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Abstract
Aims To compare the shape of the anterior surface of the peripapillary sclera (PPS) between glaucoma and healthy subjects.
Methods 88 primary open angle glaucoma (POAG), 98 primary angle closure glaucoma (PACG) and 372 age-matched and gender-matched healthy controls were recruited in this study. The optic nerve head of one randomly selected eye of each subject was imaged with spectral domain optical coherence tomography. The shape of the PPS was measured through an angle defined between a line parallel to the nasal anterior PPS boundary and one parallel to the temporal side. A negative value indicated that the PPS followed an inverted v-shaped configuration (peak pointing towards the vitreous), whereas a positive value indicated that it followed a v-shaped configuration.
Results The mean PPS angle in normal controls (4.56±5.99°) was significantly smaller than that in POAG (6.60±6.37°, p=0.011) and PACG (7.90±6.87°, p<0.001). The v-shaped PPS was significantly associated with older age (β=1.79, p<0.001), poorer best-corrected visual acuity (β=3.31, p=0.047), central corneal thickness (β=−0.28, p=0.001), peripapillary choroidal thickness (β=−0.21, p<0.001) and presence of POAG (β=1.94, p<0.009) and PACG (β=2.96, p<0.001). The v-shaped configuration of the PPS significantly increased by 1.46° (p=0.001) in healthy controls for every 10-year increase in age, but not in glaucoma groups.
Conclusions The v-shaped configuration of the PPS was more pronounced in glaucoma eyes than in healthy eyes. This posterior bowing of the PPS may have an impact on the biomechanical environment of the optic nerve head.
- glaucoma
- imaging
- sclera and episclera
Data availability statement
Data are available upon reasonable request. The deidentified participant data were generated at the Singapore Eye Research Institute, Singapore and derived data supporting the findings of this study are available from the corresponding author (MJAG) on request.
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Introduction
Glaucoma, the leading cause of irreversible blindness worldwide, is a group of optic neuropathies derived from progressive retinal ganglion cells (RGC) loss.1 The optic nerve head (ONH) is the main site of RGC axons’ damage in glaucoma.2 Glaucomatous optic neuropathy is accompanied by structural changes of ONH tissues such as narrowing of the neuroretinal rim3 and cupping due to prelaminar thinning and bowing of the lamina cribrosa (LC).4 5 The biomechanical theory of glaucoma suggests that mechanical loads yield ONH deformations that could drive RGC cell death (directly or indirectly).6 The ONH is exposed to a number of mechanical loads including the intraocular pressure (IOP),1 the cerebrospinal fluid pressure (CSFP),7–9 optic nerve traction during eye movements10–13 and ciliary muscle pulling during accommodation.14 15
The peripapillary sclera (PPS) provides mechanical support for the ONH tissues. Specifically, the PPS and the LC bear the IOP-related stress and strain collectively as a biomechanical unit.2 Therefore, any alterations in the morphology and biomechanical properties of the PPS should strongly influence the biomechanical environment to which RGC axons are exposed within the ONH.16 17 While ex vivo studies have assessed IOP-induced deformations of the PPS,18 19 studies describing its morphology in vivo are currently lacking.
Recently, we found that the PPS followed a v-shaped configuration in elderly Chinese adults and such a shape was more pronounced with age.20 This finding was later confirmed in healthy subjects from multiple ethnic backgrounds using a wider age range.21 The posterior bowing (v-shaped configuration) of the PPS with ageing may explain increased susceptibility of RGC axons to IOP due to a changed structural support within the ONH. In this study, we aimed to assess the shape configuration of the PPS in glaucoma eyes and in eyes from age-matched and gender-matched healthy controls.
Methods
Subject recruitment and clinical tests
Totally 186 glaucoma cases were recruited from the glaucoma clinics at Singapore National Eye Centre. Of 372 healthy controls with age and gender matched to the glaucoma cases were selected from the database of our previous work.20 The angles of the PPS were analysed and compared between primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG) and healthy controls. The study was approved by the SingHealth Centralized Institutional Review Board and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
Glaucoma cases were defined by the presence of glaucomatous optic neuropathy, defined as vertical cup-to-disc ratio of >0.7 and/or neuroretinal rim narrowing with corresponding visual field defect(s). The detailed criteria for glaucomatous visual field defect were described in detail in our previous papers.20 22 Subjects with spherical equivalent (SE) less than minus three dioptres were excluded from this study to avoid potential confounding effects from moderate and high myopia.
Optical coherence tomography imaging and processing
The ONH of one randomly selected eye of each subject was imaged with enhanced depth imaging spectral domain optical coherence tomography (OCT) (SD–OCT; Spectralis, Heidelberg Engineering, Germany). Each OCT volume (raster scan) consisted of 97 serial horizontal B scans (384 A scans per B scans and 20 B scans averaging) covering a rectangular region of 15°×10° centred on the ONH. The distance between consecutive B scans was slightly different across eyes and was around 32 µm. The resolution of each B scan was 3.9 µm axially and around 12 µm horizontally.
Raw OCT volumes were enhanced using adaptive compensation. The compensation algorithm was able to increase the visibility of the anterior PPS surface by removing blood vessel shadows and improving tissue contrast.23 24 Each enhanced OCT volume was resampled to obtain a central slice in the subject-specific fovea-disc direction. Specifically, the fovea-disc axis was manually marked and recorded using MATLAB (MathWorks, Natick, Massachusetts, USA) from scanning laser ophthalmoscopy fundus image of the corresponding OCT scan. Resampling was performed using the Resample Transformed Image module with a Lanczos interpolation algorithm in the 3D visualisation software Amira (V.6.0; FEI, Hillsboro, Oregon, USA). Resampled images had the same resolution as the original B scans.
Measurements of ONH parameters
The central (horizontal) slice in the fovea-disc direction of each ONH was analysed with a custom-written MATLAB application. For each image, Bruch’s membrane (BM) opening (BMO), defined as the end point of the BM layer or the retinal pigment epithelium/BM complex on both side of the ONH, was manually marked first. A peripapillary ring was defined from the BMO centre with an inner and outer radii of 1200 µm and 1800 µm. The projections of these two rings were automatically added to the image as four vertical lines (figure 1). The BM and the PPS within the rings were then manually delineated by a single grader (TAT). The position of the PPS was defined by a sharp change in axial signal intensity. Using the aforementioned delineations, the following ONH parameters were automatically calculated by the MATLAB application. Note that a detailed description of these parameters can be found in our previous study.20
Illustration of the measurements of ONH parameters. The top row of the figure shows the location of the assessed B-scan on the scanning laser ophthalmoscopy fundus image. (A) BMO was marked from the central B-scan first. Then a peripapillary ring was defined from the BMO centre with an inner and outer radius of 1200 μm and 1800 μm. The BM and anterior scleral surface within the ring were delineated subsequently. (B) All measurements were automatically calculated from these delineations. BMO,Bruch’s membrane opening; PPS, peripapillarysclera; ONH, optic nerve head.
PPS angle
The PPS angle was defined as the angle between a line parallel to the nasal side of the anterior boundary of the sclera and another line parallel to the temporal side (figure 1B). The direction of each parallel line was defined by the two end points of the considered PPS segment in the peripapillary ring (figure 1B). A negative value indicates that PPS follows an inverted v-shaped configuration (peak pointing towards the vitreous; figure 2A). A positive PPS angle value (between the two lines) indicates that PPS follows a v-shaped configuration (peak pointing towards the orbit; figure 2B).
OCT images of (A) a normal subject with a negative PPS angle and (B) a PACG subject with a positive PPS angle. OCT, optical coherence tomography; PACG, primary angle closure glaucoma; PPS, peripapillary sclera.
Peripapillary choroidal thickness
The peripapillary choroidal thickness (ChT) was defined as the thickness between the BM and PPS boundaries within the peripapillary ring and was represented as a mean thickness in micrometres (figure 1A).
Statistics
Demographic and ocular characteristics were compared among normal, POAG and PACG groups. Continuous variables were described by their mean and SD. We used t-tests with false discovery rate correction to compare the differences of demographic and ocular parameters among groups. We used univariate and multivariate linear regression models to assess the correlations of the PPS angle with demographic and ocular parameters. Correlations of the PPS angle with other parameters were further assessed within each group (control, POAG and PACG) in a subgroup analysis, using univariate and multivariate regressions. Variables with p value less than 0.2 in the univariate analysis were subsequently included in the multivariate analysis. Statistics were performed using R (V.4.0.0, R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at p<0.05.
Results
Subjects and ocular parameters
Table 1 shows the demographic and ocular characteristics of the study subjects. There were 88 POAG, 98 PACG cases and 372 healthy controls in the analysis. There were no differences in age among healthy controls (66.07±7.09 years, range: 48–82 years), POAG (66.98±7.93 years, range: 47–84 years) and PACG (65.89±6.92 years, range: 49–81 years) groups. The axial length of POAG cases (24.14±1.22 mm) was significantly higher than that of normal controls (23.47±0.89 mm; p<0.001) and PACG subjects (23.15±0.79 mm; p<0.001). The axial length of PACG eyes was significantly smaller than that of heathy controls (23.15±0.79 vs 23.47±0.89 mm; p=0.004). IOP in PACG eyes was significantly higher than that in control eyes (16.04±3.44 vs 14.91±2.46 mm Hg, p=0.008). The disc size of healthy eyes (1.64±0.18 mm) was significantly smaller than those of POAG (1.72±0.22 mm; p=0.008) and PACG eyes (1.71±0.19 mm, p=0.008). SE was significantly greater in PACG eyes compared with POAG and healthy eyes (table 1). The mean PPS angle in normal control was significantly smaller than that in POAG (4.56±5.99° vs 6.60±6.37°, p=0.011) and PACG (4.56±5.99° vs 7.90±6.87°, p<0.001).
Demographic and ocular characteristics of the 558 study subjects
Correlations of PPS angle with demographic and ocular characteristics
In the multivariate linear regression analysis, the PPS angle increased by 1.44° for every 10-year increase in age, decreased by 0.21° for every 10 µm increase in central cornea thickness (CCT), decreased by 0.15° for every 10 µm increase in ChT, increased by 1.94° in the presence of POAG and increased by 2.95° in the presence of PACG (table 2). PPS angle was significantly correlated with best-corrected visual acuity (BCVA) under univariate analysis but not under multivariate analysis.
Linear regression models: peripapillary sclera angle with demographic and ocular parameters
Correlations of PPS angle with demographic and ocular characteristics in subgroups
In the subgroup analysis, univariate regression showed that age, CCT, ChT were significantly associated with PPS angle in normal and POAG groups (table 3 and figure 3). Furthermore, BCVA and SE were significantly associated with PPS angle in POAG group but not in the normal group. None of the parameters was correlated with PPS angle in PACG group.
Rate of changes of PPS angle with age in normal, POAG and PACG groups. y = b + ax is the linear regression model; R is Pearson correlation coefficients. PACG, primary angle closure glaucoma; POAG, primary open angle glaucoma; PPS, peripapillarysclera.
Linear regression model: peripapillary sclera angle with demographic and ocular parameters in subgroups
In POAG group, PPS angle was only correlated with ChT and SE under multivariate analysis (table 3). Age, CCT, ChT were still significantly associated with PPS angle in the normal group under multivariate analysis. None of the parameters was correlated with PPS angle in PACG group under multivariate analysis.
Discussion
In this case–control study, we compared the shape of the anterior sclera in the peripapillary region between glaucoma cases and normal controls. The v-shaped configuration (posterior bowing) of the PPS was more pronounced in glaucoma cases when compared with healthy eyes. The posterior bowing of the PPS was more prominent with increasing age, thinner cornea, thinner choroid. We believe that posterior bowing of the PPS with age and glaucoma may strongly influence the biomechanical environment of the ONH, which could in turn further accelerate glaucoma progression.
The v-shaped configuration of the PPS between glaucoma and controls
In this study, we found that the anterior sclera of both POAG and PACG eyes had a more pronounced v-shaped configuration indicating a more posteriorly bowed PPS in glaucoma subjects when compared with age-matched and gender-matched controls. Our results are related to our previous study, in which we also found that the anterior sclera had a more pronounced v-shaped configuration in older subjects.20 Under normal loading conditions, the PPS configuration is likely a result of the interactions between mechanical loads (such as IOP and CSFP) and the stiffness and morphology of ocular tissues.25 26 However, with ageing, several phenomena could alter this delicate balance of forces, including the degeneration of ONH connective tissues (especially elastin), scleral thinning,27 28 a reduction in CSFP29 and an increased optic nerve traction force due to the stiffening of the optic nerve dura sheath. All of these may drive the obliqueness of the PPS boundaries that have been observed in elderly subjects through a growth and remodelling process. We also speculate that the bowing of the PPS in old age may make the ONH more susceptible to mechanical loads, especially IOP. Specifically, since IOP is perpendicular to the loading surface, a more posteriorly bowed PPS may lead to a larger force component in the lateral direction, which may increase the stresses and strains within the LC30 and endanger RGC axons.
Bellezza et al 31 showed that the connective tissues (the LC and scleral canal wall) of the ONH changed early in an experimental model of glaucoma, and that ‘permanent’ posterior deformations were seen in those ONHs in early stages of glaucoma. Wu and associates32 also reported that progressive posterior deformations of the anterior LC surface were observed prior to detectable retinal nerve fibre layers’ thinning and visual field defect. These long-term deformations are likely to be driven by a phenomenon known as tissue growth and remodelling, a similar process that could affect the obliqueness of the PPS as reported in this study. We believe that providing improved understanding of ONH morphology as presented herein will be required to improve our understanding of glaucoma.
Changes of the PPS shape with age
We and others have previously found that the v-shaped configuration (or posterior bowing) of the PPS increased with age in healthy adults.20 21 In this study, we found that the posterior bowing of the PPS was also positively correlated with age in normal and POAG subjects in the univariate analysis. However, in the multivariate analysis, the correlation was significant only in normal eyes (table 3). It could be because the PPS angle of glaucoma eyes was larger at young age, thus the rate of progression with ageing was smaller and less significant when compared with normal eyes. It is also possible that the connective tissues might be stiffer in POAG and PACG eyes, as previously speculated,33 34 thus limiting structural changes of the PPS. Further studies are required to quantify the impact of PPS obliqueness on the biomechanical responses of the ONH and the corresponding consequences of progressive bowing or obliqueness of the scleral boundaries with ageing and glaucoma.
The PPS shape is correlated with other ocular parameters
Overall, we found that the v-shaped configuration of the PPS was associated with a thin cornea and a thin choroid in multivariate analysis. The same trend was observed in normal and POAG groups for choroidal thickness and only in healthy controls for CCT. The existence of a thin cornea and a deep cup has already been confirmed as risk factors for the development of POAG from ocular hypertension35 and for the progression of glaucoma.36 The v-shaped configuration of the PPS could be an additional risk factor together with these ocular determinants in POAG. It should be noted that in the multivariate analysis, CCT was not correlated with PPS angle in POAG group. A longitudinal study would be required to confirm whether the change in PPS shape is a good predictor for the onset and progression of glaucoma. In addition, differences in the determinants of PPS shape between PACG and POAG may suggest the possible existence of inherently different mechanisms involved in glaucoma development and progression or similar mechanisms but with different extents of vulnerability of the ONH in the response of mechanical loading. As both POAG and PACG groups have a larger PPS angle compared with those of normal controls, one can also speculate that a more posteriorly bowed PPS is a consequence of glaucoma. Again, longitudinal studies are needed to confirm whether PPS bowing is a cause or consequence of glaucoma.
Limitations
There are a number of limitations in our study. First, this cross-sectional study does not allow us to draw conclusions on a causal relationship between PPS angle and glaucoma. A longitudinal study is required in future studies to further explore the relationship between PPS angle and the onset and progression of glaucoma. Second, the posterior surfaces of the PPS were not visible. Thus, the thicknesses of the PPS were not assessed, which is an important factor that may influence the PPS angle. Third, only one central B scan in the horizontal direction was used to define the two-dimensional shape of the PPS. It is possible that PPS shape in the vertical direction could be more relevant to glaucoma. Therefore, a three-dimensional shape definition may be required to observe the entire and sectoral difference of the PPS configuration.
Conclusions
In this study, the PPS followed a v-shaped configuration that was more pronounced in glaucoma eyes; it was associated with thinner cornea and thinner choroid. The posterior bowing of the PPS that is known to exist with ageing and glaucoma may have an impact on the biomechanical environment of the ONH and could potentially affect glaucoma progression.
Data availability statement
Data are available upon reasonable request. The deidentified participant data were generated at the Singapore Eye Research Institute, Singapore and derived data supporting the findings of this study are available from the corresponding author (MJAG) on request.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors Design of study: XW, TAT, MJAG, C-YC and TA. Conduct of study: TAT, XW and MEN. Collection and management of data: TAT, XW, YCT and HMH. Analysis and interpretation of data: XW, TAT, HMH, YCT and MJAG. Preparation of manuscript: XW, TAT, TA and MJAG. Review or approval of manuscript: NGS, TA, C-YC and MJAG.
Funding The study was supported by Beijing Natural Science Foundation (7194288 (XW)) and National Natural Science Foundation of China (12002025 (XW)), by the Singapore Ministry of Education Academic Research Funds Tier 1 (R-397-000-294-114 (MG)) and Tier 2 (R-397-000-280-112 and R-397-000-308-112 (MG)), by the National Medical Research Council (TA; NMRC/STAR/0023/2014), and by the National Institute for Health Research, Biomedical Research Centre, Moorfields Eye Hospital National Health Service, Foundation Trust and University College London, Institute of Ophthalmology (NGS). The sponsor or funding organisation had no role in the design or conduct of this research. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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