Changes in the Lamina and Prelamina After Intraocular Pressure Reduction in Patients With Primary Open-Angle Glaucoma and Acute Primary Angle-Closure

Abstract

Purpose.: To compare changes in the prelamina and lamina of patients with POAG and acute primary angle-closure (APAC) after IOP reduction.

Methods.: We analyzed 20 patients with POAG who were scheduled to undergo glaucoma surgery and 17 patients with APAC scheduled for laser peripheral iridoplasty. Horizontal B-scans of the optic nerve head were obtained using Heidelberg Spectralis optical coherence tomography. The prelaminar position (PLP), laminar position (LP), and prelaminar thickness (PLT) were measured. Scans were obtained before and at 1 month after the intervention. Regression analysis was used to evaluate factors related to the changes in PLP, LP, and PLT.

Results.: Mean IOP reduction after the intervention was 21.69 ± 4.26 mm Hg in the POAG group and 23.06 ± 4.54 mm Hg in the APAC group (P = 0.746). After IOP reduction, the mean changes in the PLP were 21.92 ± 13.16 μm in the POAG group and 47.84 ± 28.05 μm in the APAC group (comparison between two groups, P < 0.001). After IOP reduction, the mean changes in the LP were 19.17 ± 7.25 μm in the POAG group and 32.70 ± 23.23 μm in the APAC group (comparison between two groups, P < 0.001). After IOP reduction, the APAC group exhibited a significantly greater increase in PLT than the POAG group (comparison between two groups, P < 0.001). Cumulative IOP insult, IOP percent reduction, duration of IOP elevation, and diagnosis of APAC were significantly related to the changes in the prelamina and lamina in regression analysis.

Conclusions.: IOP reduction leads to different responses of the prelamina and lamina between POAG and APAC patients. Anterior movement of the prelamina and lamina and thickening of the prelamina were more pronounced in the optic nerve head of APAC patients.

Introduction

The structure of the optic nerve head (ONH) and the material properties of the components of the ONH are important in the pathogenesis of glaucoma. ^1–3 Considerable research has therefore been focused on the biomechanics of the ONH to explain how the IOP contributes to glaucomatous optic nerve damage. ^4–9 These studies have used several models, including monkey and human eyes, computer modeling techniques, and in vivo imaging. Acute IOP elevation leads to a significant increase in the optic disc cup with enlargement of the disc diameter and area. ¹⁰ Stretching and expansion of the scleral canal by the elevated IOP is thought to result in minimal posterior laminar displacement, and in some cases, anterior laminar displacement. ^11,12 Agoumi et al. ¹³ demonstrated acute optic disc surface changes with compression of the prelaminar tissues. In their study, the prelaminar displacement differed significantly between glaucoma patients and normal controls after IOP elevation. The change was greatest in younger controls, followed by older controls and glaucoma patients. Long-term changes to the ONH, such as tissue remodeling in response to the force due to chronic IOP elevation, occurs within and around the ONH. ¹⁴ Decreased compliance with tissue remodeling, by age or by glaucoma, may result in minimal prelaminar displacement, as suggested by the findings of Agoumi et al. ¹³  

Displacement or deformation of the lamina in response to IOP elevation may contribute to axonal damage at the level of the lamina. ^14–17 It remains unknown whether reducing the pressure in the ONH region will reverse the displacement or deformation of the lamina. Clinically, the visual field defects progress in POAG patients after glaucoma surgery. ^18,19 Electrophysiologically, the “dying” retinal ganglion cells (RGCs) show irreversible damage, even after reducing the IOP with surgery. ²⁰ In contrast, although visual field damage may occur when the ONH is exposed to an elevated IOP, further progression is not observed when the causative pathogenesis is resolved in acute primary angle-closure (APAC) patients. ²¹ The influence of the prelaminar and laminar changes on the disease prognosis after IOP change remains to be determined. Here, we compared the differences in the changes of the prelamina and lamina in POAG and APAC patients after IOP reduction to find out whether the different response of the ONH might contribute to this difference. 

In the present study, we measured the change in the position of the prelamina and lamina and thickness of the prelamina using spectral-domain optical coherence tomography (SD-OCT) in POAG and APAC patients with an elevated IOP. After reducing the IOP surgically or with laser peripheral iridotomy (LPI), we observed the changes in the prelamina and lamina to reveal a difference in the ONH response to IOP changes in POAG and APAC patients. 

Methods

POAG patients who were scheduled to undergo either a trabeculectomy or Ahmed glaucoma valve implantation for uncontrolled IOP, and APAC patients who were scheduled to undergo LPI were included in the study. The diagnosis of APAC was based clinically on a history of pain and vision loss with an elevated IOP with closed iridocorneal angle. The iridocorneal angle was assessed by direct observation of the iridocorneal touch with a slit lamp or indentation gonioscopy to determine the width of the anterior chamber angle. APAC patients with previous symptoms of blurred vision or halo, history of elevated IOP, or ocular findings suggesting previous subacute or acute angle-closure attack were excluded. Participants were recruited from Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, between June and September 2012. Only one eye of each patient was selected for analysis. 

The study was performed after obtaining informed consent from the participants and followed all of the guidelines for experimental investigation of human subjects required by the Institutional Review Board of Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. All investigations were performed in accordance with the tenets of the Declaration of Helsinki. 

Each participant underwent a comprehensive ophthalmic assessment, which included measurement of best-corrected visual acuity, slit-lamp biomicroscopy, Goldmann applanation tonometry, dilated stereoscopic examination of the ONH and fundus, color disc photography, red-free retinal nerve fiber layer (RNFL) photography (VX-10; Kowa Optimed, Tokyo, Japan), Cirrus OCT (Carl Zeiss Meditec, Dublin, CA), and achromatic automated perimetry using the 24-2 Swedish Interactive Threshold Algorithm standard program (Humphrey Visual Field Analyzer; Carl Zeiss Meditec). Experienced ophthalmologists performed OCT using a Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). 

To determine the IOP history of the patients, we asked patients to bring their ocular medical records from previously visited ophthalmologic clinics or health promotion centers. Patients who were followed up for at least 2 years and had at least five IOP recordings were enrolled. Cumulative IOP insult was defined as the area (computed using the trapezoidal rule) under its IOP-time curve. ²² Because the follow-up period varied between patients, 1 year prior to intervention was plotted on the IOP-time curve. 

Pre- and postintervention IOP were measured with the Goldmann applanation tonometry in all patients by one examiner (CKP). At each measurement, the average of the two measurements was considered. When the two measurements differed by more than 5 mm Hg, a third measurement was performed, and the average of the two closest measurements was considered. IOP before intervention was measured on the intervention day before surgery or LPI. Duration of IOP elevation was defined as the period from when IOP was first elevated to more than 25 mm Hg, with maximum tolerated medical treatment, to when surgery or LPI was performed. All ocular hypotensive medications were continued up to the time of surgery or LPI. 

Imaging SD-OCT of the ONH

The Heidelberg Spectralis uses a scanning superluminescent diode to emit a scan beam with a wavelength of 870 nm to provide 40,000 A-scans/s with a depth resolution of 7 μm in tissue and a transversal resolution of 14 μm for images of ocular microstructures. The instrument combines OCT technology with a confocal scanning laser ophthalmoscope (Heidelberg Engineering), which provides a reference infrared fundus image. The entire ONH was scanned with the Heidelberg Spectralis OCT (Spectralis software Version 5.1.1.0, Eye Explorer Software 1.6.1.0; Heidelberg Engineering) with a 20° retinal window. An internal nasal fixation light was used to center the disc in the 10° × 15° rectangle, while the entire ONH was scanned using a 6-mm-long line (512 A-scans) at approximately 50-μm intervals (the scan line distance is determined automatically by the machine). An average of 35 frames with speckle noise reduction for each cross-sectional B-scan was produced. The scan was performed at baseline and at 1 month after IOP reduction. The scan of the entire ONH resulted in approximately 30 cross-sectional B-scans for each participant (Fig. 1). Of these, B-scans in the rim area that did not visualize the prelamina and lamina regions were excluded from the analysis (green scan lines in Fig. 1). The remaining B-scans in the cup area were analyzed (orange scan lines in Fig. 1). The baseline OCT scan was set as a reference, and all subsequent scans were registered to this baseline to ensure that the same point on the ONH was imaged at the postintervention scan. 

Figure 1

 

SD-OCT images of the prelamina and anterior lamina. A 10° × 15° rectangle was centered on the ONH, and the entire ONH was scanned horizontally at 50-μm intervals (green scan lines). Of these B-scans, the B-scans at the cup area (orange scan lines) were analyzed. The PLP and LP were measured for each B-scan. (A) Representative images at the superior cup margin; (B) at the center of the ONH; and (C) at the inferior cup margin. The reference line (white horizontal line) connected the end of the Bruch's membrane (orange glyphs). From a perpendicular line drawn from the center of the reference line, PLP (A-1, B-1, C-1) and LP (A-2, B-2, C-2) were measured. Two additional points were used for the measurement of PLP and LP. PLP was the distance (yellow vertical line) from the center of the reference line to the anterior prelaminar surface. LP was the distance (green vertical line) from the center of the reference line to the anterior laminar surface. PLT was the difference between PLP and LP.

Measurement of the Position of the Prelamina and Lamina and Prelaminar Thickness

All measurements were obtained along a perpendicular line from the reference line connecting the end of the Bruch's membrane. The prelaminar position (PLP) and laminar position (LP) were measured for each of the B-scans at the center of the reference line. Two additional points, temporally and nasally 100 μm apart from the center of the reference line, were measured. The average of the three measurements (from the three points) was considered as the PLP and LP of the each selected B-scan. The PLP was the distance from the reference line to the anterior prelaminar tissue surface (Figs. 1, A-1, B-1, C-1). The LP was the distance from the reference line to the anterior laminar tissue surface (Figs. 1, A-2, B-2, C-2). The PLT was defined as the distance between the anterior prelaminar tissue surface and the anterior laminar tissue surface. It is obtained by subtracting the PLP from the LP at three measurement points; the average of the three measurements was used. Two observers (H-YLP, H-YS) measured the PLP, LP, and PLT in a masked fashion without knowing the clinical diagnosis. 

Statistical Analysis

Statistical analysis was performed using SPSS software (Version 11.1; SPSS, Chicago, IL). The Mann-Whitney test was used to compare data between groups. The Wilcoxon signed-rank test was used to compare measured values between pre- and postintervention. 

To evaluate the interobserver reproducibility of our measurement method, 30 randomly selected cross-sectional B-scans were evaluated. The analysis was based on five independent series of reevaluations made by the two examiners (H-YLP, H-YS). The absolute agreement of a single observer's measurement and the mean of all five measurements made by the two observers were calculated using the intraclass correlation coefficient (ICC) in a two-way mixed-effect model. According to Fleiss, ²³ ICC scores ≥ 0.75, between 0.40 and 0.75, and ≤ 0.4 are considered to be excellent, moderate, and poor, respectively. 

Univariate and multivariate regression analysis was used to analyze the association of the changes in the prelamina and lamina with variables such as age, axial length, mean IOP during follow-up, maximum measured IOP during follow-up, cumulative IOP insult, number of glaucoma medications, IOP before intervention, IOP percentage reduction, duration of IOP elevation, diagnosis, baseline PLT, baseline PLP, baseline LP, and optic disc size. Because the diagnosis is nominal in scale, it was investigated as an independent factor using a regression model, and dummy variables were used with the POAG group as a standard. Variables with a significance at P < 0.10 in the univariate analysis were included in the multivariate model. The level of statistical significance was set at P < 0.05. 

Results

Age (P = 0.622), axial length (P = 0.187), and optic disc size determined using Cirrus OCT (P = 0.570) were similar between groups. Mean RNFL thickness (P < 0.001) and mean deviation of perimetry (P < 0.001) differed significantly between the POAG and APAC groups. Mean IOP (P < 0.001), maximum measured IOP (P < 0.001), and cumulative IOP insult (P = 0.042) during follow-up, which shows the IOP history before acute IOP elevation, were significantly different between the two groups. Acute IOP elevation requiring intervention was not significantly different between the two groups, in terms of the IOP before intervention (P = 0.521). The duration of IOP elevation, however, was longer in the POAG group (78.16 ± 21.54 days) compared with the APAC group (2.57 ± 1.32 days, P < 0.001). IOP after intervention (P = 0.711) and percentage reduction of IOP (P = 0.453) were not significantly different between the two groups (Table 1). Mean IOP reduction following intervention was 21.69 ± 4.26 mm Hg in the POAG group and 23.06 ± 4.54 mm Hg in the APAC group (P = 0.663). 

Table 1

 

Baseline Characteristics of the Subjects

	POAG Patients Undergoing Glaucoma Surgery, n = 20	APAC Patients Undergoing LPI, n = 17	P Value*
Age, y	52.16 ± 5.23	51.27 ± 6.23	0.622
Spherical equivalent, diopters	−1.28 ± 1.18	0.62 ± 0.78	0.126
Axial length, mm	24.03 ± 2.22	22.15 ± 0.89	0.187
Average RNFL thickness, μm	75.48 ± 8.26	91.20 ± 8.28	<0.001
Mean deviation of perimetry, dB	−7.10 ± 3.01	−1.83 ± 0.88	<0.001
Optic disc size, mm2	2.22 ± 0.54	2.18 ± 0.59	0.57
IOP history during follow-up
Mean IOP, mm Hg	24.54 ± 7.01	15.72 ± 2.50	<0.001
Maximum measured IOP, mm Hg	26.32 ± 5.96	17.12 ± 1.91	<0.001
Cumulative IOP insult, mm Hg × mo	388 ± 120	210 ± 72	0.042
IOP related to the intervention
IOP before intervention, mm Hg	37.82 ± 6.46	38.16 ± 4.51	0.521
IOP after intervention, mm Hg	16.13 ± 3.26	15.74 ± 3.20	0.711
Percentage reduction of IOP, %	15.36 ± 4.08	15.40 ± 3.95	0.453
Duration of IOP elevation, d	78.16 ± 21.54	2.57 ± 1.32	<0.001
Number of glaucoma medications	2.85 ± 0.54	2.71 ± 0.71	0.626

 Values shown are the mean ± SD.

*   Mann-Whitney test.

The position of the prelamina and lamina and prelaminar thickness measured by the two observers had excellent measurement reproducibility (intraclass coefficient range, 0.927–0.954 for all measurements). 

In the POAG group, the changes in the PLP (Fig. 2B) and LP (Fig. 2A) were not significantly different after the IOP reduction over the entire ONH. Anterior movement of the prelamina (Fig. 2D) and lamina (Fig. 2C) after IOP reduction was significant in the APAC group. In the POAG group, the mean change in the PLP and LP after IOP reduction was 21.92 ± 13.16 μm and 19.17 ± 7.25 μm, respectively, which was significantly different from the mean change after IOP reduction in the APAC group, which was 47.84 ± 28.05 μm (P < 0.001) and 32.70 ± 23.23 μm (P < 0.001), respectively. The PLT before IOP reduction was significantly thinner in the POAG group compared with the APAC group (P < 0.001). The mean change in the PLT in the POAG group was 25.52 ± 13.94 μm, which was significantly different compared with the APAC group (62.91 ± 18.74 μm, P < 0.001; Table 2). 

Figure 2

 

The LP and PLP in POAG (A, B) and APAC (C, D) patients after IOP reduction by surgery or LPI. *P < 0.05 by Wilcoxon signed-rank test between pre- and postintervention values.

Table 2

 

Changes in the Thickness and Displacement of the Prelamina and Lamina

	POAG Patients Undergoing Glaucoma Surgery	APAC Patients Undergoing LPI	P Value*
Δ Prelaminar thickness	25.52 ± 13.94	62.91 ± 18.74	<0.001
Δ Prelaminar position	21.92 ± 13.16	47.84 ± 28.05	<0.001
Δ Laminar position	19.17 ± 7.25	32.70 ± 23.23	<0.001

 Values shown are the mean ± standard deviation. Δ, the change in each value before and after intervention.

*  Mann-Whitney test.

In the multivariate regression analysis, lower cumulative IOP insult, shorter duration of baseline IOP elevation, and APAC diagnosis had a significant influence on the changes of PLT, PLP, and LP. Greater IOP percentage reduction had a significant positive relationship with the changes in PLP and PLT (Table 3). 

Table 3

 

Univariate and Multivariate Regression Analysis of the Thickness and Displacement of the Prelamina and Lamina

	ΔPLT		ΔPLP		ΔLP
	Univariate	Multivariate	Univariate	Multivariate	Univariate	Multivariate
Age	0.545	—	0.61	—	0.762	—
Axial length	0.41	—	0.479	—	0.311	—
Mean IOP during follow-up	0.038	0.111	0.021	0.222	0.173	0.384
Maximum measured IOP during follow-up	0.111	—	0.217	—	0.218	—
Cumulative IOP insult	0.046	0.003	0.035	<0.001	0.047	0.021
Number of glaucoma medications	0.616	—	0.626	—	0.714	—
IOP before intervention	0.152	0.218	0.144	0.263	0.562	—
IOP reduction, %	0.011	<0.001	0.042	<0.001	0.21	—
Duration of IOP elevation	0.012	<0.001	0.01	<0.001	0.022	<0.001
Diagnosis, 1 = POAG; APAC = 2	0.034	<0.001	0.02	<0.001	0.038	<0.001
Baseline prelaminar thickness	0.239	—	0.429	—	0.716	—
Baseline prelaminar position	0.316	—	0.082	0.372	0.503	—
Baseline laminar position	0.531	—	0.551	—	0.31	—
Optic disc size	0.267	—	0.194	—	0.224	—

 Values shown are the P values for the coefficients of regression analysis. Δ, the change in each value before and after intervention.

Discussion

The connective tissues of the ONH are the load-bearing tissues of the peripapillary sclera, scleral canal wall, and lamina cribrosa. ³ With acute IOP elevation, ONH surface movement is observed in animal experiments and clinical studies. ^7,8,10 Recently, the prelamina and lamina were imaged in glaucoma patients using the Heidelberg Spectralis SD-OCT. ^13,24,25 These in vivo studies showed that changes in the prelaminar and lamina occur after IOP changes. Anterior movement and thickening of the prelamina and/or lamina were found after glaucoma surgery in POAG patients. In the present study, we observed the changes in the prelamina and lamina after IOP reduction by imaging the ONH with Heidelberg Spectralis SD-OCT. The study subjects were POAG patients scheduled to undergo glaucoma surgery for uncontrolled IOP and APAC patients scheduled to undergo LPI. The mean IOP elevation was approximately 38 mm Hg before intervention, and the IOP reduction after intervention was approximately 24 mm Hg. The changes in the prelamina and lamina were significantly greater in the APAC patients compared with the POAG patients after IOP reduction. APAC patients showed significant anterior movement of the prelamina and lamina with thickening of the prelamina compared with POAG patients. Chronic elevation of IOP subjects the prelamina and lamina to consistent stress, leading to tissue remodeling in the extracellular matrix of those tissues. ^14–17 In POAG eyes, the lamina cribrosa contained a greater percentage of elastin and the orientation of the laminar beams increased in the horizontal direction to bear stress. ^15,16 As we demonstrated, POAG patients had a greater PLP and LP, which indicates a cupped and excavated optic disc compared with the optic disc of the APAC patients (Fig. 2). The cupped and excavated ONH of POAG patients showed minimal changes in the prelamina and lamina after IOP reduction, however, and the change was greater in the ONH of APAC patients (representative cases are shown in Fig. 3). A recent study demonstrated that corneal hysteresis was related to morphologic changes in the ONH after IOP reduction. ²⁶ Similar to reduced corneal hysteresis, chronically elevated IOP and more frequent IOP insults in POAG patients compared with APAC patients may lead to stiffer, less deformable lamina and prelamina. 

Figure 3

 

Representative cases. (A) Left eye of 54-year-old woman with APAC. Horizontal B-scan of the ONH at the center is shown ([A-1], pre-iridotomy; [A-2], postiridotomy). The reference line (white horizontal line) connecting the end of the Bruch's membrane (orange glyphs) and three vertical lines (green vertical line) from the reference line are marked. The position of the anterior laminar surface (black glyphs) is shown, and the preoperative position of the prelamina and lamina is marked by a small horizontal green line at each surface. Preoperative reference line and vertical and horizontal green measurement lines are directly overlapped on the postoperative B-scan. Note the anterior movement of the prelamina and anterior laminar surface. (B) Left eye of 53-year-old woman with POAG does not show significant change of the position of the prelamina and anterior laminar surface ([B-1], preoperatively; [B-2], postoperatively).

Our study is a first to compare the changes of the prelamina and lamina after IOP reduction between POAG and APAC patients in vivo. The IOP reduction was considerable and longer (24.20 mm Hg and 17.54 days) compared with that in previous studies (12–13 mm Hg and 2 minutes). ¹³ A study by Lee et al. ²⁵ showed that anterior movement and thickening of the lamina and thickening of the prelamina after the reduction of IOP contributes to reversal of optic disc cupping in glaucoma patients after trabeculectomy. The patients in their study were all POAG patients, and the difference in the change of lamina and prelamina according to the type of glaucoma diagnosis was not analyzed. 

Several points should be considered while interpreting our results. The study sample was small, and the two groups were not matched in terms of the baseline characteristics, including patient age, which may have affected the results. In addition, the methods for measuring the position of the prelamina and lamina and prelaminar thickness in vivo must be validated. Preoperative and postoperative images were acquired independently at different time points. Although the Spectralis has a follow-up mode that indentifies the previous scan position, it did not work well in our patients because changes in the prelamina and lamina occurred after IOP reduction. If the changes were measured in only few sections per patient, the scan position may be critical for interpreting the result. To overcome this limitation, however, we measured the position of the prelamina and lamina and prelaminar thickness along the ONH in several horizontal scans. When imaging patients before intervention, edematous cornea, owing to elevated IOP, interrupted the images in some patients. 

In summary, the findings of the present study revealed that IOP reduction leads to different changes in the prelamina and lamina between POAG and APAC patients. Despite more frequent IOP insults and longer duration of IOP elevation, POAG patients showed less anterior movement of the prelamina and lamina and less prelaminar thickening compared with those in APAC patients. 

Acknowledgments

Disclosure: H.-Y.L. Park, None; H.-Y. Shin, None; K.I. Jung, None; C.K. Park, None