Factors Affecting Plastic Lamina Cribrosa Displacement in Glaucoma Patients

Abstract

Purpose.: To investigate factors associated with irreversible components of anterior lamina cribrosa (LC) depth in glaucoma patients.

Methods.: A total of 141 glaucoma patients and 51 healthy control subjects were enrolled. The optic nerve head (ONH) was imaged using the enhanced depth imaging (EDI) modes of Spectralis optical coherence tomography (OCT). The depth of the LC was measured at the midhorizontal, superior, and inferior midperipheral regions of the ONH of each eye. Analyzed factors associated LC depth included age, axial length, intraocular pressure (IOP), disc size, central corneal thickness, average retinal nerve fiber layer (RNFL) thickness, and mean deviation (MD).

Results.: In glaucoma patients, the LC was more deeply located compared with the control group at the midhorizontal and superior and inferior midperipheral B-scans (All P < 0.001). Age, initial IOP, and treated IOP was correlated with mean LC depth (All P < 0.001), and those correlations remained after adjusting for MD and RNFL thickness (All P < 0.001). In multivariate analysis, younger age, high untreated IOP, and thinner RNFL thickness was significantly associated with a deeper LC (P = 0.015, <0.001, and 0.042). There was an interaction between age and MD as predictors for LC depth (P = 0.007).

Conclusions.: The anterior LC surface is more deeply located in glaucoma patients compared with healthy controls. In glaucoma patients, age, initial IOP, and RNFL thickness were influential factors related to LC depth. These factors should be considered in clinical application of plastic LC displacement in glaucoma patients.

Introduction

The lamina cribrosa (LC) is a sieve-like collagenous structure through which retinal ganglion cell axons traverse.^1,2 Many researchers have suggested that intraocular pressure (IOP)–induced forces (stress) and resulting deformation of tissues of the optic nerve head (ONH; strain), such as the LC contribute to the pathogenesis of glaucoma.^3–5 Burgoyne et al.³ suggested that deformation of the LC within the ONH is a manifestation of IOP-related connective tissue damage and that axonal damage is likely to occur concurrently with LC damage.³ 

Experimental glaucoma monkey models have demonstrated progressive posterior migration of the anterior and posterior LC insertions.⁶ The LC is located more posteriorly within the ONH in glaucomatous eyes than in healthy eyes, based on histologic studies using glaucomatous eyes or in vivo studies using enhanced depth imaging optical coherence tomography (EDI OCT).^7–9 Therefore, a deep LC may indicate that the ONH has been put under substantial mechanical stress. 

There is a wide spectrum of individual susceptibility to IOP-related glaucomatous axonal loss.⁴ To understand individual sensitivity to IOP, it seems to be important to investigate how biomechanic effects of elevated IOP on ONH are influenced by the tissue's properties.⁵ However, direct measurement of the ONH biomechanical environment is challenging. An alternative approach is to use animal experiments or models. A computational model designed by Sigal et al.¹⁰ suggested that ONH biomechanics are strongly dependent on sclera biomechanical properties and are also influenced by eye size. Their study was limited because the effects of input factor variations were only tested by altering input factors separately from an assumed baseline model, and models can be somewhat arbitrary. 

Investigation of posterior LC displacement in glaucoma patients in vivo and determination of its associated factors may be helpful to understand the biomechanics of ONH. Using Stratus OCT, our group previously reported a strong negative correlation between the age and LC depth in POAG patients.¹¹ With the advent of EDI mode spectral-domain optical coherence tomography (SD-OCT), it has become possible to evaluate the morphology and anterior surface of the LC more specifically in vivo.^12–15 Recently, Ren et al.¹⁶ found that older eyes have a lamina that is shallower than younger eyes at a given level of visual field and this age-related difference increases with advancing disease severity. Their study evaluated LC depth only in high–risk ocular hypertension and early glaucoma patients. 

The purpose of this study was to determine the factors that are independently associated with the anterior LC depth in a large sample size of early- to advanced-stage glaucoma patients. We included several clinical factors that have not been determined yet including age, IOP, axial length in the multivariate analysis. Investigation of anterior LC depth in glaucoma patients under treatment may represent plastic, permanent deformation of the LC rather than hypercompliant change. We presumed that knowledge of other factors besides the IOP could help clarify the biomechanical response of the ONH and the pathogenesis of glaucoma. 

Methods

This cross-sectional, case-control study protocol was approved by the institutional review board of the Catholic University of Korea, Seoul, Korea. The study design followed the tenets of the Declaration of Helsinki for biomedical research. Individuals meeting the eligibility criteria were enrolled between August 2013 and October 2013 in the Department of Ophthalmology, St. Mary's Hospital, Seoul, Korea. 

Inclusion criteria for all patients included a best-corrected visual acuity of 20/40 or better, refractive error of greater than −7 spherical diopters (D), a 2 D cylinder, open angle on gonioscopy, and a transparent ocular medium (nuclear color or opalescence, cortical, or posterior subcapsular lens opacity < 1) according to the Lens Opacities Classification System III.¹⁷ Exclusion criteria included a history of ocular trauma, intraocular surgery, systemic, or ocular conditions other than glaucoma known to affect the optic nerve structure, and consistently unreliable visual fields. 

Each patient had undergone comprehensive ophthalmic examinations, including a best-corrected visual acuity test, slit-lamp biomicroscopy, IOP measurement by Goldmann applanation tonometry, gonioscopy, central corneal thickness measurements using ultrasonic pachymetry (SP-3000; Tomey Corp., Nagoya, Japan), and dilated fundoscopic examination. Stereoscopic optic disc photography and monoscopic red-free digital fundus photography (Canon Cf-60 UW with Canon EOS D-6 CCD camera; Canon, Tokyo, Japan) were performed. Standard automated perimetry (SAP) was performed using a Humphrey field analyzer (Carl Zeiss Meditec, Dublin, CA, USA), applying the Swedish interactive threshold algorithm (SITA) standard and program 24-2 test. A reliable test was defined as less than 30% fixation losses, false-positives, or false-negatives. The visual field indices, expressed as the mean deviation (MD) and the pattern standard deviation (PSD), were also evaluated. A visual field was defined as a glaucomatous visual field defect if repeatable SAP results revealed a cluster of three or more points that were lower than a 5% probability level or a cluster of two or more points that were lower than a 1% probability level, PSD with a 5% probability level or lower, or glaucoma hemifield test outside normal limits. 

Primary open-angle glaucoma was defined as the presence of a glaucomatous optic disc (diffuse, focal thinning of the neuroretinal rim, or notching), an untreated IOP greater than 21 mm Hg, and an associated glaucomatous visual field defect without ocular disease or conditions that may elevate the IOP. Patients were defined as having normal tension glaucoma (NTG) if they had an abnormal glaucomatous optic disc, a glaucomatous visual field defect, and IOP less than or equal to 21 mm Hg during the repeated measurements taken on different days. The healthy control group was defined as those having normal anterior and posterior segments, an IOP less than or equal to 21 mm Hg with no history of increased IOP, an absence of glaucomatous disc appearance (i.e., intact neuroretinal rim without pallor of the optic disc, peripapillary hemorrhages), and no visible RNFL defect according to red-free photography, with no abnormality on SAP. 

We divided the glaucoma patients into three stages of glaucoma progression depending on their MD score, as defined by Anderson and Patella's classification: the early stage (MD ≥ −6 dB), the moderate stage (−12 dB ≤ MD < −6 dB), and the advanced stage (MD < −12 dB).¹⁸ 

EDI of the ONH

The ONH was imaged using SD-OCT (Spectralis OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) via the EDI technique. Imaging was performed within 3 months of stereoscopic photography and SAP. A new, upgraded program of Heidelberg Spectralis (Heidelberg Engineering GmbH) included an EDI mode, which automatically places the OCT reference plane toward the bottom of the OCT acquisition screen.¹⁶ The zero delay is then placed at the bottom of the screen, which enhances the images from the deeper layers of the ONH without inverting the image. The OCT device was set to image a 15° × 10° rectangle for horizontal scans covering the optic disc. This rectangle was scanned into approximately 65 sections, each of which had on average 42-OCT frames. From these horizontal B-scans, three frames (center, midsuperior, midinferior) that passed through the ONH were selected. 

Measuring the LC Depth

The anterior LC depth was determined by measuring the distance from the Bruch's membrane opening plane to the level of the anterior LC surface. The anterior borders of the LC were defined by the highly reflective structure below the optic cup. The line connecting the two termination points of Bruch's membrane edges was used as a reference plane for LC depth measurements (Fig. 1). The distance from the reference line to the level of the anterior border of the LC was measured at three points (vertical center of reference line, temporally and nasally 100 μm from the center of reference line). The average of the three values was defined as the anterior LC depth of the B-scan. We averaged LC measurements of each B-scan and used it as mean LC depth. We also measured the maximum LC depth of each eye (the maximum value among the maximum LC depths in center, midsuperior, and midinferior scans). All measurements were performed using ImageJ software (http://imagej.nih.gov/ij/; provided in the public domain by the National Institutes of Health, Bethesda, MD, USA). When the anterior border of the LC was not visualized clearly on a particular B-scan image, an adjacent, horizontal EDI OCT scan was used for measurements. When the margin of the anterior LC was not visualized clearly even in the adjacent scans, we excluded those eyes. 

Figure 1

 

Measurement of anterior LC depth using SD-OCT (A). Lamina cribrosa depth was estimated at the 3 B-scans (mid-superior, center, mid-inferior). (B) Distances from the reference line connecting both ends of Bruch's membrane and the anterior border of the LC were measured at three points: the center of the reference line (white arrow) and two additional points at 100 μm from the central point of the reference line in the temporal and nasal direction, respectively. The anterior borders of the LC were defined by the highly reflective structure below the optic cup. The distance from the reference line to the anterior LC surface was defined as the anterior LC depth. The average of the three measurements obtained from the three points was considered the representative value of the anterior LC depth at each B-scan.

To evaluate the intraobserver and interobserver reproducibility of the LC depth measurement, 30 randomly selected SD-OCT cross-sectional B-scans were evaluated. The absolute agreement of a single observer's measurement and the measurements conducted by the two observers were calculated with the intraclass correlation coefficient (ICC) from a two-way mixed-effect model. 

Spectralis OCT for Peripapillary RNFL Measurement

Spectral-domain OCT imaging was performed with a Heidelberg Spectralis OCT system, which provides up to 40,000 A-scans per second. A scan circle with a diameter of 3.45 mm was positioned manually at the center of the optic disc. The Spectralis OCT software calculates the average RNFL thickness for the overall globe (360°). The peripapillary RNFL thickness evaluated in this study was average RNFL thickness. As suggested by the manufacturer, scans with a signal strength of less than 15 (range, 0–40) were excluded from the analysis. 

Confocal Scanning Laser Ophthalmoscopy

Topographic analysis of the ONH was performed using confocal scanning laser ophthalmoscopy with a Heidelberg Retina Tomograph II (HRT II; Heidelberg Engineering GmbH). The spherical equivalent refractive error of each eye was adjusted in the dioptric ring of the HRT. The topographic images were obtained through dilated pupils and were analyzed using Advanced Glaucoma Analysis 3.0 software (Heidelberg Engineering GmbH). All scans were required to have an intrascan SD of less than 30 μm. In cases of poor centration (more than one-quarter of the disc outside the target circle), the scans were excluded from analyses. The margin of the optic disc was traced manually by experienced users while viewing the stereo photographs under a stereoscopic viewer, and the inner edge of Elschnig's ring was defined by at least a four-point contour line. This was reviewed by a glaucoma specialist (CKP) who was blinded to patient identity and clinical history. The HRT II software displays several windows in which the topographic results are detailed. Regarding optic disc stereometric parameters, disc area was used in this study. 

Statistical Analysis

Statistical analyses were performed using SPSS software (ver. 17.0; SPSS, Chicago, IL, USA). Differences between the two groups were assessed using Student's t-test for continuous parameters and the χ² test for categoric parameters. The correlation between parameters was evaluated using the Pearson correlation coefficients and partial correlation coefficients. Regression analysis was used to determine the factors associated with the anterior LC depth in glaucoma patients. A value of P less than 0.05 was deemed to indicate statistical significance. 

Results

Of the 199 subjects initially enrolled, seven were excluded due to poor image quality or vascular shadowing, leaving 141 glaucomatous eyes and 51 healthy eyes to be enrolled in this analysis. All subjects were Asian (Korean). There was no significant difference in RNFL thickness, MD, and mean LC depth between the included eyes and the excluded eyes (all P > 0.05). Table 1 lists the demographics of the study population. No significant differences appeared in terms of age, sex, axial length, or disc size between the healthy and glaucoma patients. The initial IOP was higher in the glaucoma group (21.37 ± 6.13 mm Hg) than in the healthy group (14.26 ± 2.74 mm Hg, P < 0.001). No significant differences appeared between the IOP in the healthy control group and the treated IOP (13.86 ± 3.10 mm Hg) in the glaucoma group (P = 0.448). In glaucoma patients, the mean MD was −9.00 ± 7.65 dB (range, −29.83–1.54 dB). Overall, 71 eyes had normal-tension glaucoma and 70 eyes had POAG. 

Table 1

 

Clinical Characteristics of Subjects in the Study

	Control, n= 51	Glaucoma, n= 141	PValue*
Age, y	55.9 ± 11.6	59.3 ± 13.0	0.122
Sex, male/female	19/32	57/84	0.740
Initial IOP, mm Hg	14.26 ± 2.74	21.37 ± 6.13	<0.001
Treated IOP, mm Hg	14.26 ± 2.74	13.86 ± 3.10	0.448
Axial length, mm	23.83 ± 1.06	23.93 ± 1.18	0.597
CCT, μm	536.81 ± 27.02	533.13 ± 31.67	0.501
Disc size, mm2	2.07 ± 0.40	2.18 ± 0.45	0.163
RNFL thickness, μm	94.10 ± 6.48	68.56 ± 12.66	<0.001
MD, dB	−0.39 ± 1.14	−9.00 ± 7.65	<0.001
PSD, dB	1.56 ± 0.33	7.80 ± 4.40	<0.001
LC depth, μm
Inferior	285.90 ± 92.69	464.74 ± 114.76	<0.001
Midhorizontal	306.00 ± 85.14	471.77 ± 125.47	<0.001
Superior	320.30 ± 96.22	521.30 ± 133.04	<0.001
Mean	306.32 ± 87.21	487.18 ± 119.58	<0.001
Maximum	340.61 ± 90.20	537.64 ± 123.10	<0.001

 CCT, central corneal thickness; IOP, intraocular pressure; LC, lamina cribrosa; MD, mean deviation; PSD, pattern standard deviation.

 Statistically significant values (P < 0.05) are shown in bold.

*  Student's t-test for continuous variables and χ² test for categorical data between control and glaucoma group.

The reproducibility of the anterior LC depth measurement by two observers was excellent (ICC = 0.990 and 95% confidence interval [CI] = 0.978–996). Intraobserver ICC values for the anterior LC depth were also excellent (0.992, CI = 0.983–0.997). 

Anterior LCs were located deeper in the ONH in the glaucoma patients than in the healthy groups on inferior, midhorizontal, and superior scans (all P < 0.001). Mean LC depth in the glaucoma group (487.18 ± 119.58 μm) was significantly greater than in the healthy group (306.32 ± 87.21 μm, P < 0.001; Table 1). Maximum LC depth is 340.61 ± 90.20 μm in control group and 537.64 ± 123.10 μm in the glaucoma group (P < 0.001) 

In the glaucoma group, age was negatively correlated with anterior LC depth (r = −0.394, P < 0.001; Table 2, Fig. 2) and the initial and treated IOP was positively correlated with the anterior LC depth (r = 0.391, P < 0.001; r = 0.320, P < 0.001, respectively). The correlation between LC depth and age, initial and treated IOP remained after adjusting MD and RNFL thickness (r = −0.339, P < 0.001, r = 0.419, P < 0.001, r = 0.256, P < 0.001, respectively). 

Figure 2

 

Scatterplot of mean LC depth versus age (A), mean LC depth versus initial IOP (B), and MD versus age (C).

Table 2

 

Correlation Between Clinical Parameters and Mean LC Depth

	r*	PValue	r†	PValue†
Age	−0.394	<0.001	−0.339	<0.001
Initial IOP	0.391	<0.001	0.419	<0.001
Treated IOP	0.320	<0.001	0.256	0.004
Axial length	−0.004	0.965	−0.004	0.965
Disc size	0.108	0.223	0.162	0.078
CCT	0.050	0.585	−0.032	0.735

*  Statistically significant values (P < 0.05) are shown in bold.

*  r, Pearson's correlation coefficient.

†  r, Partial correlation coefficient adjusted by MD and RNFL thickness.

Age showed a negative correlation with treated IOP (r = −0.229, P = 0.006) and axial length (r = −0.511, P < 0.001), MD (r = −0.216, P = 0.010), and RNFL thickness (r = −0.187, P = 0.026; Table 3). Initial IOP displayed a negative correlation with MD (r = −0.301, P = 0.001), and RNFL thickness (r = −0.222, P = 0.017). 

Table 3

 

Correlation Among Clinical Factors

	Initial IOP		Treated IOP		Axial Length		Disc Size		CCT		MD		RNFL Thickness
	r	PValue	r	PValue	r	PValue	r	PValue	r	PValue	r	PValue	r	PValue
Age	−0.123	0.189	−0.229	0.006	−0.511	<0.001	−0.015	0.860	−0.114	0.202	−0.216	0.010	−0.187	0.026
Initial IOP			0.384	0.001	−0.146	0.166	0.080	0.401	0.125	0.214	−0.301	0.001	−0.222	0.017
Treated IOP					0.033	0.723	−0.002	0.985	0.347	<0.001	0.085	0.318	0.013	0.877
Axial length							−0.137	0.156	0.087	0.355	0.167	0.072	0.105	0.260
Disc size									−0.144	0.124	−0.135	0.121	−0.128	0.143
CCT											0.178	0.047	0.020	0.822

 Statistically significant values (P < 0.05) are shown in bold. r, Pearson's correlation coefficient.

In a multivariate analysis of factors affecting LC depth in glaucoma subjects, younger age, high initial IOP, and thin RNFL thickness were risk factors for a deeper LC (P = 0.015, <0.001, 0.042; Table 4). There was an interaction between age and MD as predictors for LC depth (P = 0.007). 

Table 4

 

Univariate and Multivariate Analysis of the Factors Associated With Mean LC Depth in Glaucoma Patients

	Univariate Analysis			Multivariate Analysis
	Regression Coefficient	95% CI	PValue	Regression Coefficient	95% CI	PValue
Age	−3.611	−5.038 to −2.185	<0.001	−2.107	−3.797 to −0.416	0.015
Initial IOP	7.757	4.353 to 11.162	<0.001	7.753	4.198 to 11.309	<0.001
Treated IOP	12.462	6.215 to 18.709	<0.001			0.509
Axial length	−3.396	−18.093 to 17.301	0.965			0.079
Disc size	29.108	−17.886 to 76.103	0.223			0.085
CCT	0.183	−0.479 to 0.845	0.585			0.594
MD	2.967	0.393 to 5.541	0.024			0.659
RNFL thickness	−0.237	−1.833 to 1.360	0.770	−1.933	−3.792 to −0.073	0.042
Age × MD				0.078	0.022 to 0.134	0.007

 Statistically significant values (P < 0.05) are shown in bold.

The regression equation for mean LC depth showed that age-related difference in mean LC depth was greater in glaucoma patients with moderate to advanced stage than those with early stage (Fig. 3). Mean LC depth = 603.913 −1.624 × age (P = 0.130) in early-stage glaucoma (n = 68), LC depth = 787.601 − 5.282 × age (P = 0.006) in moderate-stage glaucoma (n = 34), and LC depth = 734.629 − 4.462 × age (P < 0.001) in advanced-stage glaucoma (n = 39). 

Figure 3

 

Scatterplot of age versus mean LC depth according to glaucoma stage. The regression equation was mean LC depth = 603.913 − 1.624 × age (P = 0.130) in early-stage glaucoma (MD ≥ −6 dB), LC depth = 787.601 − 5.282 × age (P = 0.006) in moderate-stage glaucoma (MD < −6 dB and ≥ −12 dB), LC depth = 734.629 − 4.462 × age (P < 0.001) in advanced-stage glaucoma (MD < −12 dB).

Figures 4A and 4B show representative cases of glaucoma patients. A 76-year-old patient with POAG (untreated IOP 35 mm Hg, follow-up IOP 11 mm Hg) had a mean anterior LC depth of 528 μm, whereas a 77-year-old patient (untreated IOP 24 mm Hg, treated IOP 14 mm Hg) had a mean LC depth of 323 μm. Initial IOP played an important role in LC displacement in glaucoma patients. 

Figure 4

 

The optic disc (A-1, B-1), visual-field examination (A-2, B-2), and SD-OCT B-scans (A-3, B-3). In a 76-year-old woman (A) and a 77-year-old man (B) with POAG and an advanced visual-field defect, mean LC depth was 528 and 323 μm, respectively. Initial IOP was higher in the former patient.

Discussion

The current study demonstrated that the anterior LC surface is more deeply located in glaucoma patients than healthy controls. In glaucoma patients, initial increased IOP definitely played a role in posterior LC displacement. Age was negatively correlated with mean LC depth (r = −0.394, P < 0.001), suggesting that movement of the LC seemed to be greater in younger glaucoma patients. Thin RNFL thickness was associated with deeper mean LC depth in multivariate analysis (P = 0.042). There was an interaction between age and MD as predictors for LC depth (P = 0.007). Age-related difference in mean LC depth was statistically significant in moderate (P = 0.006) to advanced stage (P < 0.001) of glaucoma, but not in early-stage glaucoma (P = 0.130). Posterior LC displacement in glaucoma seemed to be the result of biomechanical response of the LC to IOP affected by various factors. 

Some researchers have suggested that the biomechanical environment of the ONH plays a critical role in glaucomatous changes.^19,20 Biomechanics of sclera and LC, and its IOP-induced changes seem to contribute to both the pathogenesis of glaucoma and to an individual's susceptibility to the disease.^19,20 Regarding assessment of the mechanical responsiveness of the LC and sclera to IOP, measurement of the posterior LC displacement may be a relatively feasible method according to in vivo human studies. In the current study, anterior LC surface was located more posteriorly in glaucoma than in control eyes. Displacement of the lamina in response to IOP elevation may cause the pores to deform and pinch the traversing axons, and eventually glaucomatous optic neuropathy develops.²¹ The posterior LC displacement in the glaucoma group in the interindividual comparison seems to represent its irreversible component in the current study and previous studies.⁹ 

No differences appeared between follow-up IOP in glaucoma patients and mean IOP in healthy subjects, but a significant difference was observed between the initial IOP in the glaucoma group and the mean IOP in normal controls (P < 0.001). Initial untreated IOP was positively associated with anterior LC depth in glaucomatous eyes (r = 0.391, P < 0.001). Because untreated IOP was one of the factors associated with LC depth in multivariate analysis, these results also suggest that IOP-induced LC deformation in glaucoma is at least partially irreversible. 

The biomechanics of the LC have been studied through ex vivo models and animal models or theoretical models of the human eye involving acute-IOP related LC deformation.^5,10,22–25 With the advent of SD-OCT, in vivo human studies are possible, and one demonstrated that acute IOP elevation by approximately 10 mm Hg induced compression of prelaminar tissue.²¹ According to that report, movement of the anterior lamina surface was not remarkable in glaucoma patients or controls. It is possible that LC was resistant to that degree and duration of IOP increase. Also, that study only included a sample size of 12 patients per each glaucoma or control group. In our study, we found that untreated IOP greatly influenced LC displacement. Therefore, a significant IOP increase may be needed to push the anterior surface of the LC posteriorly. 

Some early glaucoma experimental models using monkeys demonstrated that posterior LC displacement is counteracted as the LC is pulled taut by simultaneous sclera canal expansion, but the net result of the IOP-induced deformation is minor posterior displacement of the LC.^4,26,27 In studies using postmortem or living human eyes, including the current study, the central and midperipheral LC is located more posteriorly in glaucomatous eyes than in healthy eyes, supporting the theory of backward displacement of the LC in glaucoma.^7–9,23 More chronic IOP elevation seems to cause greater posterior displacement of the LC than does short-term, mild IOP elevation. 

Intraocular pressure was not the only factor related to anterior LC depth in glaucoma. First, age is a great influential factor on the amount of anterior LC displacement in glaucoma corresponding to previous studies.^11,16 Age was negatively correlated with LC depth in glaucoma as confirmed by multivariate analysis. Therefore, the negative correlation between age and LC depth in glaucoma seemed to be caused by the different LC response of an aged ONH to increased IOP. The aged ONH is more likely to have stiff connective tissues and ex vivo human studies have found that the mechanical compliance of the human LC decreases with age in response to IOP change.^28–30 Considerable evidence indicates that the human ONH becomes more susceptible to progressive glaucomatous damage as it ages. Age is an independent risk factor for the prevalence of the neuropathy at all stages of damage.^28,31,32 In most, but not all, population-based studies, either IOP does not increase with age or, if it does, the magnitude of increase is not likely to be clinically important.^33–39 Less displacement in elderly patients may be induced by increased stiffness of connective tissue in aged ONHs. Age-related differences in LC or sclera composition might contribute to glaucoma susceptibility in older patients, but we are still unsure whether a less compliant LC leads to more collapse or compression of the LC, harming the optic nerve axon.²⁰ 

In this study, initial IOP was the most decisive factor for the permanent component of LC displacement in glaucoma patients, so LC deformation induced by a high IOP seems to be more irreversible in glaucoma subjects. Given the greater LC depth in glaucoma patients, we can speculate that the initial IOP was likely high despite being currently well controlled. 

Thin RNFL thickness induced deeper mean LC depth in multivariate analysis (P = 0.042) corresponding to previous study that showed that anterior LC depth was greater in eyes with a thinner RNFL.¹⁶ Therefore, glaucomatous damage seems to have an association with mean LC depth. Retinal nerve fiber layer thickness had a negative correlation with age (r = −0.187, P = 0.026; Table 3). Age had a negative relationship with mean LC depth (r = −0.394, P < 0.001; Table 2). The relationship between the RNFL thickness and LC depth might not be significant in the univariate analysis because of the correlations among age, LC depth, and RNFL thickness. Multivariate analysis revealed that the RNFL thickness was negatively correlated with the LC depth when other factors including age were similar. With regard to MD, there was an interaction between age and MD as predictors for LC depth (P = 0.007), although MD was not significantly associated with mean LC depth in multivariate analysis. Mean deviation is an adjusted value for age, but both mean LC depth and RNFL thickness are not corrected for age. It may be one of explanations for different results between RNFL thickness and MD regarding the mean LC depth. With regard to the interaction between MD and age, the regression equation for mean LC depth showed that the age-related difference of LC depth was greater in moderate- to advanced-stage glaucoma than in early-stage glaucoma corresponding to the Ren et al. study.¹⁶ 

Reversal of LC displacement was observed by anterior LC movement with a lowered IOP in eyes with open-angle glaucoma.^13,40,41 The magnitude of LC depth reduction was significantly associated with younger age, higher untreated IOP, higher baseline IOP, and greater percentage of IOP reduction.⁴¹ However, in addition to reversibility, irreversible posterior displacement of the LC also was observed in human glaucomatous eyes as a posterolateral extension of the anterior laminar surface including the current study.^7,8 Although eyes with a high untreated IOP and young age induced more reduction of LC displacement after a decrease in IOP, they also exhibited a greater anterior LC depth as an irreversible component in the current study. 

The sclera opening area may have a direct effect on the ONH biomechanics rather than the disc size regarding the load bearing tissue. However, it is not feasible to measure the sclera opening using SD-OCT in vivo. It can be one of limitations in the current study. 

The precise mechanism of how IOP combines with other factors to cause glaucomatous optic nerve damage is still not fully understood. We investigated the irreversible biomechanical strain of the ONH tissues indirectly through an in vivo human study. Lamina cribrosa depth was displaced more posteriorly in glaucoma patients compared with healthy controls. In glaucoma patients, age as well as IOP and RNFL thickness was significantly related to LC depth. There was an interaction between age and MD as one of predictors for plastic LC displacement. Thus, clinical application of plastic LC displacement in glaucoma patients requires consideration of several confounding factors. 

Acknowledgments

The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/KJ6sPb. 

Disclosure: K.I. Jung, None; Y. Jung, None; K.T. Park, None; C.K. Park, None