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Comparison of Lamina Cribrosa Curvature in Pseudoexfoliation and Primary Open-Angle Glaucoma

Open AccessPublished:September 20, 2020DOI:https://doi.org/10.1016/j.ajo.2020.09.028

      Purpose

      To compare lamina cribrosa curvature (LCC) in pseudoexfoliation glaucoma (PXG) and primary open-angle glaucoma (POAG) and to elucidate the factors associated with LCC in both groups.

      Design

      Retrospective, cross-sectional study.

      Method

      Forty eyes with PXG and visual field mean deviation–matched 40 eyes with POAG were included. Spectral domain optical coherence tomography enhanced depth imaging was used to acquire LC images. The LCC index (LCCI) was calculated as LCC depth/LCC width × 100. Calculated LCCI values were compared between the PXG and POAG groups. Logistic regression analysis was performed to investigate the factors related to the presence of PXG. Factors associated with LCCI were determined by uni- and multivariable linear regression analyses in both groups.

      Result

      Visual field mean deviation (−11.7 ± 9.7 dB vs −1.0 ± 8.5 dB, P = .731) and retinal nerve fiber thickness (647.4 ± 22.7 μm vs 68.3 ± 19.9 μm, P = .857) did not differ between the 2 groups. However, the mean (8.8 ± 2.9 in PXG, 6.6 ± 1.9 in POAG) and sectoral LCCIs assessed at 0, 30, 60, 90, and 120° were significantly greater in the PXG than in the POAG group (all, P < .05), but not at 150° (P = .113). Logistic regression analysis revealed that higher average LCCI (odds ratio [OR] = 1.509 [95% confidence interval 1.180-2.047], P = .003) and older age (OR = 1.074 [95% confidence interval 1.017-1.147], P = .019) were associated with the presence of PXG. IOP was associated with mean LCCI only in the POAG group (β = 0.150 [95% confidence interval 0.018-0.281], P = .027) while none of the factors showed association with LCCI in PXG.

      Conclusion

      PXG eyes had more steeply curved LC than POAG eyes with a similar level of glaucoma severity. The clinical implication(s) of steeper LCC in PXG should be investigated in a forthcoming study.
      Pseudoexfoliation syndrome is an age-related condition in which abnormal fibrillar extracellular material is produced and accumulated in many ocular tissues.
      • Lindberg J.G.
      Clinical investigations on depigmentation of the pupillary border and translucency of the iris in cases of senile cataract and in normal eyes in elderly persons.
      In particular, a substantial percentage of patients with pseudoexfoliation develop glaucoma,
      • Lindberg J.G.
      Clinical investigations on depigmentation of the pupillary border and translucency of the iris in cases of senile cataract and in normal eyes in elderly persons.
      • Ritch R.
      • Schlotzer-Schrehardt U.
      Exfoliation syndrome.
      • Heijl A.
      • Bengtsson B.
      • Hyman L.
      • Leske M.C.
      Natural history of open-angle glaucoma.
      • Olivius E.
      • Thorburn W.
      Prognosis of glaucoma simplex and glaucoma capsulare. A comparative study.
      • Kim S.
      • Sung K.R.
      • Lee J.R.
      • et al.
      Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral-domain optical coherence tomography enhanced depth imaging.
      • Ersöz M.G.
      • Kunak Mart D.
      • Hazar L.
      • et al.
      Evaluation of prelaminar region and lamina cribrosa with enhanced depth imaging optical coherence tomography in pseudoexfoliation glaucoma.
      • Moghimi S.
      • Nekoozadeh S.
      • Motamed-Gorji N.
      • et al.
      Lamina cribrosa and choroid features and their relationship to stage of pseudoexfoliation glaucoma.
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      • Quigley H.A.
      • Addicks E.M.
      • Green W.R.
      • et al.
      Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage.
      • Gaasterland D.
      • Tanishima T.
      • Kuwabara T.
      Axoplasmic flow during chronic experimental glaucoma. 1. Light and electron microscopic studies of the monkey optic nervehead during development of glaucomatous cupping.
      • Quigley H.
      • Anderson D.R.
      The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve.
      • Burgoyne C.F.
      • Downs J.C.
      • Bellezza A.J.
      • et al.
      The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage.
      • Ha A.
      • Kim T.J.
      • Girard M.J.A.
      • et al.
      Baseline lamina cribrosa curvature and subsequent visual field progression rate in primary open-angle glaucoma.
      • Kim Y.W.
      • Jeoung J.W.
      • Kim D.W.
      • et al.
      Clinical assessment of lamina cribrosa curvature in eyes with primary open-angle glaucoma.
      • Netland P.A.
      • Ye H.
      • Streeten B.W.
      • et al.
      Elastosis of the lamina cribrosa in pseudoexfoliation syndrome with glaucoma.
      • Pena J.D.
      • Netland P.A.
      • Vidal I.
      • et al.
      Elastosis of the lamina cribrosa in glaucomatous optic neuropathy.
      • Braunsmann C.
      • Hammer C.M.
      • Rheinlaender J.
      • et al.
      Evaluation of lamina cribrosa and peripapillary sclera stiffness in pseudoexfoliation and normal eyes by atomic force microscopy.
      • Anastasopoulos E.
      • Founti P.
      • Topouzis F.
      Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.
      • Konstas A.G.
      • Mantziris D.A.
      • Stewart W.C.
      Diurnal intraocular pressure in untreated exfoliation and primary open-angle glaucoma.
      • Ritch R.
      • Schlotzer-Schrehardt U.
      • Konstas A.G.
      Why is glaucoma associated with exfoliation syndrome?.
      • Kim Y.W.
      • Jeoung J.W.
      • Girard M.J.
      • et al.
      Positional and curvature difference of lamina cribrosa according to the baseline intraocular pressure in primary open-angle glaucoma: a swept-source optical coherence tomography (SS-OCT) Study.
      • Lee E.J.
      • Kim T.-W.
      • Kim H.
      • et al.
      Comparison between lamina cribrosa depth and curvature as a predictor of progressive retinal nerve fiber layer thinning in primary open-angle glaucoma.
      • Lee S.H.
      • Kim T.W.
      • Lee E.J.
      • et al.
      Lamina cribrosa curvature in healthy Korean eyes.
      • Kim C.-S.
      • Seong G.J.
      • Lee N.-H.
      • et al.
      Prevalence of primary open-angle glaucoma in central South Korea the Namil study.
      • Iwase A.
      • Suzuki Y.
      • Araie M.
      • et al.
      The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study.
      which is associated with a faster progression and a poorer prognosis than primary open-angle glaucoma (POAG).
      • Heijl A.
      • Bengtsson B.
      • Hyman L.
      • Leske M.C.
      Natural history of open-angle glaucoma.
      The reasons for a poorer prognosis in pseudoexfoliation glaucoma (PXG) are not clear. Generally PXG results in a higher intraocular pressure (IOP) and IOP fluctuation.
      • Olivius E.
      • Thorburn W.
      Prognosis of glaucoma simplex and glaucoma capsulare. A comparative study.
      However, even with similar IOP levels, PXG causes progressively greater glaucomatous damage.
      • Heijl A.
      • Bengtsson B.
      • Hyman L.
      • Leske M.C.
      Natural history of open-angle glaucoma.
      Our group previously reported that the lamina cribrosa (LC) was thinner in patients with PXG compared with patients with POAG with a similar glaucoma severity level.
      • Kim S.
      • Sung K.R.
      • Lee J.R.
      • et al.
      Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral-domain optical coherence tomography enhanced depth imaging.
      Ersöz and associates
      • Ersöz M.G.
      • Kunak Mart D.
      • Hazar L.
      • et al.
      Evaluation of prelaminar region and lamina cribrosa with enhanced depth imaging optical coherence tomography in pseudoexfoliation glaucoma.
      and Moghimi and associates
      • Moghimi S.
      • Nekoozadeh S.
      • Motamed-Gorji N.
      • et al.
      Lamina cribrosa and choroid features and their relationship to stage of pseudoexfoliation glaucoma.
      reported that thinner prelaminar and laminar tissues were associated with the presence of PXG and laminar thickness had a stronger association with disease severity and progression.
      Glaucoma is an optic neuropathy characterized by progressive loss of retinal ganglion cells (RGCs) and their axons.
      • Weinreb R.N.
      • Aung T.
      • Medeiros F.A.
      The pathophysiology and treatment of glaucoma: a review.
      According to a theoretical mechanism, changes in LC morphology are important in the development of glaucoma associated with elevated IOP. Postmortem examination of patients with glaucoma with high IOP showed that the LC was posteriorly bowed and compressed.
      • Quigley H.A.
      • Addicks E.M.
      • Green W.R.
      • et al.
      Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage.
      Consequently, LC deformation may impose mechanical stress on the axons that pass through the laminar pores, blocking axoplasmic transport and eventually resulting in the apoptosis of RGCs.
      • Gaasterland D.
      • Tanishima T.
      • Kuwabara T.
      Axoplasmic flow during chronic experimental glaucoma. 1. Light and electron microscopic studies of the monkey optic nervehead during development of glaucomatous cupping.
      ,
      • Quigley H.
      • Anderson D.R.
      The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve.
      Deformation of the capillary within the lamina beams may also decrease perfusion to intralaminar axon regions, leading to ischemic damage of the RGCs.
      • Burgoyne C.F.
      • Downs J.C.
      • Bellezza A.J.
      • et al.
      The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage.
      A recent publication reported that an increase in LC curvature was strongly associated with more rapid deterioration in POAG.
      • Ha A.
      • Kim T.J.
      • Girard M.J.A.
      • et al.
      Baseline lamina cribrosa curvature and subsequent visual field progression rate in primary open-angle glaucoma.
      Therefore, in the current study, our aim was to evaluate and compare LC curvature between eyes with PXG and POAG and to elucidate associated factors with LC curvature.

      Methods

       Study Subjects

      This study recruited subjects from an ongoing Asan Glaucoma Progression Study, which is a retrospective cohort study conducted at Asan Medical Center in Seoul, Korea. Forty patients with PXG and visual field (VF) mean deviation (MD) and 40 matched patients with POAG were retrospectively recruited by reviewing medical records from April 2009 to October 2019 at the glaucoma clinic of the Asan Medical Center. The Institutional Review Board of the Asan Medical Center approved the present study, and because of the retrospective nature of the study, the requirement for informed consent was waived. The study design was executed in accordance with principles of the Declaration of Helsinki.
      The participants underwent a complete ophthalmologic examination, including visual acuity, Goldmann applanation tonometry, status of eye drops use, stereoscopic examination of optic disc, stereoscopic optic disc/retinal nerve fiber layer (RNFL) photography, spectral-domain optical coherence tomography (OCT; Spectralis, Heidelberg Engineering, Heidelberg, Germany), and standard automated perimetry (Humphrey Field Analyzer II and 24-2 Swedish interactive threshold algorithm; Carl Zeiss Meditec, Dublin, California, USA). In addition, manifest refraction, best-corrected visual acuity, central corneal thickness, and axial length (IOL Master; Carl Zeiss Meditec) were measured at the initial visit.
      POAG was diagnosed according to the following criteria: 1) an open angle on gonioscopy; 2) the presence of RNFL defects or glaucomatous optic disc change (neuroretinal rim thinning, disc excavation, or disc hemorrhage); and 3) corresponding VF defects as confirmed by ≥2 reliable VF examinations. A glaucomatous VF change was defined as the fulfillment of ≥2 of the following criteria: 1) outside normal limits on the glaucoma hemifield test; 2) ≥3 abnormal points with <5% probability of being normal, including 1 of them with a probability <1% by pattern deviation plot; or 3) a pattern standard deviation of probability <5%. These VF defects were confirmed with 2 consecutive reliable tests (fixation loss rate ≤20%, false positive and false negative error rate ≤15%).
      PXG was diagnosed in the same manner as the glaucomatous changes described above, with the addition of the presence of pseudoexfoliation materials on the pupillary margin, crystalline lens, or intraocular lens surface. The optic nerve head images were acquired with spectral-domain OCT using the enhanced depth imaging technique within 1 week of the initial visit. RNFL thickness was also measured with the same device. If both eyes met the inclusion criteria, 1 eye was chosen at random. We excluded subjects with a history of previous intraocular surgery other than cataract extraction, any retinal disease including epiretinal membrane, or any neurologic disease (eg, stroke or brain tumor) potentially causing VF loss.
      POAG eyes were selected and matched to PXG eyes for VF MD (≤2 dB) to minimize the glaucoma severity on LC curvature.

       Lamina Cribrosa Imaging

      LC curvature was assessed with spectral-domain OCT enhanced depth imaging and evaluated at 6 locations with equal angle differences (30°) selected from 24 radial scan images. The 6 images were defined as planes 0 (vertical section), 30, 60, 90, 120, and 150° clockwise in the right eye and counterclockwise in the left eye, respectively (Figure 1). Measurements were performed with a manual caliper tool in a Heidelberg Eye Explorer (version 1.10.2.0; Heidelberg Engineering, Heidelberg, Germany) by 2 experienced observers (H.J.W., K.R.S.) who were blinded to participant clinical information.
      Figure thumbnail gr1
      Figure 1Measurement of the lamina cribrosa (LC) curvature index. (A and B). Six images were selected from 24 automatically scanned images from each eye. (C). The LC curvature index was measured as the LC curvature depth (LCCD)/LC curvature width × 100. OD, oculus dexter; OS, oculus sinister.
      LC curvature was determined by the LC curvature index (LCCI). LCCI was determined by the width of the LC reference line and the LC curve depth (LCCD). The width of the LC reference line was defined as the width of the line connecting the 2 points on the anterior LC surface meeting the lines drawn from each Bruch membrane opening termination point perpendicular to the Bruch membrane opening reference line. The maximum depth from the reference line to the anterior LC surface was defined as the LCCD (Figure 1). The LCCI was calculated as (LCCD/width of the LC reference line) × 100. Since the curvature is normalized relative to LC width, it describes the shape of the LC independent of the actual size of the optic nerve head.
      • Kim Y.W.
      • Jeoung J.W.
      • Kim D.W.
      • et al.
      Clinical assessment of lamina cribrosa curvature in eyes with primary open-angle glaucoma.

       Statistical Analysis

      Normality of the data was tested with the Shapiro-Wilk test. The baseline clinical characteristics were compared between the eyes with PXG and eyes with POAG using the independent t test for continuous variables and the χ2 test for categorical variables. The interobserver reproducibility of the LCCI measurement was tested with the intraclass correlation coefficient. Univariable and multivariable linear regression were used to determine the causality of LCCI and other parameters. Univariable and multivariable logistic regression analyses were used to determine the factors associated with the presence of PXG. Variables with P < .1 in univariable analysis and a variance inflation factor <3 (to exclude collinearity) were included in the multivariable analysis, and stepwise variable selection was used to obtain the final multivariable model. Statistical analysis was performed with R software (version 3.6.1; R Foundation, Vienna, Austria). P ≤ .05 was considered statistically significant.

      Results

      Of the 40 eyes in each of the PXG and POAG groups, 26 (57.5%) and 18 (45.0%) patients were men, respectively. Table 1 shows the clinical characteristics of our participants. The PXG group was significantly older (72.1 ± 8.9 years vs 64.0 ± 13.5 years, P = .002) and the prevalence of systemic hypertension was greater (P = .012). However, there were no significant differences in IOP (17.0 ± 5.4 mm Hg vs 15.1 ± 4.6 mm Hg, P = .091), glaucoma medications in use (1.68 ± 1.05 vs 1.65 ± 0.92, P = .910), spherical equivalent (−0.38 ± 2.45 diopters [D] vs −1.26 ± 2.16 D, P = .095), axial length (24.1 ± 1.3 mm vs 24.3 ± 1.2 mm, P = .461), central corneal thickness (537.7 ± 30.4 μm vs 542.6 ± 52.3 μm, P = .616), VF MD (−11.7 ± 9.7 dB vs −11.0 ± 8.5 dB, P = .731), and RNFL thickness determined by spectral-domain OCT (67.4 ± 22.7 μm vs 68.3 ± 19.9 μm, P = .857).
      Table 1Demographics and Clinical Characteristics of the Participants
      PXG (n = 40)POAG (n = 40)P Value
      Age (y), mean ± SD72.1 ± 8.964.0 ± 13.5.002
      Sex (M:F)23:1718:22.263
      Laterality (R:L)26:1423:17.491
      Hypertension (Y:N)21:1910:30.012
      Diabetes mellitus (Y:N)8:327:33.775
      LogMAR VA0.3 ± 0.30.2 ± 0.4.625
      IOP (mm Hg)17.0 ± 5.415.1 ± 4.6.090
      Glaucoma medication in use (n), mean ± SD1.7 ± 1.11.7 ± 0.9.910
      Axial length (mm), mean ± SD24.1 ± 1.324.3 ± 1.2.461
      CCT (μM)537.7 ± 30.4542.6 ± 52.3.616
      VFI (%)66.5 ± 31.669.1 ± 27.3.689
      MD (dB)−11.7 ± 9.7−11.0 ± 8.5.731
      PSD (dB)7.2 ± 4.58.5 ± 4.6.214
      RNFL thickness (μM)67.4 ± 22.768.3 ± 19.9.857
      CCT = central corneal thickness; F = female; IOP = intraocular pressure; logMAR = logarithm of the minimum angle of resolution; M = male; MD = mean deviation; N = no; POAG = primary open-angle glaucoma; PSD = pattern standard deviation; PXG = pseudoexfoliation glaucoma; RNFL = retinal nerve fiber layer; SD = standard deviation; VA = visual acuity; VFI = visual field index; Y = yes.
      The LCCI measurements made by the 2 examiners showed excellent interobserver reproducibility (intraclass correlation coefficient = 0.959 [95% confidence interval {CI} = 0.878-0.987], P < .001). Table 2 and Figure 2 show comparisons of LCCD and LCCI in eyes with PXG and eyes with POAG. Compared with eyes with POAG, the eyes with PXG had a significantly higher average LCCI (8.77 ± 2.89 vs 6.56 ± 1.86, P = .001). The LCCDs and LCCIs at each of the 6 angles were significantly higher in eyes with PXG than in eyes with POAG except LCCI at 150° (8.1 ± 4.3 vs 6.8 ± 2.8, P = .113) and LCCD at 0° (113.4 ± 54.7, 93.2 ± 36.1, P = .056) and 150° (128.1 ± 60.2, 114.0 ± 42.7, P = .206).
      Table 2Comparison of Lamina Cribrosa Parameters Between Pseudoexfoliation Glaucoma and Primary Open-Angle Glaucoma
      Angle, DegreesLCCDLCCI
      PXGPOAGP ValuePXGPOAGP Value
      Average138.7 ± 38.1108.1 ± 28.9<.001
      Statistically significant (P < .05).
      8.8 ± 2.96.6 ± 1.9.001
      Statistically significant (P < .05).
      0113.4 ± 54.793.2 ± 36.1.0566.9 ± 3.45.3 ± 1.9.012
      Statistically significant (P < .05).
      30129.4 ± 52.199.4 ± 37.9.005
      Statistically significant (P < .05).
      8.00 ± 3.95.8 ± 2.4.005
      Statistically significant (P < .05).
      60150.8 ± 59.7109.6 ± 46.9.001
      Statistically significant (P < .05).
      9.6 ± 4.36.8 ± 3.0.001
      Statistically significant (P < .05).
      90152.1 ± 57.5122.3 ± 41.7.010
      Statistically significant (P < .05).
      9.7 ± 3.77.7 ± 2.6.006
      Statistically significant (P < .05).
      120158.2 ± 46.3110.4 ± 43.3<.001
      Statistically significant (P < .05).
      10.3 ± 3.77.0 ± 3.0<.001
      Statistically significant (P < .05).
      150128.1 ± 60.2114.0 ± 42.7.2068.1 ± 4.36.8 ± 2.8.113
      LCCD = lamina cribrosa curvature depth; LCCI = lamina cribrosa curvature index; POAG = primary open-angle glaucoma; PXG = pseudoexfoliation glaucoma.
      a Statistically significant (P < .05).
      Figure thumbnail gr2
      Figure 2(A). Comparison of the lamina cribrosa curvature depth (LCCD), and (B) lamina cribrosa curvature index (LCCI), in 6 circumferential optical coherence tomography scans of eyes with pseudoexfoliation glaucoma (solid line), and primary open-angle glaucoma (dotted line).
      Table 3 shows the results of a linear regression analysis to assess factors associated with the average LCCI in all participants. The uni- and multivariable analyses revealed that higher IOP (β = 0.133 [95% CI 0.029-0.237], P = .014) and the presence of PXG (β = 1.953 [95% CI 0.904-3.003], P < .001) were significantly associated with a greater LCCI.
      Table 3Factors Associated with Average LCCI Determined by Univariable and Multivariable Linear Regression Analysis
      TotalUnivariable AnalysisMultivariable Analysis
      R2β (95% CI)P Value
      Linear regression analysis.
      β (95% CI)P Value
      Linear regression analysis.
      Age0.0120.024 (−0.025 to 0.074).329
      IOP0.1050.169 (0.060-0.279).003
      Statistically significant (P < .05).
      0.133 (0.029-0.237).014
      Statistically significant (P < .05).
      CCT0.0230.010 (0.024-0.005).193
      Axial length0.0090.205 (0.688-0.278).401
      VF MD0.0060.022 (0.087-0.044).510
      RNFL thickness0.019−0.017 (−0.046 to 0.011).229
      Presence of PXG0.1752.209 (1.128-3.289)<.001
      Statistically significant (P < .05).
      1.953 (0.904-3.003)<.001
      Statistically significant (P < .05).
      PXG
       Age0.0010.008 (0.114-0.098).881
       IOP0.0590.129 (−0.041 to 0.298).132
       CCT0.007−0.008 (0.041-0.025).615
       Axial length<0.001−0.041 (0.769-0.688).910
       VF MD<0.0010.007 (−0.091 to 0.104).893
       RNFL thickness0.041−0.026 (−0.068-0.016).217
      POAG
       Age0.00280.007 (0.053-0.038).744
       IOP0.1150.138 (0.012-0.264).033
      Statistically significant (P < .05).
       CCT0.0490.008 (0.020-0.004).182
       Axial length0.0220.232 (0.743-0.279).364
       VF MD0.0480.048 (0.118-0.022).173
       RNFL thickness0.0460.003 (0.035-0.028).831
      CCT = central corneal thickness; CI = confidence interval; IOP = intraocular pressure; LCCI = lamina cribrosa curvature index; POAG = primary open-angle glaucoma; PXG = pseudoexfoliation glaucoma; RNFL = retinal nerve fiber layer; VF MD = visual field mean deviation.
      a Linear regression analysis.
      b Statistically significant (P < .05).
      The subgroup analysis revealed that none of the analyzed factors showed a significant association with LCCI in the PXG group. However, a higher IOP was the only factor associated with greater LCCI in a univariable analysis (β = 0.138 [95% CI 0.012-0.264], P = .033) of the POAG group.
      Table 4 shows the results of a logistic regression analysis to assess factors associated with the presence of PXG. In multivariable analysis, both greater average LCCI (odds ratio [OR] = 1.509 [95% CI 1.108-2.047], P = .003) and older age (OR = 1.074 [95% CI 1.017-1.147], P = .019) were significantly associated with the presence of PXG.
      Table 4Factors Associated with the Presence of Pseudoexfoliation Glaucoma
      VariablesUnivariable AnalysisMultivariable Analysis
      OR (95% CI)
      Logistic regression analysis.
      P Value
      Logistic regression analysis.
      OR (95% CI)
      Logistic regression analysis.
      P Value
      Logistic regression analysis.
      Age1.067 (1.023-1.122).0051.074 (1.017-1.147).019
      IOP1.083 (0.986-1.189).0961.032 (0.923-1.164).586
      CCT0.997 (0.987-1.008).613
      Axial length0.872 (0.600-1.247).456
      VF MD0.991 (0.944-1.041).727
      RNFL thickness0.998 (0.977-1.019).855
      Average LCCI1.532 (1.193-1.967).0011.509 (1.180-2.047).003
      CCT = central corneal thickness; CI = confidence interval; IOP = intraocular pressure; LCCI = lamina cribrosa curvature index; OR = odds ratio; PXG = pseudoexfoilation glaucoma; RNFL = retinal nerve fiber layer thickness; VF MD = visual field mean deviation.
      a Logistic regression analysis.

       Representative Cases

      Figure 3 shows representative cases in the PXG and POAG groups. A 74-year-old woman with PXG exhibited a steep LC curvature, and the average LCCI was 11.10 (VF MD −12.21 dB). Conversely, an 83-year-old man with POAG demonstrated a relatively flat LC curvature with an average LCCI of 6.25 (VF MD −13.52 dB).
      Figure thumbnail gr3
      Figure 3(A). Representative case of a 74-year-old woman with pseudoexfoliation glaucoma (PXG) showing steeper lamina cribrosa curvature (visual field mean deviation [MD] = −12.21 dB, lamina cribrosa curvature index = 11.10). (B). An 83-year-old man with primary open-angle glaucoma (POAG) showing a relatively flat lamina cribrosa curvature (visual field MD = −13.52 dB; LCCI = 6.25).

      Discussion

      In this study, we found that LC curvature was significantly steeper in the PXG group than in the POAG group. Similarly, greater LCCI was related to the presence of PXG. A previous study demonstrated that increased mean LCCI was related to glaucomatous VF progression in patients with POAG.
      • Ha A.
      • Kim T.J.
      • Girard M.J.A.
      • et al.
      Baseline lamina cribrosa curvature and subsequent visual field progression rate in primary open-angle glaucoma.
      The authors suggested that a steeper LC curvature might impose more stress on the axons of RGC axons, hampering glaucomatous progression. Hence, our result may give a clue as to why patients with PXG show more rapid glaucomatous progression and poorer prognosis than patients with POAG, even with similar IOP levels. Previous studies
      • Kim S.
      • Sung K.R.
      • Lee J.R.
      • et al.
      Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral-domain optical coherence tomography enhanced depth imaging.
      • Ersöz M.G.
      • Kunak Mart D.
      • Hazar L.
      • et al.
      Evaluation of prelaminar region and lamina cribrosa with enhanced depth imaging optical coherence tomography in pseudoexfoliation glaucoma.
      • Moghimi S.
      • Nekoozadeh S.
      • Motamed-Gorji N.
      • et al.
      Lamina cribrosa and choroid features and their relationship to stage of pseudoexfoliation glaucoma.
      found that the LC was thinner in PXG than POAG or healthy eyes; thus, it can be presumed that it is much more susceptible to deformation (with a similar level of pressure stress) in eyes with PXG than in those with POAG.
      The LC is one of the ocular structures where pathologic changes are found in pseudoexfoliation syndrome.
      • Netland P.A.
      • Ye H.
      • Streeten B.W.
      • et al.
      Elastosis of the lamina cribrosa in pseudoexfoliation syndrome with glaucoma.
      ,
      • Pena J.D.
      • Netland P.A.
      • Vidal I.
      • et al.
      Elastosis of the lamina cribrosa in glaucomatous optic neuropathy.
      Braunsmann and associates
      • Braunsmann C.
      • Hammer C.M.
      • Rheinlaender J.
      • et al.
      Evaluation of lamina cribrosa and peripapillary sclera stiffness in pseudoexfoliation and normal eyes by atomic force microscopy.
      evaluated LC stiffness in cadaveric eyes with PXG and reported that it was markedly reduced. Since the LC is the primary site of axonal injury in glaucoma, alteration of elasticity and decreased LC stiffness may predispose patients with pseudoexfoliation to glaucoma development.
      • Anastasopoulos E.
      • Founti P.
      • Topouzis F.
      Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.
      It is likely that abnormal elastosis weakens the LC structure, causing it to become more posteriorly bowed and thereby damaging the RGC axons more frequently.
      Generally, PXG manifests with a high and severely fluctuating IOP despite the administration of IOP-lowering treatments.
      • Ritch R.
      • Schlotzer-Schrehardt U.
      Exfoliation syndrome.
      ,
      • Konstas A.G.
      • Mantziris D.A.
      • Stewart W.C.
      Diurnal intraocular pressure in untreated exfoliation and primary open-angle glaucoma.
      ,
      • Ritch R.
      • Schlotzer-Schrehardt U.
      • Konstas A.G.
      Why is glaucoma associated with exfoliation syndrome?.
      However, the mean IOP of patients with PXG was 17.03 mm Hg in our study, and not statistically different from the mean IOP of patients with POAG, suggesting possible effects of other risk factors. Thinning and decreased stiffness of LC tissues may be possible factors accelerating glaucomatous damage in patients with PXG.
      Kim and associates
      • Kim Y.W.
      • Jeoung J.W.
      • Girard M.J.
      • et al.
      Positional and curvature difference of lamina cribrosa according to the baseline intraocular pressure in primary open-angle glaucoma: a swept-source optical coherence tomography (SS-OCT) Study.
      reported that the LC had greater curvature and was more posteriorly located in high-tension glaucoma eyes than in normal-tension glaucoma or healthy eyes. Since the LCCI reflects mechanical strain of the optic nerve head,
      • Lee E.J.
      • Kim T.-W.
      • Kim H.
      • et al.
      Comparison between lamina cribrosa depth and curvature as a predictor of progressive retinal nerve fiber layer thinning in primary open-angle glaucoma.
      higher IOP may cause strain on the LC, and therefore lead to increased LCCI. Our results also showed that higher IOP was related to greater LCCI in all patients.
      However, we only confirmed a statistically significant correlation between IOP and LCCI in the POAG group. A correlation of IOP with LCCI in patients with open-angle glaucoma was reported in previous studies.
      • Kim Y.W.
      • Jeoung J.W.
      • Girard M.J.
      • et al.
      Positional and curvature difference of lamina cribrosa according to the baseline intraocular pressure in primary open-angle glaucoma: a swept-source optical coherence tomography (SS-OCT) Study.
      We are not certain why the eyes with PXG in our study did not reveal any relevant factors associated with greater LCCI. IOP exhibited a relatively lower P value (.132) among analyzed covariates, but it did not reach statistical significance. Hence, it would be appropriate to say that unknown factors in PXG may contribute more importantly to steeper LC curvature. In this context, it would be interesting to explore further at the histologic level to discover factors associated with a steeper LC curvature in eyes with PXG. Notably, in light of the previous POAG results
      • Ha A.
      • Kim T.J.
      • Girard M.J.A.
      • et al.
      Baseline lamina cribrosa curvature and subsequent visual field progression rate in primary open-angle glaucoma.
      it is essential to ascertain factors associated with steeper LC curvature in eyes with PXG, since it may be linked to higher probability of glaucomatous progression. In the meantime, IOP values analyzed in this study were average of 2 or 3 times measurements performed at baseline. Considering greater fluctuation of IOP in PXG, longitudinal IOP assessment may present different result in this regard, and this is one of caveats in our study. This issue should be investigated in a forthcoming long-term study.
      There are other limitations to note. First, the group sample sizes of each were relatively small. In addition, overall ages were different between the PXG and POAG groups as demonstrated by the independent t test. This result might be related to a natural clinical characteristic of PXG because it usually develops in older age. Even though age was not related to LCCI in normal subjects
      • Lee S.H.
      • Kim T.W.
      • Lee E.J.
      • et al.
      Lamina cribrosa curvature in healthy Korean eyes.
      and patients with POAG,
      • Kim Y.W.
      • Jeoung J.W.
      • Kim D.W.
      • et al.
      Clinical assessment of lamina cribrosa curvature in eyes with primary open-angle glaucoma.
      we cannot exclude the effect of age. Also, the current study included only Korean patients. Because Asian populations, including those from Korean
      • Kim C.-S.
      • Seong G.J.
      • Lee N.-H.
      • et al.
      Prevalence of primary open-angle glaucoma in central South Korea the Namil study.
      and Japan,
      • Iwase A.
      • Suzuki Y.
      • Araie M.
      • et al.
      The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study.
      are known to have a higher prevalence of normal-tension glaucoma, our results may not be generalizable to other ethnic populations.
      Furthermore, LC curvature was analyzed from cross-sectional images, which may not represent the whole LC feature. We analyzed 6 frames imaged at different angles to include more information and overcome this issue. However, it would be better to acquire 3-dimensional LC configuration in a future study. Last, the OCT software did not provide automatic segmentation of the LC and therefore measurements could possibly have been inaccurate, although we did confirm excellent reproducibility.
      To the best of our knowledge, this is the first study comparing the LC curvature between eyes with PXG and POAG. In conclusion, the eyes with PXG had a more steeply curved LC than eyes with POAG. This finding may explain the more rapid progression of PXG, considering previous studies demonstrating steeper LC as a risk factor for POAG progression. Consequently, we plan to investigate this subject further in a forthcoming longitudinal study.
      All authors have completed and submitted the ICMJE form for disclosure of potential conflicts of interest. Funding/Support: This study received no funding. Financial Disclosures: The authors indicate no financial support or conflicts of interest. All authors attest that they meet the current ICMJE criteria for authorship.

      References

        • Lindberg J.G.
        Clinical investigations on depigmentation of the pupillary border and translucency of the iris in cases of senile cataract and in normal eyes in elderly persons.
        Acta Ophthalmol Suppl. 1989; 190: 1-96
        • Ritch R.
        • Schlotzer-Schrehardt U.
        Exfoliation syndrome.
        Surv Ophthalmol. 2001; 45: 265-315
        • Heijl A.
        • Bengtsson B.
        • Hyman L.
        • Leske M.C.
        Natural history of open-angle glaucoma.
        Ophthalmology. 2009; 116: 2271-2276
        • Olivius E.
        • Thorburn W.
        Prognosis of glaucoma simplex and glaucoma capsulare. A comparative study.
        Acta Ophthalmol (Copenh). 1978; 56: 921-934
        • Kim S.
        • Sung K.R.
        • Lee J.R.
        • et al.
        Evaluation of lamina cribrosa in pseudoexfoliation syndrome using spectral-domain optical coherence tomography enhanced depth imaging.
        Ophthalmology. 2013; 120: 1798-1803
        • Ersöz M.G.
        • Kunak Mart D.
        • Hazar L.
        • et al.
        Evaluation of prelaminar region and lamina cribrosa with enhanced depth imaging optical coherence tomography in pseudoexfoliation glaucoma.
        Turk J Ophthalmol. 2018; 48: 109-114
        • Moghimi S.
        • Nekoozadeh S.
        • Motamed-Gorji N.
        • et al.
        Lamina cribrosa and choroid features and their relationship to stage of pseudoexfoliation glaucoma.
        Invest Ophthalmol Vis Sci. 2018; 59: 5355-5365
        • Weinreb R.N.
        • Aung T.
        • Medeiros F.A.
        The pathophysiology and treatment of glaucoma: a review.
        JAMA. 2014; 311: 1901-1911
        • Quigley H.A.
        • Addicks E.M.
        • Green W.R.
        • et al.
        Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage.
        Arch Ophthalmol. 1981; 99: 635-649
        • Gaasterland D.
        • Tanishima T.
        • Kuwabara T.
        Axoplasmic flow during chronic experimental glaucoma. 1. Light and electron microscopic studies of the monkey optic nervehead during development of glaucomatous cupping.
        Invest Ophthalmol Vis Sci. 1978; 17: 838-846
        • Quigley H.
        • Anderson D.R.
        The dynamics and location of axonal transport blockade by acute intraocular pressure elevation in primate optic nerve.
        Invest Ophthalmol. 1976; 15: 606-616
        • Burgoyne C.F.
        • Downs J.C.
        • Bellezza A.J.
        • et al.
        The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage.
        Prog Retin Eye Res. 2005; 24: 39-73
        • Ha A.
        • Kim T.J.
        • Girard M.J.A.
        • et al.
        Baseline lamina cribrosa curvature and subsequent visual field progression rate in primary open-angle glaucoma.
        Ophthalmology. 2018; 125: 1898-1906
        • Kim Y.W.
        • Jeoung J.W.
        • Kim D.W.
        • et al.
        Clinical assessment of lamina cribrosa curvature in eyes with primary open-angle glaucoma.
        PLoS One. 2016; 11: e0150260
        • Netland P.A.
        • Ye H.
        • Streeten B.W.
        • et al.
        Elastosis of the lamina cribrosa in pseudoexfoliation syndrome with glaucoma.
        Ophthalmology. 1995; 102: 878-886
        • Pena J.D.
        • Netland P.A.
        • Vidal I.
        • et al.
        Elastosis of the lamina cribrosa in glaucomatous optic neuropathy.
        Exp Eye Res. 1998; 67: 517-524
        • Braunsmann C.
        • Hammer C.M.
        • Rheinlaender J.
        • et al.
        Evaluation of lamina cribrosa and peripapillary sclera stiffness in pseudoexfoliation and normal eyes by atomic force microscopy.
        Invest Ophthalmol Vis Sci. 2012; 53: 2960-2967
        • Anastasopoulos E.
        • Founti P.
        • Topouzis F.
        Update on pseudoexfoliation syndrome pathogenesis and associations with intraocular pressure, glaucoma and systemic diseases.
        Curr Opin Ophthalmol. 2015; 26: 82-89
        • Konstas A.G.
        • Mantziris D.A.
        • Stewart W.C.
        Diurnal intraocular pressure in untreated exfoliation and primary open-angle glaucoma.
        Arch Ophthalmol. 1997; 115: 182-185
        • Ritch R.
        • Schlotzer-Schrehardt U.
        • Konstas A.G.
        Why is glaucoma associated with exfoliation syndrome?.
        Prog Retin Eye Res. 2003; 22: 253-275
        • Kim Y.W.
        • Jeoung J.W.
        • Girard M.J.
        • et al.
        Positional and curvature difference of lamina cribrosa according to the baseline intraocular pressure in primary open-angle glaucoma: a swept-source optical coherence tomography (SS-OCT) Study.
        PLoS One. 2016; 11: e0162182
        • Lee E.J.
        • Kim T.-W.
        • Kim H.
        • et al.
        Comparison between lamina cribrosa depth and curvature as a predictor of progressive retinal nerve fiber layer thinning in primary open-angle glaucoma.
        Ophthalmol Glaucoma. 2018; 1: 44-51
        • Lee S.H.
        • Kim T.W.
        • Lee E.J.
        • et al.
        Lamina cribrosa curvature in healthy Korean eyes.
        Sci Rep. 2019; 9: 1756
        • Kim C.-S.
        • Seong G.J.
        • Lee N.-H.
        • et al.
        Prevalence of primary open-angle glaucoma in central South Korea the Namil study.
        Ophthalmology. 2011; 118: 1024-1030
        • Iwase A.
        • Suzuki Y.
        • Araie M.
        • et al.
        The prevalence of primary open-angle glaucoma in Japanese: the Tajimi Study.
        Ophthalmology. 2004; 111: 1641-1648