 547.91 (30.95) | 0.853 |
| CCT, µm | 16.17 (2.11) | 16.34 (2.20) | 15.77 (1.88) | 16.33 (2.19) | 0.215 |
| SFCT, µm | 167.07 (59.98) | 186.59 (59.94) | 164.55 (51.39) | 138.69 (58.04) | <0.001 |
| Myopic maculopathy, n (%) | <0.001 | ||||
| C0 | 154 (75.1) | 78 (88.6) | 43 (69.4) | 33 (60.0) | |
| C1 | 25 (12.2) | 6 (6.8) | 12 (19.4) | 7 (12.7) | |
| C2 | 25 (12.2) | 4 (4.5) | 6 (9.7) | 15 (27.3) | |
| C3 | 1 (0.5) | 0 (0.0) | 1 (1.6) | 0 (0.0) | |
| BMO shift parameter | |||||
| BMO area, mm2 | 3.65 (1.06) | 3.22 (0.71) | 3.59 (0.89) | 4.41 (1.28) | <0.001 |
| ASCO area, mm2 | 4.42 (3.06) | 3.29 (0.73) | 4.14 (1.57) | 6.56 (4.98) | <0.001 |
| Deviation angle, degrees | 26.76 (24.53) | 26.02 (22.68) | 28.51 (26.84) | 25.97 (25.01) | 0.799 |
| Center shift distance, mm | 0.51 (0.20) | 0.49 (0.16) | 0.50 (0.20) | 0.58 (0.23) | 0.017 |
| Center shift direction, n (%) | 0.492 | ||||
| Inferotemporal | 72 (35.1) | 36 (40.9) | 21 (33.9) | 15 (27.3) | |
| Temporal | 127 (62.0) | 50 (56.8) | 40 (64.5) | 37 (67.3) | |
| Superotemporal | 1 (0.5) | 0 (0.0) | 0 (0.0) | 1 (1.8) | |
| Superior | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Superonasal | 1 (0.5) | 1 (1.1) | 0 (0.0) | 0 (0.0) | |
| Inferonasal | 3 (1.5) | 1 (1.1) | 1 (1.6) | 1 (1.8) | |
| Inferior | 1 (0.5) | 0 (0.0) | 0 (0.0) | 1 (1.8) | |
| PPA parameter | |||||
| Area of γ-zone, mm2 | 1.71 (2.20) | 1.06 (0.58) | 1.45 (0.94) | 3.04 (3.77) | <0.001 |
| Angular extent of γ-zone, degrees | 159.27 (59.00) | 143.07 (35.02) | 160.15 (59.50) | 184.20 (78.18) | <0.001 |
| Maximal radial extent of γ-zone ratio | 0.68 (0.37) | 0.61 (0.30) | 0.68 (0.34) | 0.80 (0.47) | 0.011 |
| Location of maximal radial extent, n (%) | 0.066 | ||||
| Inferotemporal | 73 (35.6) | 42 (47.7) | 19 (30.6) | 12 (21.8) | |
| Temporal | 117 (57.1) | 39 (44.3) | 39 (62.9) | 39 (70.9) | |
| Superotemporal | 8 (3.9) | 3 (3.4) | 3 (4.8) | 2 (3.6) | |
| Superior | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| Superonasal | 2 (1.0) | 2 (2.3) | 0 (0.0) | 0 (0.0) | |
| Inferonasal | 1 (0.5) | 0 (0.0) | 0 (0.0) | 1 (1.8) | |
| Inferior | 4 (2.0) | 2 (2.3) | 1 (1.6) | 1 (1.8) |
ASCO, anterior scleral canal opening; BMO, Bruch's membrane opening; CCT, central corneal thickness; IOP, intraocular pressure; PPA, parapapillary atrophy; SFCT, sub-foveal choroidal thickness.
The P values in bold represent statistical significance.
According to the META-PM classification, the majority of participants (75.1%) were graded C0, 12.2% C1, 12.2% C2, and 0.5% C3. Measurements of BMO shift parameters revealed a mean BMO area of 3.65 ± 1.06 mm² and a mean ASCO area of 4.42 ± 3.06 mm². The mean deviation angle was 27.76 ± 24.53 degrees, and the mean center shift distance was 0.51 ± 0.20 mm. The direction of the center shift was predominantly temporal (62.0%) or inferotemporal (35.1%), with no superior or superonasal shifts observed. Analysis of gamma zone parameters showed a mean area of 1.71 ± 2.20 mm² and a mean angular extent of 159.27 ± 59.00 degrees. The mean maximal radial extent ratio was 0.68 ± 0.37. The maximal radial extent was most-commonly located temporally (57.1%) or inferotemporally (35.6%), with no superior locations identified.
Associations Among BMO Shift, Gamma Zone, and AL/SE
Univariate and multivariate linear regression analyses were conducted to examine associations between baseline demographic and clinical parameters with final follow-up AL and SE values (Supplementary Fig. S1; Tables 2, 3). In multivariate models, AL was significantly associated with male sex (P = 0.004), earlier myopia onset (P = 0.015), and reduced SFCT (P = 0.039). SE, in contrast, was correlated with later myopia onset (P < 0.001), thicker SFCT (P = 0.005), and less severe myopic macular disease (MMD; P = 0.005).
Table 2.
Linear Regression Analysis to Determine the Associations of Baseline BMO Shift Parameters With Axial Length and Spherical Equivalent After 10 Years of Follow-Up
| Axial Length | Spherical Equivalent | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis | |||||||||
| B | β | P Value | B | β | P Value | B | β | P Value | B | β | P Value | |
| Age, y | 0.004 | 0.007 | 0.916 | 0.072 | 0.121 | 0.054 | 0.197 | 0.176 | 0.012 | −0.093 | −0.085 | 0.170 |
| Sex, F | −0.632 | −0.235 | <0.001 | −0.411 | −0.155 | 0.004 | 0.094 | 0.019 | 0.791 | −0.295 | −0.061 | 0.260 |
| Age of myopia onset, y | −0.101 | −0.211 | 0.003 | −0.073 | −0.153 | 0.015 | 0.384 | 0.437 | <0.001 | 0.315 | 0.359 | <0.001 |
| SFCT, µm | −0.009 | −0.399 | <0.001 | −0.003 | −0.130 | 0.039 | 0.017 | 0.411 | <0.001 | 0.007 | 0.175 | 0.005 |
| MMD category | ||||||||||||
| C0/C1 | Ref | Ref | – | Ref | Ref | – | Ref | Ref | – | Ref | Ref | – |
| C2/more severe | 1.447 | 0.359 | <0.001 | 0.429 | 0.106 | 0.112 | −3.583 | −0.472 | <0.001 | −1.374 | −0.185 | 0.005 |
| BMO area, mm2 | 0.260 | 0.590 | <0.001 | 0.078 | 0.181 | 0.039 | −0.457 | −0.551 | <0.001 | −0.213 | −0.268 | 0.001 |
| ASCO area, mm2 | 0.755 | 0.594 | <0.001 | 0.384 | 0.301 | <0.001 | −1.091 | −0.456 | <0.001 | −0.136 | −0.058 | 0.448 |
| Deviation angle, degrees | 0.001 | 0.017 | 0.241 | 0.008 | 0.081 | 0.247 | ||||||
| Center shift distance, mm | 1.540 | 0.227 | 0.001 | 0.856 | 0.128 | 0.036 | −1.204 | −0.094 | 0.179 | |||
| Center shift direction | ||||||||||||
| Temporal | Ref | Ref | – | Ref | Ref | – | Ref | Ref | – | |||
| Inferotemporal | −0.354 | −0.126 | 0.075 | −0.194 | −0.037 | 0.600 | −0.217 | −0.043 | 0.425 | |||
| Other | −0.097 | −0.012 | 0.863 | −2.342 | −0.156 | 0.027 | −0.517 | −0.037 | 0.505 | |||
BMO, Bruch's membrane opening; MMD, myopic macular disease.
B, unstandardized regression coefficient; β, standardized regression coefficient.
The unit of B is expressed as mm or D per unit increase in the corresponding independent variable for axial length and spherical equivalent, respectively. For categorical variables, B represents the difference from the reference category. β is dimensionless.
AL and SE values obtained at the final follow-up examination were used as dependent variables in the regression analyses.
All demographic characteristics and clinical data, including SFCT, MMD category, and BMO shift parameter, were measured at baseline.
The P values in bold represent statistical significance.
Table 3.
Linear Regression Analysis to Determine the Associations of Baseline Gamma Zone Parameters With Axial Length and Spherical Equivalent After 10 Years of Follow-Up
| Axial Length | Spherical Equivalent | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis | |||||||||
| B | β | P Value | B | β | P Value | B | β | P Value | B | β | P Value | |
| Age, y | 0.004 | 0.007 | 0.916 | 0.069 | 0.117 | 0.060 | 0.197 | 0.176 | 0.012 | −0.103 | −0.095 | 0.134 |
| Sex, F | −0.632 | −0.235 | <0.001 | −0.549 | −0.208 | <0.001 | 0.094 | 0.019 | 0.791 | −0.193 | −0.040 | 0.460 |
| Age of myopia onset, y | −0.101 | −0.211 | 0.003 | −0.095 | −0.197 | 0.002 | 0.384 | 0.437 | <0.001 | 0.337 | 0.384 | <0.001 |
| SFCT, µm | −0.009 | −0.399 | <0.001 | −0.005 | −0.231 | <0.001 | 0.017 | 0.411 | <0.001 | 0.009 | 0.214 | <0.001 |
| MMD category | ||||||||||||
| C0/C1 | Ref | Ref | – | Ref | Ref | – | Ref | Ref | – | Ref | Ref | – |
| C2/more severe | 1.447 | 0.359 | <0.001 | 0.577 | 0.142 | 0.042 | −3.583 | −0.472 | <0.001 | −1.447 | −0.195 | 0.005 |
| Area of gamma zone, mm2 | 0.312 | 0.510 | <0.001 | 0.311 | 0.520 | <0.001 | −0.549 | −0.477 | <0.001 | −0.296 | −0.270 | 0.003 |
| Angular extent of gamma zone, degrees | 0.008 | 0.349 | <0.001 | −0.004 | −0.170 | 0.048 | −0.021 | −0.495 | <0.001 | −0.001 | −0.025 | 0.768 |
| Maximal radial extent ratio | 0.876 | 0.240 | <0.001 | −0.394 | −0.111 | 0.127 | −1.308 | −0.190 | 0.006 | 0.337 | 0.052 | 0.458 |
| Location of maximum radial extent | ||||||||||||
| Temporal | Ref | Ref | – | Ref | Ref | – | Ref | Ref | – | |||
| Inferotemporal | −0.524 | −0.187 | 0.009 | −0.479 | −0.173 | 0.002 | 0.356 | 0.067 | 0.345 | |||
| Other | −0.353 | −0.069 | 0.333 | −0.907 | −0.176 | 0.003 | −1.051 | −0.108 | 0.130 | |||
PPA, parapapillary atrophy.
B, unstandardized regression coefficient; β, standardized regression coefficient.
The unit of B is expressed as mm or D per unit increase in the corresponding independent variable for axial length and spherical equivalent, respectively. For categorical variables, B represents the difference from the reference category. β is dimensionless.
AL and SE values obtained at the final follow-up examination were used as dependent variables in the regression analyses.
All demographic characteristics and clinical data, including SFCT, MMD category, and gamma zone parameter, were measured at baseline.
The P values in bold represent statistical significance.
Multivariate analysis of BMO shift parameters identified larger BMO area (P = 0.039), larger ASCO area (P < 0.001), and greater center shift distance (P = 0.036) were significantly associated with greater AL. For SE, only BMO area demonstrated a significant inverse association (P = 0.001) after adjusting for confounders. Notably, baseline gamma zone parameters exhibited significant associations with both AL and SE in the multivariable analysis. The gamma zone area was significantly correlated with AL (P < 0.001) and SE (P = 0.003). The angular extent of the gamma zone (P = 0.048) and inferotemporal location of the maximal radial extent (P = 0.002) were also independently associated with AL.
Gamma Zone Area and Axial Elongation Rate
To further explore the relationship between the gamma zone and the process of axial elongation, participants were stratified into quartiles (Q1–Q4) based on the baseline gamma zone area (Fig. 2A). Quartiles Q1 to Q3 demonstrated comparable AL growth rates, whereas Q4 exhibited a significantly higher AL change rate compared to Q1 to Q3 (0.155 [0.098–0.223] vs. 0.070 [0.040–0.130] mm/year, P < 0.0001), a difference that persisted when Q1 to Q3 were pooled (Fig. 2B).
Figure 2.
Association between gamma zone area and axial length (AL) change rate. (A, B) Violin plots showing the distribution of AL change rates across gamma zone area quartiles. A Quartile-specific distributions: Q1, median (IQR) = 0.08 (0.040–0.125); Q2, 0.07 (0.030–0.140); Q3, 0.07 (0.035–0.140); and Q4, 0.155 (0.098–0.223). B Comparison between the lower three quartiles combined (Q1–3, median [IQR] = 0.07 [0.040–0.130]) and the top quartile (Q4, 0.155 [0.098–0.223]). (C) Nonlinear regression curve depicting the relationship between gamma zone area and AL change rate. (D) Line chart illustrating longitudinal AL changes stratified by gamma zone area. Gamma zone, gamma parapapillary atrophy; AL, axial length.
Nonlinear regression modeling revealed a triphasic pattern: initial deceleration of AL growth in Q1 (<0.59 mm²), mild acceleration in Q2 to Q3 (0.59–0.93 mm²), and rapid acceleration in Q4 (Fig. 2C). Longitudinal trends confirmed that the Q4 group exhibited faster cumulative AL increase over the 10-year follow-up compared with Q1 to Q3 (Fig. 2D). Further analysis showed that, compared with the pooled Q1 to Q3 groups, the Q4 group was significantly positively associated with the AL change rate, and this association remained significant after adjustment for age, sex, baseline AL, and SFCT (Table 4).
Table 4.
Linear Regression Analysis to Determine the Associations of Baseline Gamma Zone Area (Q4 vs. Q1–Q3) With Axial Length Change Rate (mm/year) Over 10 Years of Follow-Up
| Axial Length Change Rate | ||||||
|---|---|---|---|---|---|---|
| Univariate Analysis | Multivariate Analysis | |||||
| B | β | P Value | B | β | P Value | |
| Age, y | −0.020 | 0.003 | <0.001 | 0.062 | 0.050 | 0.222 |
| Sex, F | −0.035 | 0.017 | 0.039 | −0.497 | 0.208 | 0.019 |
| Age of myopia onset, y | −0.007 | 0.003 | 0.023 | −0.132 | 0.041 | 0.002 |
| SFCT, µm | −0.001 | 0.0001 | <0.001 | −0.007 | 0.002 | <0.001 |
| Area of γ-zone (Q4 vs. Q1-3), mm2 | ||||||
| Q1–3 | Ref | Ref | — | Ref | Ref | — |
| Q4 | 0.063 | 0.018 | <0.001 | 0.625 | 0.259 | 0.018 |
B, unstandardized regression coefficient; β, standardized regression coefficient; SFCT, sub-foveal choroidal thickness.
The regression coefficient (B) represents the change in axial length growth rate (mm/year) per unit increase in the corresponding independent variable. For categorical variables, B represents the difference from the reference category. β is dimensionless.
All demographic characteristics and clinical data, including SFCT and gamma zone parameters, were measured at baseline.
Axial length was measured longitudinally during the 10-year follow-up period, and axial length change rate was calculated based on the interval between the baseline and final follow-up examinations.
These findings suggest that gamma zone expansion beyond the Q4 threshold may represent a critical point for accelerated axial elongation and myopia progression.
Discussion
ONH alterations, particularly gamma zone expansion, are hallmark features of pathological myopia associated with axial elongation. Although cross-sectional studies have demonstrated strong correlations between the gamma zone and AL, longitudinal evidence is essential to delineate gamma zone progression and its relationship with axial elongation, thereby clarifying the dynamic remodeling of the myopic ONH and peripapillary tissues.18 In this prospective cohort study, we developed an automated OCT-based software to quantify BMO displacement and gamma zone parameters, and investigated their associations with myopia progression. In multivariable regression analyses, the BMO area and gamma zone area emerged as the variables associated with both AL and SE, suggesting their potential utility as clinically measurable markers. In contrast, the ASCO area, center shift distance, gamma zone angular extent, and the inferotemporal location of gamma zone were independently related to AL. Notably, the gamma zone area exhibited a nonlinear relationship with AL change rate; once the gamma zone area exceeded the critical threshold (Q4), AL elongation accelerated markedly compared with Q1 to Q3.
In our cohort, the gamma zone area positively correlated with both the BMO area and AL, and the BMO area itself was positively associated with AL. Axial elongation during myopization drives characteristic posterior pole remodeling, mechanistically explaining the expansion of the gamma zone and enlargement of BMO.28 In line with our findings, Guo et al. reported in a 5-year longitudinal cohort of Chinese school children that gamma zone enlargement was independently associated with greater axial elongation during myopia progression.29 This is consistent with the study by Zhang et al.,18 who documented increases in both horizontal and vertical BMO diameters. Our multivariate models further highlighted that parameters representing structural misalignment—center shift distance between BMO and ASCO and gamma zone angular extent—were positively correlated with AL. Strong collinearity between the BMO area and gamma zone area was observed, supporting the hypothesis that BMO enlargement and shift contribute synergistically to gamma zone development.17,30 The inferotemporal predominance of maximal gamma zone radial extent aligns with prior studies, which reflects asymmetric tensile stress generated by the nasal-superior orbital origin on the temporal-inferior peripapillary region.17,20 Because the optic nerve originates from the nasal-upper region of the bony orbit, the temporal-inferior and inferior peripapillary regions may be exposed to the greatest posterior traction, which may explain the inferotemporal predominance of the maximal gamma zone extent. Additionally, posterior traction transmitted through the optic nerve dura mater may stretch the temporal peripapillary scleral flange during ocular adduction, providing another explanation for temporal gamma zone enlargement.31
Importantly, our study identified a nonlinear relationship between the gamma zone area and AL change rate. Quartile analyses revealed three distinct phases: Q1 (<0.59 mm²) exhibited an inverse relationship between the gamma zone area and AL change rate; Q2 to Q3 (0.59–0.93 mm²) showed a modest increase; and Q4 (>1.47 mm²) demonstrated an acceleration in AL growth. This nonlinear pattern suggests that the emergence and expansion of the gamma zone are not merely consequences of axial elongation. Structural changes at the posterior pole may actively participate in the dynamic process of axial elongation. Therefore, we propose a self-reinforcing mechanism of myopization (Fig. 3). In emmetropic eyes, BM sits stably between the RPE and choriocapillaris. With axial elongation, misalignment develops between BM and the internal scleral surface, producing a nasal BM overhang and initiating gamma zone formation. Temporal border tissue transforms from an internally oblique to externally oblique configuration, generating localized backward displacement of the posterior peripapillary sclera. In mild or moderate myopic eyes, BM exhibits nonlinear viscoelastic behavior, stiffening with stretch, which may initially limit axial elongation.11,32 However, once AL exceeds approximately 26 mm, biomechanical stress on BM may exceed its capacity, producing larger BMO and circular gamma zone. Loss of BM counterforce allows rapid acceleration of axial elongation, driving swift myopia progression. This model is supported by our observation of both temporal and circular gamma zone in highly myopic eyes.
Figure 3.
Proposed biomechanical mechanism linking gamma zone enlargement to axial elongation. Schematic cross-sections depict ONH remodeling during progression from emmetropia (top) to moderate myopia (middle) and high myopia (bottom). (Emmetropia) BM is stably anchored between the retinal pigment epithelium (inner) and choriocapillaris (outer) with no displacement. (Moderate myopia) Axial elongation induces temporal misalignment between BM and inner scleral surface, producing a nasal BM overhang and gamma zone formation. BM's intrinsic elastic counterforce partially resists elongation, slowing AL increase. (High myopia) Excessive mechanical stress exceeds BM's biomechanical capacity. The gamma zone expands circumferentially, and loss of BM-mediated restraint accelerates axial elongation, driving rapid progression to advanced high myopia. Gamma zone, gamma parapapillary atrophy; BM, Bruch's membrane; BMO, Bruch's membrane opening.
Although BM/BMO remodeling may represent a major structural component in the formation of the gamma zone, accumulating evidence indicates that scleral biomechanics also plays an important role in this process. Consistently, Xue et al. reported that the gamma zone was associated with longer AL and larger BMO area, which is in agreement with our observation that the gamma zone area correlated with both AL and BMO area.22 However, their study further evaluated peripapillary scleral configuration, which provided complementary evidence to our study. Their novel finding was that greater backward bowing of the peripapillary sclera, quantified by the peripapillary scleral angle, was linearly and spatially associated with the presence, shape, and extent of gamma zone. This finding supported the concept that the gamma zone should not be interpreted solely as a consequence of BM/BMO displacement. Rather, the gamma zone may represent a localized manifestation of coupled BM–scleral remodeling. These cohort-based observations can be integrated with the anatomic framework proposed by Jonas et al.,11 in which regional enlargement and shifting of BM during axial elongation may induce BMO displacement, nasal BM overhang, and temporal or inferotemporal absence of BM, whereas progressive deformation of the peripapillary sclera, lamina cribrosa, and scleral canal may occur as coupled biomechanical adaptations. Our finding that the ASCO area was positively associated with AL complements previous studies by suggesting that scleral deformation may accompany axial elongation during myopia progression. Nevertheless, the respective roles of BM and sclera in myopia progression, as well as their causal relationship in gamma zone formation and axial elongation, remain incompletely defined. Future longitudinal studies are warranted to further clarify the interaction between BM and scleral during myopization.
From a clinical perspective, these findings raise the possibility that gamma zone monitoring may inform the selection or adjustment of myopia-control strategies, particularly in eyes approaching the Q4 threshold. These eyes with higher risk of accelerated axial elongation may warrant closer follow-up and consideration of timely initiation or escalation of myopia-control strategies. As participants with prior myopia-control interventions were excluded to characterize the natural course of gamma development, future longitudinal studies including treated eyes are needed to determine whether gamma zone progression can inform the selection or titration of interventions such as orthokeratology or low-dose atropine.
Several limitations merit consideration. First, all participants were Chinese adolescents recruited from an optometry clinic, which may introduce selection bias and limit generalizability. Pediatric myopia progression involves active ONH and peripapillary remodeling rather than simple passive axial elongation,19,29 whereas adult high myopia may be more strongly influenced by remodeling of an already elongated posterior segment, including chorioretinal atrophy, posterior staphyloma, BM defects, and progressive peripapillary structural deformation.11 Therefore, the gamma zone threshold identified in this adolescent cohort should not be directly extrapolated to adult high myopia populations. Future cross-age and multiethnic longitudinal studies are warranted to validate the gamma zone threshold for accelerated axial elongation. Second, we did not assess peripapillary scleral flange parameters, which may also contribute to axial elongation. Future studies should explore the quantification of BMO/gamma zone and scleral flange morphology in axial elongation to provide a more comprehensive biomarker panel for myopia progression. Third, because BM integrity was not evaluated via SS-OCT in this study, our theory remains unsupported by direct evidence. Future studies combining gamma zone quantification with direct BM imaging are needed to validate this hypothetical model. Finally, the progression of pathological myopia is a lifelong process, but this study was limited to a 10-year follow-up period. Follow-up periods of 20 years or longer are needed to determine whether the Q4 gamma zone threshold is associated with long-term outcomes, including myopic maculopathy progression and glaucomatous optic neuropathy.
Conclusions
We developed a novel OCT-based algorithm for automated quantification of BMO displacement and gamma zone parameters. Analysis revealed that gamma zone enlargement correlates strongly with myopia progression. Importantly, the gamma zone area exhibited a nonlinear relationship with AL change rate: once the gamma zone exceeded a critical threshold, AL elongation accelerated dramatically, likely due to reduced biomechanical counterforce from BM. These findings underscore the clinical relevance of monitoring the gamma zone in high myopia and provide mechanistic insight into posterior pole remodeling during progressive axial elongation.
Supplementary Material
Acknowledgments
The authors thank all staff members involved in the management and maintenance of the Zhongshan High Myopia Cohort (ZHMC). The authors also thank Guangzhou Huishi Medical Technology Co., Ltd. for its participation in the development of the novel OCT-based parapapillary atrophy (PPA) measurement software.
Supported by the GBRCE for Major Blinding Eye Diseases Prevention and Treatment, the Hainan Province Clinical Medical Center, the National Natural Science Foundation of China (82371086), the Projects of Research Center for Sharp Vision at The Hong Kong Polytechnic University (P0057931, ST), the Health and Medical Research Fund-Research Fellowship Scheme, Health Bureau, Hong Kong (07210207, ST).
Author Contributions Statements: Study concept and design: WW and MH; Acquisition, analyses, or interpretation: WW, ST, and YW; Drafting of the manuscript: WW, ST, YW, YL, ZH, HY, and ZL; Critical revision of the manuscript for important intellectual content: all authors; Statistical analyses: YW, YL, and WW; Obtained funding: WW, MH, and ST; Administrative, technical, or material support: ST and MH; Study supervision: WW and MH.
Ethics Approval: The study was approved by the Ethics Committee of Zhongshan Ophthalmic Center (Approval No. 2023KYPJ090). It was registered in the UK Clinical Trials Registry (ISRCTN56368396, https://www.isrctn.com/).
Data Availability: Access to ZHMC study data requires authorization from Zhongshan Ophthalmic Center. Requests should be directed to the corresponding author (Dr. Wei Wang, wangwei@gzzoc.com) and will be reviewed by the ZOC committee, with processing taking up to approximately 90 days. The OCT-based software developed in this study for the automated quantification of BMO displacement and gamma zone parameters is provided in Supplementary File S1 and will be made publicly available upon publication.
Disclosure: Y. Wu, None; Y. Liang, None; Z. Huang, None; Z. Li, None; H. Hong, None; B. Yan, None; M. Shang, None; Y. Xue, None; S. Tan, None; H. Yu, None; M. He, None; W. Wang, None
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