1040-5488/14/9111-1320/0 VOL. 91, NO. 11, PP. 1320Y1327 OPTOMETRY AND VISION SCIENCE Copyright * 2014 American Academy of Optometry
ORIGINAL ARTICLE
Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in Glaucoma Hyun-Ho Jung*, Mi-Sun Sung*, Hwan Heo*, and Sang-Woo Park†
ABSTRACT Purpose. To compare the parameters of the macular ganglion cell-inner plexiform layer (mGCIPL) thickness measured by Cirrus high-definition optical coherence tomography in normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Methods. Eighty patients with NTG, 80 patients with POAG, and 100 normal control subjects were enrolled. The mGCIPL and peripapillary retinal nerve fiber layer (pRNFL) thicknesses measured by Cirrus high-definition optical coherence tomography were compared in patients with glaucoma. The areas under the receiver operating characteristic curve (AROCs) were calculated to compare the diagnostic power of the mGCIPL thickness with that of the pRNFL thickness. Pearson correlation coefficients were determined to investigate the correlation between the mGCIPL or pRNFL thickness parameters and the mean deviation (MD) values of visual field tests. Results. All parameters of the mGCIPL thickness were significantly different between normal control subjects and patients with glaucoma. The superior, superotemporal, and superonasal thickness of mGCIPL and the superior thickness of pRNFL showed significant reductions and significantly higher AROCs for distinguishing between normal eyes and eyes with glaucoma in POAG compared with those in NTG. In NTG or POAG groups, the mGCIPL and pRNFL parameters with the highest AROC were the minimum and average thickness, respectively. The average, minimum, inferior, inferotemporal, and inferonasal thickness of mGCIPL and the average and inferior thickness of pRNFL were correlated with MD in NTG (p G 0.05 for all parameters), whereas all parameters of the mGCIPL thickness except the inferonasal thickness and all parameters of the pRNFL thickness except the temporal thickness were correlated with MD in POAG (p G 0.05 for all parameters). Conclusions. The diagnostic ability of the mGCIPL thickness was comparable to that of the pRNFL thickness in patients with NTG or POAG. The mGCIPL loss in NTG was localized and mainly concentrated on the inferior portion compared with diffuse mGCIPL loss in POAG. (Optom Vis Sci 2014;91:1320Y1327) Key Words: macular ganglion cell-inner plexiform layer, peripapillary retinal nerve fiber layer, normal-tension glaucoma, primary open-angle glaucoma, Cirrus HD-OCT
I
dentifying and consecutively monitoring structural damage before the development of irreversible vision loss is important in the management of glaucoma. Optical coherence tomography (OCT) is one of the instruments used to objectively evaluate structural damage caused by glaucoma. Optical coherence tomography determines the thickness of each retinal layer by calculating the echo time delay of backscattered light reflected off that layer.1 The diagnosis of glaucoma by OCT is made mostly on the basis of the thickness of the peripapillary retinal nerve fiber layer (pRNFL) and the optic nerve head (ONH) configuration.
*MD † MD, PhD Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju, Korea (all authors).
A number of studies have reported that the measurement of the pRNFL thickness has high reproducibility and diagnostic ability in distinguishing glaucomatous eyes from normal eyes.2Y7 However, several factors such as myopia or the size of the optic nerve can result in errors in measurements of the pRNFL thickness.8,9 About 50% of the retinal ganglion cells (RGCs) are present in the macula.10 Since Zeimer et al.11 reported that retinal thickness at the posterior pole is reduced by glaucomatous damage, several studies have been carried out to diagnose glaucoma by comparing all retinal layers in the macula. However, the reproducibility and diagnostic power of this approach were reported to be lower than those of the measurement of pRNFL thickness.12,13 Spectral domain OCT allows measuring the thickness of each retinal layer with improved resolution.14 Among commercially available OCT instruments, Cirrus high-definition (HD) OCT (Carl Zeiss Meditec Inc, Dublin, CA) provides the ganglion cell
Optometry and Vision Science, Vol. 91, No. 11, November 2014
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Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al.
analysis (GCA) algorithm, which measures the macular ganglion cell-inner plexiform layer (mGCIPL) thickness. The GCA algorithm measures the topographical thickness, average thickness, and minimum thickness of the mGCIPL. The automated segmentation algorithm is expected to provide improved precision to evaluate structural changes of the RGCs, which are preferentially damaged by glaucoma.15 Although the pathophysiology of glaucoma is unclear, there are intraocular pressure (IOP)Ydependent and Yindependent risk factors of glaucoma. Normal-tension glaucoma (NTG) has usually been regarded as a variant of primary open-angle glaucoma (POAG). Besides IOP, several clinical characteristics are found in patients with NTG compared with patients with POAG: a more localized RNFL defect, thinner inferotemporal neuroretinal rim, a deeper and more central visual field (VF) defect closer to the fixation, and slower glaucoma progression rate.16Y24 Therefore, it is important to classify types of glaucoma in determining treatment options and predicting disease progression. In this study, we investigated whether structural changes in mGCIPL differ between NTG and POAG. In addition, we compared the diagnostic power of the mGCIPL thickness with that of the pRNFL thickness in NTG and POAG.
METHODS Participants Subjects who met the eligibility criteria below and underwent examination by Cirrus HD-OCT were enrolled in this crosssectional study from a database of Korean patients attending the Chonnam National University Hospital Glaucoma Clinic from June 2011 to June 2012. Informed written consent was obtained from all participants in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board of Chonnam National University Hospital. To be included in the study, all participants had to meet the following criteria: 18 years or older, best-corrected visual acuity of greater than or equal to 20/40, spherical refraction within T5.0 diopters, and astigmatism within T3.0 diopters. Participants were excluded if they had a history of intraocular surgery (other than uncomplicated cataract surgery) or other eye diseases leading to VF abnormalities (such as neurological diseases). Participants underwent a full ophthalmic examination, including best-corrected visual acuity, automated refraction, slit-lamp examination of the anterior segment of the eye, IOP measurement with Goldmann applanation tonometry, fundus examination, anterior chamber angle examination by gonioscopy, central corneal thickness (CCT) measurement with an ultrasound pachymeter (UP-1000; Nidek Co, Ltd, Tokyo, Japan), ONH and RNFL examination with disc photography and red-free photography (Topcon TRC-NW6; Topcon Corporation, Tokyo, Japan) to evaluate glaucomatous optic nerve damage, Swedish interactive threshold algorithm 30-2 perimetry with the Humphrey Field Analyzer (Carl Zeiss Meditec Inc), and OCT scanning using Cirrus HD-OCT. Normal control participants were recruited from patients who came for a routine eye examination. The inclusion criteria were as follows: healthy participants with no family history of glaucoma,
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no intraocular surgery, an IOP of less than or equal to 21 mm Hg, nonglaucomatous ONH, and normal VF. Patients with glaucoma were included if they had an open anterior chamber angle and glaucomatous optic nerve damage accompanied by VF defects. Glaucomatous optic nerve damage was defined as the vertical cup-to-disc ratio of greater than or equal to 0.6, or above 0.2 asymmetry between the vertical cup-to-disc ratio of both eyes, or focal notching or generalized loss of the neuroretinal rim. Criteria for glaucomatous VF defects were as follows: greater than or equal to three significant (p G 0.05) nonedge contiguous points (including Q 1 at the p G 0.01 level) on the same side of the horizontal meridian in the pattern standard deviation (PSD) plot, confirmed by greater than or equal to two consecutive examinations. Only reliable VF test results (falsepositive errors, G15%; false-negative errors, G15%; fixation loss, G20%) were included. According to mean deviation (MD) values of VF tests, patients with glaucoma were classified into three groups, referred to as early (MD no worse than j6 dB), moderate (MD between j6 and j12 dB), and severe (MD worse than j12 dB).25 Normal-tension glaucoma was defined as an IOP of less than 21 mm Hg on diurnal testing with applanation tonometry before treatment, an open angle confirmed by gonioscopy, glaucomatous optic disc damage, and corresponding VF defects. Primary openangle glaucoma was defined as an IOP of greater than 21 mm Hg on diurnal testing with applanation tonometry before treatment, an open angle confirmed by gonioscopy, glaucomatous optic disc damage, and corresponding VF defects. If both eyes of a participant met the above criteria, only one randomly selected eye was included for data analysis. According to the pattern deviation probability plot, patients with glaucoma were classified into the paracentral scotoma group or nonparacentral scotoma group. Paracentral scotoma was defined as glaucomatous VF defect within 12 points of a central 12-degree radius on the Swedish interactive threshold algorithm 30-2 VF test regardless of VF defect outside the central 12 degrees. Nonparacentral scotoma was defined as glaucomatous VF defect outside central 12 degrees and no VF defect within central 12 degrees.
OCT Imaging After pupil dilation, all measurements were performed by one professional examiner with experience in taking OCT images using Cirrus HD-OCT. Macular images were obtained using the Macular Cube 200 by 200 scan protocol, which provides the results obtained from 200 horizontal B-scans composed of 200 A-scans per B-scan over 1024 samplings within a cube measuring 6 by 6 by 2 mm. The GCA algorithm measures the combined thickness of the RGC layer and IPL by identifying the outer boundary of RNFL and the outer boundary of IPL in the macula. The average, minimum, and topographical (superior, superotemporal, superonasal, inferior, inferotemporal, and inferonasal) thickness of mGCIPL is measured within a 14.13-mm2 elliptical annulus area (vertical inner and outer radii of 0.5 and 2.0 mm, respectively; horizontal inner and outer radii of 0.6 and 2.4 mm, respectively) centered on the fovea within the cube. The minimum thickness is determined by sampling 360 spokes of measurements extending from the center of the fovea to the edge of
Optometry and Vision Science, Vol. 91, No. 11, November 2014
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1322 Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al. TABLE 1.
Demographic characteristics of participants Normal
NTG
POAG
No. participants 100 80 80 Age, y 55.7 T 14.1 57.6 T 13.2 56.8 T 16.6 Sex (male/female) 47/53 36/44 38/42 MD, dB j0.51 (j1.40, j0.15) j5.89 (j8.22, j4.07) j5.95 (j8.38, j4.14) PSD, dB 1.56 (1.12, 1.88) 5.33 (3.78, 8.32) 5.50 (3.81, 8.64) CCT, Km 537.5 T 15.7 540.3 T 30.7 542.3 T 29.9 Type of VF defect (no. participants) Paracentral scotoma 35 38 Nonparacentral scotoma 45 42
p1
p2
p3
0.952 0.976 0.980 0.881 1.000 0.874 G0.001 G0.001 0.897 G0.001 G0.001 0.718 0.961 0.910 0.978 0.751
Data are expressed as the mean T SD or median (first and third quartile values). p values were calculated using the W2 test (sex and type of VF defect distribution) and one-way ANOVA or the Kruskal-Wallis test (other variables). p1, normal versus NTG; p2, normal versus POAG; p3, NTG versus POAG.
the ellipse in 1-degree intervals and selecting the spoke with the lowest average.26,27 The optic disc cube 200 by 200 protocol provides the results obtained from 200 horizontal B-scans composed of 200 A-scans per B-scan, measures pRNFL thickness with a 3.46-mm-diameter circle using the center of the optic disc as the center of the circle, and performs the analysis with the RNFL scanning protocol. It calculates the total and quadrant (superior, inferior, temporal, and nasal) RNFL thicknesses. Only scans with an image quality factor of greater than or equal to 6 and without eye movements or blinking artifacts were used for analysis. Scans with apparent segmentation errors (misidentification of the inner or outer retinal boundaries on OCT cross-sectional images resulting in readings of zero or abnormally low values) were excluded.
of variance (ANOVA), or the Kruskal-Wallis test. A post hoc test with Bonferroni adjustment was then used to determine significance between pairs of relevant groups. The area under the receiver operating characteristic curve (AROC) was used to assess the ability to discriminate between normal control subjects and glaucoma patients. The method of DeLong et al.28 was used to determine the statistical difference between AROCs. To analyze changes of the mGCIPL or pRNFL thickness according to glaucoma severity, Pearson correlation coefficients were determined between the mGCIPL or pRNFL thickness parameters and the MD values of VF tests. p values less than 0.05 were considered statistically significant.
RESULTS Participants
Statistical Analysis SPSS version 12.0 (SPSS, Chicago, IL) and MedCalc version 9.6 (MedCalc, Mariakerke, Belgium) were used for statistical analysis. The normality of distribution was verified using the Shapiro-Wilk normality test. Descriptive statistics included mean and SD for normally distributed variables and median, first quartile, and third quartile values for nonnormally distributed variables. Differences between glaucoma groups and normal control subjects were evaluated using the W2 test, one-way analysis
This study initially enrolled 330 patients with NTG or POAG. Of the 330 patients, we excluded 131 patients with severe glaucoma. In addition, we excluded 12 patients with OCT images of low quality, 8 patients with OCT images that had intraretinal segmentation errors, and 19 patients with unreliable VF results. In the final analysis, 80 patients diagnosed as having NTG and 80 patients diagnosed as having POAG were enrolled. In addition, 100 age- and sex-matched normal control subjects were enrolled for statistical comparisons.
TABLE 2.
The mGCIPL thickness of normal control subjects and patients with glaucoma Parameters Average Minimum Superior Superotemporal Superonasal Inferior Inferotemporal Inferonasal
Normal 82.7 T 79.9 T 83.4 T 82.0 T 84.6 T 80.3 T 82.4 T 82.5 T
7.9 8.4 9.0 8.0 8.7 9.0 8.9 8.6
NTG 70.6 T 9.1 60.5 T 14.0 72.7 T 11.9 71.9 T 9.4 76.4 T 13.5 68.5 T 12.1 68.8 T 12.4 71.8 T 13.1
POAG
p1
p2
p3
68.4 T 10.2 59.8 T 15.7 67.2 T 13.7 67.4 T 13.0 70.5 T 12.5 67.3 T 10.5 68.3 T 13.8 71.4 T 11.3
G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001
G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001
0.705 0.896 0.008 0.012 0.003 0.818 0.996 0.999
Data are expressed as the mean T SD. p values were calculated using one-way ANOVA. p1, normal versus NTG; p2, normal versus POAG; p3, NTG versus POAG. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al.
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TABLE 3.
The pRNFL thickness of normal control subjects and patients with glaucoma Parameters Average Superior Inferior Temporal Nasal
Normal
NTG
POAG
p1
p2
p3
96.9 T 9.9 120.9 T 16.9 127.0 T 18.2 71.0 T 13.2 66.9 T 10.3
78.0 T 9.7 93.7 T 18.5 90.1 T 22.6 60.6 T 11.0 62.8 T 7.9
74.7 T 12.3 86.1 T 16.4 89.7 T 17.8 61.5 T 13.5 63.4 T 13.1
G0.001 G0.001 G0.001 G0.001 0.257
G0.001 G0.001 G0.001 G0.001 0.348
0.218 0.002 0.954 0.742 0.976
Data are expressed as the mean T SD. p values were calculated using one-way ANOVA. p1, normal versus NTG; p2, normal versus POAG; p3, NTG versus POAG.
Table 1 shows the demographic characteristics of participants. There were no significant differences in age, sex, or average CCT among the groups. As expected, the MD and PSD showed significant differences between patients with glaucoma and normal control subjects. However, there were no significant differences in MD and PSD between the NTG and POAG groups. While 35 eyes of 35 patients and 45 eyes of 45 patients in the NTG group were classified as the paracentral scotoma group and the nonparacentral scotoma group, respectively, 38 eyes of 38 patients and 42 eyes of 42 patients of the POAG group were classified as the paracentral scotoma group and the nonparacentral scotoma group, respectively. No significant difference in proportion of patients was found between both groups (Table 1).
The mGCIPL Thickness Post hoc analysis with Bonferroni adjustment was used to compare the mGCIPL thickness in normal control subjects and patients with glaucoma (Table 2). As expected, analysis of all parameters showed that patients with glaucoma had significantly thinner mGCIPL than normal control subjects. In comparison between NTG and POAG, the superior, superotemporal, and superonasal mGCIPL thicknesses in patients with POAG were significantly thinner in comparison with those with NTG.
The pRNFL Thickness Post hoc analysis with Bonferroni adjustment was used to compare the pRNFL thickness between normal control subjects
and patients with glaucoma (Table 3). Similar to the mGCIPL thickness, the average, superior, inferior, and temporal pRNFL thicknesses were significantly thinner in patients with glaucoma in comparison with normal control subjects. However, there was no statistically significant difference in nasal pRNFL thickness between normal control subjects and glaucoma groups. The superior pRNFL thickness in the POAG group was significantly thinner in comparison with that in the NTG group.
The AROCs of the mGCIPL and pRNFL Measurements The AROCs of the mGCIPL and pRNFL thickness parameters for discriminating between healthy and glaucomatous eyes and between eyes at different subtypes of glaucoma are shown in Tables 4 and 5. The superior, superotemporal, and superonasal mGCIPL thickness showed significantly higher AROCs in the POAG group than in the NTG group. The same tendency was observed for the superior pRNFL thickness, although the difference did not reach statistical significance (p = 0.051). The minimum thickness of mGCIPL and the average thickness of pRNFL showed the highest AROCs among thickness parameters of the respective layers (NTG: 0.93 and 0.94, p = 0.999; POAG: 0.94 and 0.96, p = 0.892; Fig. 1). In the glaucoma groups, the best parameter for discriminating between normal eyes and eyes with glaucoma was the average thickness of pRNFL. Among the topographical parameters of the mGCIPL thickness, the inferotemporal thickness showed the highest AROC in
TABLE 4.
Comparisons of the AROCs and sensitivities (with 95% confidence intervals [CIs]) at specificities set at 80 and 95% for mGCIPL thickness parameters NTG Parameters Average Minimum Superior Superotemporal Superonasal Inferior Inferotemporal Inferonasal
POAG
AROC
95% CI
Specificity at 80%
Specificity at 95%
AROC
95% CI
Specificity at 80%
Specificity at 95%
p*
0.90 0.93 0.80 0.81 0.78 0.86 0.87 0.82
0.85Y0.95 0.89Y0.97 0.72Y0.88 0.72Y0.90 0.70Y0.86 0.80Y0.90 0.82Y0.92 0.76Y0.88
0.79 0.91 0.60 0.60 0.56 0.72 0.71 0.62
0.58 0.75 0.31 0.31 0.30 0.47 0.45 0.30
0.90 0.94 0.92 0.91 0.88 0.88 0.85 0.84
0.86Y0.94 0.91Y0.98 0.89Y0.95 0.88Y0.96 0.84Y0.92 0.83Y0.92 0.80Y0.90 0.78Y0.90
0.78 0.91 0.90 0.90 0.78 0.78 0.70 0.62
0.58 0.76 0.76 0.75 0.58 0.57 0.48 0.30
0.945 0.911 0.009 0.013 0.029 0.898 0.880 0.826
*Comparison between NTG and POAG by the DeLong test. Optometry and Vision Science, Vol. 91, No. 11, November 2014
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
1324 Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al. TABLE 5.
Comparisons of the AROCs and sensitivities (with 95% confidence intervals [CIs]) at specificities set at 80 and 95% for pRNFL thickness parameters NTG Parameters Average Superior Inferior
POAG
AROC
95% CI
Specificity at 80%
Specificity at 95%
AROC
95% CI
Specificity at 80%
Specificity at 95%
p*
0.94 0.86 0.90
0.89Y0.99 0.80Y0.92 0.86Y0.94
0.94 0.67 0.79
0.80 0.52 0.58
0.96 0.94 0.90
0.92Y1.00 0.90Y0.99 0.86Y0.94
1.00 0.94 0.80
0.81 0.82 0.58
0.886 0.051 0.975
*Comparison between NTG and POAG by the DeLong test.
patients with NTG, whereas the superior thickness showed the highest AROCs in patients with POAG.
The Correlations between the OCT Parameters and the MD Values of VF Tests Pearson correlation coefficients between the pRNFL thickness or mGCIPL thickness and MD are shown in Table 6. The average and minimum mGCIPL thickness and average pRNFL thickness showed significant correlations with MD in the NTG or POAG groups. Among the topographical parameters, the inferotemporal, inferior, and inferonasal mGCIPL thickness showed significant correlations with MD in the NTG group, whereas the superior, superotemporal, superonasal, inferior, and inferotemporal mGCIPL thickness showed significant correlations with MD in POAG group. The inferonasal mGCIPL thickness showed correlations with MD in the POAG group, although the correlation did not reach statistical significance (R 2 = 0.308, j0.259; p = 0.051, 0.054).
DISCUSSION Normal-tension glaucoma has been reported to share clinical similarities with POAG. The arbitrary difference between NTG and POAG is the level of IOP, determined mainly by diurnal IOP measurements. Previous studies reported that NTG showed slower progression, deeper and more localized VF defect, thinner neuroretinal rim, and greater prevalence of disc hemorrhage than POAG.22,29,30 In addition, although there is still controversy over the structural difference between NTG and POAG, several studies reported that NTG showed more localized inferior or inferotemporal RNFL defects compared with POAG.21,31,32 Ahrlich et al.33 reported that VF progression in NTG was more localized and concentrated within the central and superotemporal fields, whereas VF progression in POAG was more randomly distributed in the superotemporal and inferotemporal fields. Recently, Kim et al.34 compared the thickness of the macular ganglion cell complex (GCC) in NTG and POAG using spectral
FIGURE 1. The AROCs of the best parameters. (A) POAG; (B) NTG. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al. TABLE 6.
Correlation between Cirrus HD-OCT parameters and the MD values of VF tests
Parameters
r
mGCIPL thickness, Km Average 0.29 Minimum 0.44 Superior 0.05 Superotemporal 0.16 Superonasal 0.02 Inferior 0.42 Inferotemporal 0.39 Inferonasal 0.31 pRNFL thickness, Km Average 0.45 Superior 0.22 Inferior 0.41 Temporal j0.01 Nasal j0.02
NTG
POAG
MD
MD p
r
p
0.021 0.002 0.910 0.262 0.963 0.007 0.010 0.029
0.318 0.451 0.430 0.425 0.363 0.370 0.374 0.308
0.011 G0.001 0.021 0.001 0.041 0.031 0.029 0.051
0.44 0.41 0.35 0.29 0.11
G0.001 0.001 0.009 0.299 0.418
G0.001 0.265 0.004 0.918 0.489
p values were calculated using the Pearson correlation test. r, Pearson coefficient of correlation.
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domain OCT and found that macular GCC loss was localized in the inferior hemifield in NTG but was diffusely distributed in POAG. Firat et al.35 showed that macular GCC was significantly thicker in patients with NTG than in patients with POAG. These studies suggest that there is a difference between NTG and POAG in structural damage of macular GCC. However, little is known about changes in the mGCIPL thickness in NTG. To the best of our knowledge, this is the first study to evaluate the mGCIPL thickness in NTG and POAG subgroups according to glaucoma severity. We investigated correlations between the mGCIPL parameters and VF indices. The inferotemporal, inferior, and inferonasal thickness of mGCIPL significantly correlated with MD in the NTG group, whereas the superior, superotemporal, superonasal, inferior, and inferotemporal thickness of mGCIPL showed significant correlations with MD in the POAG group. These findings imply that, as glaucoma severity increases, the mGCIPL thickness decreases in a localized area (especially in the inferior hemifield) in NTG but diffusely decreases in POAG (Fig. 2). To assess the diagnostic ability of each parameter, we calculated the AROCs of all parameters. A number of studies reported that the glaucoma diagnostic ability of macular GCC (the sum of the innermost retinal layer, RNFL, RGC layer, and IPL) or mGCIPL is comparable or superior to that of pRNFL.9,36Y45 In our study, the minimum mGCIPL thickness and average pRNFL thickness showed the highest AROCs. In line with previous studies,44,45
FIGURE 2. Representative mGCIPL images obtained using Cirrus HD-OCT in patients with glaucoma. The mGCIPL loss in POAG (A, C) was diffuse, whereas the mGCIPL loss in NTG (B, D) was localized and mainly concentrated in the inferior portion. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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1326 Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al.
our study showed that the diagnostic ability of these two best parameters was comparable in both groups. Of the topographical parameters of the mGCIPL thickness, the parameter with the highest AROC in patients with NTG was the inferotemporal thickness. In particular, the AROC of the inferotemporal mGCIPL thickness showed statistically significant differences when compared with those of superior, superotemporal, and superonasal mGCIPL thicknesses in patients with NTG (p = 0.031, 0.048, and 0.004, respectively), whereas the parameter with the highest AROC in patients with POAG was the superior thickness. In contrast with NTG, the AROC of the superior mGCIPL thickness showed no significant differences with the inferotemporal, inferior, and inferonasal mGCIPL thickness in the POAG group. Shin et al.46 reported that the mGCIPL thickness can be a more valuable diagnostic parameter than the pRNFL thickness in patients with a central field defect. In the present study, because we included a considerable number of subjects who had a mixed pattern of paracentral and peripheral scotoma, the comparison between an isolated parafoveal scotoma group and an isolated peripheral scotoma group was unsuitable. Therefore, our subjects were classified into the paracentral scotoma group or nonparacentral scotoma group. No significant difference in proportion of patients was found between the NTG and POAG groups. On the basis of our results, we suppose that a possibility of bias from subject selection is little. Further studies considering the pattern of VF defect will be needed to more accurately assess the diagnostic ability of mGCIPL in NTG or POAG. Our study has several limitations. First, our study included only a Korean population, and it cannot be excluded that the results of similar studies with patients of different ethnicities may be different. Second, our sample size was relatively small. Third, our study evaluated the data from patients with different severities of glaucoma in a cross-sectional way. As glaucoma progresses, there may be a different pattern of changes in the mGCIPL thickness in patients with NTG and POAG. Therefore, a prospective longitudinal study will also be needed to confirm our results. Fourth, because the participants who underwent glaucoma filtering surgery were excluded, there might be a possibility of selection bias. For instance, patients with deep paracentral scotoma who underwent trabeculectomy could be excluded in POAG. However, because this type of patient was uncommon in our database, it is less likely to affect our results. Moreover, in light of previous studies that glaucoma filtering surgery can affect the measurement of retinal thickness by OCT,47,48 our exclusion criteria may be reasonable. In conclusion, the diagnostic ability of the mGCIPL thickness was comparable to that of the pRNFL thickness in patients with either NTG or POAG. The mGCIPL loss in NTG was localized and mainly concentrated on the inferior portion compared with diffuse mGCIPL loss in POAG. Paying more attention to the inferior portion of the mGCIPL would be helpful in managing patients with NTG.
ACKNOWLEDGMENTS None of the authors has any financial/conflicting interests to disclose. Received October 26, 2013; accepted July 2, 2014.
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Sang Woo Park Department of Ophthalmology Chonnam National University Medical School and Hospital, 8 Hak-Dong, Dong-Gu Gwangju 501-757 Korea e-mail: [email protected]
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ORIGINAL ARTICLE
Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in Glaucoma Hyun-Ho Jung*, Mi-Sun Sung*, Hwan Heo*, and Sang-Woo Park†
ABSTRACT Purpose. To compare the parameters of the macular ganglion cell-inner plexiform layer (mGCIPL) thickness measured by Cirrus high-definition optical coherence tomography in normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG). Methods. Eighty patients with NTG, 80 patients with POAG, and 100 normal control subjects were enrolled. The mGCIPL and peripapillary retinal nerve fiber layer (pRNFL) thicknesses measured by Cirrus high-definition optical coherence tomography were compared in patients with glaucoma. The areas under the receiver operating characteristic curve (AROCs) were calculated to compare the diagnostic power of the mGCIPL thickness with that of the pRNFL thickness. Pearson correlation coefficients were determined to investigate the correlation between the mGCIPL or pRNFL thickness parameters and the mean deviation (MD) values of visual field tests. Results. All parameters of the mGCIPL thickness were significantly different between normal control subjects and patients with glaucoma. The superior, superotemporal, and superonasal thickness of mGCIPL and the superior thickness of pRNFL showed significant reductions and significantly higher AROCs for distinguishing between normal eyes and eyes with glaucoma in POAG compared with those in NTG. In NTG or POAG groups, the mGCIPL and pRNFL parameters with the highest AROC were the minimum and average thickness, respectively. The average, minimum, inferior, inferotemporal, and inferonasal thickness of mGCIPL and the average and inferior thickness of pRNFL were correlated with MD in NTG (p G 0.05 for all parameters), whereas all parameters of the mGCIPL thickness except the inferonasal thickness and all parameters of the pRNFL thickness except the temporal thickness were correlated with MD in POAG (p G 0.05 for all parameters). Conclusions. The diagnostic ability of the mGCIPL thickness was comparable to that of the pRNFL thickness in patients with NTG or POAG. The mGCIPL loss in NTG was localized and mainly concentrated on the inferior portion compared with diffuse mGCIPL loss in POAG. (Optom Vis Sci 2014;91:1320Y1327) Key Words: macular ganglion cell-inner plexiform layer, peripapillary retinal nerve fiber layer, normal-tension glaucoma, primary open-angle glaucoma, Cirrus HD-OCT
I
dentifying and consecutively monitoring structural damage before the development of irreversible vision loss is important in the management of glaucoma. Optical coherence tomography (OCT) is one of the instruments used to objectively evaluate structural damage caused by glaucoma. Optical coherence tomography determines the thickness of each retinal layer by calculating the echo time delay of backscattered light reflected off that layer.1 The diagnosis of glaucoma by OCT is made mostly on the basis of the thickness of the peripapillary retinal nerve fiber layer (pRNFL) and the optic nerve head (ONH) configuration.
*MD † MD, PhD Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju, Korea (all authors).
A number of studies have reported that the measurement of the pRNFL thickness has high reproducibility and diagnostic ability in distinguishing glaucomatous eyes from normal eyes.2Y7 However, several factors such as myopia or the size of the optic nerve can result in errors in measurements of the pRNFL thickness.8,9 About 50% of the retinal ganglion cells (RGCs) are present in the macula.10 Since Zeimer et al.11 reported that retinal thickness at the posterior pole is reduced by glaucomatous damage, several studies have been carried out to diagnose glaucoma by comparing all retinal layers in the macula. However, the reproducibility and diagnostic power of this approach were reported to be lower than those of the measurement of pRNFL thickness.12,13 Spectral domain OCT allows measuring the thickness of each retinal layer with improved resolution.14 Among commercially available OCT instruments, Cirrus high-definition (HD) OCT (Carl Zeiss Meditec Inc, Dublin, CA) provides the ganglion cell
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Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al.
analysis (GCA) algorithm, which measures the macular ganglion cell-inner plexiform layer (mGCIPL) thickness. The GCA algorithm measures the topographical thickness, average thickness, and minimum thickness of the mGCIPL. The automated segmentation algorithm is expected to provide improved precision to evaluate structural changes of the RGCs, which are preferentially damaged by glaucoma.15 Although the pathophysiology of glaucoma is unclear, there are intraocular pressure (IOP)Ydependent and Yindependent risk factors of glaucoma. Normal-tension glaucoma (NTG) has usually been regarded as a variant of primary open-angle glaucoma (POAG). Besides IOP, several clinical characteristics are found in patients with NTG compared with patients with POAG: a more localized RNFL defect, thinner inferotemporal neuroretinal rim, a deeper and more central visual field (VF) defect closer to the fixation, and slower glaucoma progression rate.16Y24 Therefore, it is important to classify types of glaucoma in determining treatment options and predicting disease progression. In this study, we investigated whether structural changes in mGCIPL differ between NTG and POAG. In addition, we compared the diagnostic power of the mGCIPL thickness with that of the pRNFL thickness in NTG and POAG.
METHODS Participants Subjects who met the eligibility criteria below and underwent examination by Cirrus HD-OCT were enrolled in this crosssectional study from a database of Korean patients attending the Chonnam National University Hospital Glaucoma Clinic from June 2011 to June 2012. Informed written consent was obtained from all participants in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board of Chonnam National University Hospital. To be included in the study, all participants had to meet the following criteria: 18 years or older, best-corrected visual acuity of greater than or equal to 20/40, spherical refraction within T5.0 diopters, and astigmatism within T3.0 diopters. Participants were excluded if they had a history of intraocular surgery (other than uncomplicated cataract surgery) or other eye diseases leading to VF abnormalities (such as neurological diseases). Participants underwent a full ophthalmic examination, including best-corrected visual acuity, automated refraction, slit-lamp examination of the anterior segment of the eye, IOP measurement with Goldmann applanation tonometry, fundus examination, anterior chamber angle examination by gonioscopy, central corneal thickness (CCT) measurement with an ultrasound pachymeter (UP-1000; Nidek Co, Ltd, Tokyo, Japan), ONH and RNFL examination with disc photography and red-free photography (Topcon TRC-NW6; Topcon Corporation, Tokyo, Japan) to evaluate glaucomatous optic nerve damage, Swedish interactive threshold algorithm 30-2 perimetry with the Humphrey Field Analyzer (Carl Zeiss Meditec Inc), and OCT scanning using Cirrus HD-OCT. Normal control participants were recruited from patients who came for a routine eye examination. The inclusion criteria were as follows: healthy participants with no family history of glaucoma,
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no intraocular surgery, an IOP of less than or equal to 21 mm Hg, nonglaucomatous ONH, and normal VF. Patients with glaucoma were included if they had an open anterior chamber angle and glaucomatous optic nerve damage accompanied by VF defects. Glaucomatous optic nerve damage was defined as the vertical cup-to-disc ratio of greater than or equal to 0.6, or above 0.2 asymmetry between the vertical cup-to-disc ratio of both eyes, or focal notching or generalized loss of the neuroretinal rim. Criteria for glaucomatous VF defects were as follows: greater than or equal to three significant (p G 0.05) nonedge contiguous points (including Q 1 at the p G 0.01 level) on the same side of the horizontal meridian in the pattern standard deviation (PSD) plot, confirmed by greater than or equal to two consecutive examinations. Only reliable VF test results (falsepositive errors, G15%; false-negative errors, G15%; fixation loss, G20%) were included. According to mean deviation (MD) values of VF tests, patients with glaucoma were classified into three groups, referred to as early (MD no worse than j6 dB), moderate (MD between j6 and j12 dB), and severe (MD worse than j12 dB).25 Normal-tension glaucoma was defined as an IOP of less than 21 mm Hg on diurnal testing with applanation tonometry before treatment, an open angle confirmed by gonioscopy, glaucomatous optic disc damage, and corresponding VF defects. Primary openangle glaucoma was defined as an IOP of greater than 21 mm Hg on diurnal testing with applanation tonometry before treatment, an open angle confirmed by gonioscopy, glaucomatous optic disc damage, and corresponding VF defects. If both eyes of a participant met the above criteria, only one randomly selected eye was included for data analysis. According to the pattern deviation probability plot, patients with glaucoma were classified into the paracentral scotoma group or nonparacentral scotoma group. Paracentral scotoma was defined as glaucomatous VF defect within 12 points of a central 12-degree radius on the Swedish interactive threshold algorithm 30-2 VF test regardless of VF defect outside the central 12 degrees. Nonparacentral scotoma was defined as glaucomatous VF defect outside central 12 degrees and no VF defect within central 12 degrees.
OCT Imaging After pupil dilation, all measurements were performed by one professional examiner with experience in taking OCT images using Cirrus HD-OCT. Macular images were obtained using the Macular Cube 200 by 200 scan protocol, which provides the results obtained from 200 horizontal B-scans composed of 200 A-scans per B-scan over 1024 samplings within a cube measuring 6 by 6 by 2 mm. The GCA algorithm measures the combined thickness of the RGC layer and IPL by identifying the outer boundary of RNFL and the outer boundary of IPL in the macula. The average, minimum, and topographical (superior, superotemporal, superonasal, inferior, inferotemporal, and inferonasal) thickness of mGCIPL is measured within a 14.13-mm2 elliptical annulus area (vertical inner and outer radii of 0.5 and 2.0 mm, respectively; horizontal inner and outer radii of 0.6 and 2.4 mm, respectively) centered on the fovea within the cube. The minimum thickness is determined by sampling 360 spokes of measurements extending from the center of the fovea to the edge of
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1322 Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al. TABLE 1.
Demographic characteristics of participants Normal
NTG
POAG
No. participants 100 80 80 Age, y 55.7 T 14.1 57.6 T 13.2 56.8 T 16.6 Sex (male/female) 47/53 36/44 38/42 MD, dB j0.51 (j1.40, j0.15) j5.89 (j8.22, j4.07) j5.95 (j8.38, j4.14) PSD, dB 1.56 (1.12, 1.88) 5.33 (3.78, 8.32) 5.50 (3.81, 8.64) CCT, Km 537.5 T 15.7 540.3 T 30.7 542.3 T 29.9 Type of VF defect (no. participants) Paracentral scotoma 35 38 Nonparacentral scotoma 45 42
p1
p2
p3
0.952 0.976 0.980 0.881 1.000 0.874 G0.001 G0.001 0.897 G0.001 G0.001 0.718 0.961 0.910 0.978 0.751
Data are expressed as the mean T SD or median (first and third quartile values). p values were calculated using the W2 test (sex and type of VF defect distribution) and one-way ANOVA or the Kruskal-Wallis test (other variables). p1, normal versus NTG; p2, normal versus POAG; p3, NTG versus POAG.
the ellipse in 1-degree intervals and selecting the spoke with the lowest average.26,27 The optic disc cube 200 by 200 protocol provides the results obtained from 200 horizontal B-scans composed of 200 A-scans per B-scan, measures pRNFL thickness with a 3.46-mm-diameter circle using the center of the optic disc as the center of the circle, and performs the analysis with the RNFL scanning protocol. It calculates the total and quadrant (superior, inferior, temporal, and nasal) RNFL thicknesses. Only scans with an image quality factor of greater than or equal to 6 and without eye movements or blinking artifacts were used for analysis. Scans with apparent segmentation errors (misidentification of the inner or outer retinal boundaries on OCT cross-sectional images resulting in readings of zero or abnormally low values) were excluded.
of variance (ANOVA), or the Kruskal-Wallis test. A post hoc test with Bonferroni adjustment was then used to determine significance between pairs of relevant groups. The area under the receiver operating characteristic curve (AROC) was used to assess the ability to discriminate between normal control subjects and glaucoma patients. The method of DeLong et al.28 was used to determine the statistical difference between AROCs. To analyze changes of the mGCIPL or pRNFL thickness according to glaucoma severity, Pearson correlation coefficients were determined between the mGCIPL or pRNFL thickness parameters and the MD values of VF tests. p values less than 0.05 were considered statistically significant.
RESULTS Participants
Statistical Analysis SPSS version 12.0 (SPSS, Chicago, IL) and MedCalc version 9.6 (MedCalc, Mariakerke, Belgium) were used for statistical analysis. The normality of distribution was verified using the Shapiro-Wilk normality test. Descriptive statistics included mean and SD for normally distributed variables and median, first quartile, and third quartile values for nonnormally distributed variables. Differences between glaucoma groups and normal control subjects were evaluated using the W2 test, one-way analysis
This study initially enrolled 330 patients with NTG or POAG. Of the 330 patients, we excluded 131 patients with severe glaucoma. In addition, we excluded 12 patients with OCT images of low quality, 8 patients with OCT images that had intraretinal segmentation errors, and 19 patients with unreliable VF results. In the final analysis, 80 patients diagnosed as having NTG and 80 patients diagnosed as having POAG were enrolled. In addition, 100 age- and sex-matched normal control subjects were enrolled for statistical comparisons.
TABLE 2.
The mGCIPL thickness of normal control subjects and patients with glaucoma Parameters Average Minimum Superior Superotemporal Superonasal Inferior Inferotemporal Inferonasal
Normal 82.7 T 79.9 T 83.4 T 82.0 T 84.6 T 80.3 T 82.4 T 82.5 T
7.9 8.4 9.0 8.0 8.7 9.0 8.9 8.6
NTG 70.6 T 9.1 60.5 T 14.0 72.7 T 11.9 71.9 T 9.4 76.4 T 13.5 68.5 T 12.1 68.8 T 12.4 71.8 T 13.1
POAG
p1
p2
p3
68.4 T 10.2 59.8 T 15.7 67.2 T 13.7 67.4 T 13.0 70.5 T 12.5 67.3 T 10.5 68.3 T 13.8 71.4 T 11.3
G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001
G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001 G0.001
0.705 0.896 0.008 0.012 0.003 0.818 0.996 0.999
Data are expressed as the mean T SD. p values were calculated using one-way ANOVA. p1, normal versus NTG; p2, normal versus POAG; p3, NTG versus POAG. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al.
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TABLE 3.
The pRNFL thickness of normal control subjects and patients with glaucoma Parameters Average Superior Inferior Temporal Nasal
Normal
NTG
POAG
p1
p2
p3
96.9 T 9.9 120.9 T 16.9 127.0 T 18.2 71.0 T 13.2 66.9 T 10.3
78.0 T 9.7 93.7 T 18.5 90.1 T 22.6 60.6 T 11.0 62.8 T 7.9
74.7 T 12.3 86.1 T 16.4 89.7 T 17.8 61.5 T 13.5 63.4 T 13.1
G0.001 G0.001 G0.001 G0.001 0.257
G0.001 G0.001 G0.001 G0.001 0.348
0.218 0.002 0.954 0.742 0.976
Data are expressed as the mean T SD. p values were calculated using one-way ANOVA. p1, normal versus NTG; p2, normal versus POAG; p3, NTG versus POAG.
Table 1 shows the demographic characteristics of participants. There were no significant differences in age, sex, or average CCT among the groups. As expected, the MD and PSD showed significant differences between patients with glaucoma and normal control subjects. However, there were no significant differences in MD and PSD between the NTG and POAG groups. While 35 eyes of 35 patients and 45 eyes of 45 patients in the NTG group were classified as the paracentral scotoma group and the nonparacentral scotoma group, respectively, 38 eyes of 38 patients and 42 eyes of 42 patients of the POAG group were classified as the paracentral scotoma group and the nonparacentral scotoma group, respectively. No significant difference in proportion of patients was found between both groups (Table 1).
The mGCIPL Thickness Post hoc analysis with Bonferroni adjustment was used to compare the mGCIPL thickness in normal control subjects and patients with glaucoma (Table 2). As expected, analysis of all parameters showed that patients with glaucoma had significantly thinner mGCIPL than normal control subjects. In comparison between NTG and POAG, the superior, superotemporal, and superonasal mGCIPL thicknesses in patients with POAG were significantly thinner in comparison with those with NTG.
The pRNFL Thickness Post hoc analysis with Bonferroni adjustment was used to compare the pRNFL thickness between normal control subjects
and patients with glaucoma (Table 3). Similar to the mGCIPL thickness, the average, superior, inferior, and temporal pRNFL thicknesses were significantly thinner in patients with glaucoma in comparison with normal control subjects. However, there was no statistically significant difference in nasal pRNFL thickness between normal control subjects and glaucoma groups. The superior pRNFL thickness in the POAG group was significantly thinner in comparison with that in the NTG group.
The AROCs of the mGCIPL and pRNFL Measurements The AROCs of the mGCIPL and pRNFL thickness parameters for discriminating between healthy and glaucomatous eyes and between eyes at different subtypes of glaucoma are shown in Tables 4 and 5. The superior, superotemporal, and superonasal mGCIPL thickness showed significantly higher AROCs in the POAG group than in the NTG group. The same tendency was observed for the superior pRNFL thickness, although the difference did not reach statistical significance (p = 0.051). The minimum thickness of mGCIPL and the average thickness of pRNFL showed the highest AROCs among thickness parameters of the respective layers (NTG: 0.93 and 0.94, p = 0.999; POAG: 0.94 and 0.96, p = 0.892; Fig. 1). In the glaucoma groups, the best parameter for discriminating between normal eyes and eyes with glaucoma was the average thickness of pRNFL. Among the topographical parameters of the mGCIPL thickness, the inferotemporal thickness showed the highest AROC in
TABLE 4.
Comparisons of the AROCs and sensitivities (with 95% confidence intervals [CIs]) at specificities set at 80 and 95% for mGCIPL thickness parameters NTG Parameters Average Minimum Superior Superotemporal Superonasal Inferior Inferotemporal Inferonasal
POAG
AROC
95% CI
Specificity at 80%
Specificity at 95%
AROC
95% CI
Specificity at 80%
Specificity at 95%
p*
0.90 0.93 0.80 0.81 0.78 0.86 0.87 0.82
0.85Y0.95 0.89Y0.97 0.72Y0.88 0.72Y0.90 0.70Y0.86 0.80Y0.90 0.82Y0.92 0.76Y0.88
0.79 0.91 0.60 0.60 0.56 0.72 0.71 0.62
0.58 0.75 0.31 0.31 0.30 0.47 0.45 0.30
0.90 0.94 0.92 0.91 0.88 0.88 0.85 0.84
0.86Y0.94 0.91Y0.98 0.89Y0.95 0.88Y0.96 0.84Y0.92 0.83Y0.92 0.80Y0.90 0.78Y0.90
0.78 0.91 0.90 0.90 0.78 0.78 0.70 0.62
0.58 0.76 0.76 0.75 0.58 0.57 0.48 0.30
0.945 0.911 0.009 0.013 0.029 0.898 0.880 0.826
*Comparison between NTG and POAG by the DeLong test. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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1324 Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al. TABLE 5.
Comparisons of the AROCs and sensitivities (with 95% confidence intervals [CIs]) at specificities set at 80 and 95% for pRNFL thickness parameters NTG Parameters Average Superior Inferior
POAG
AROC
95% CI
Specificity at 80%
Specificity at 95%
AROC
95% CI
Specificity at 80%
Specificity at 95%
p*
0.94 0.86 0.90
0.89Y0.99 0.80Y0.92 0.86Y0.94
0.94 0.67 0.79
0.80 0.52 0.58
0.96 0.94 0.90
0.92Y1.00 0.90Y0.99 0.86Y0.94
1.00 0.94 0.80
0.81 0.82 0.58
0.886 0.051 0.975
*Comparison between NTG and POAG by the DeLong test.
patients with NTG, whereas the superior thickness showed the highest AROCs in patients with POAG.
The Correlations between the OCT Parameters and the MD Values of VF Tests Pearson correlation coefficients between the pRNFL thickness or mGCIPL thickness and MD are shown in Table 6. The average and minimum mGCIPL thickness and average pRNFL thickness showed significant correlations with MD in the NTG or POAG groups. Among the topographical parameters, the inferotemporal, inferior, and inferonasal mGCIPL thickness showed significant correlations with MD in the NTG group, whereas the superior, superotemporal, superonasal, inferior, and inferotemporal mGCIPL thickness showed significant correlations with MD in POAG group. The inferonasal mGCIPL thickness showed correlations with MD in the POAG group, although the correlation did not reach statistical significance (R 2 = 0.308, j0.259; p = 0.051, 0.054).
DISCUSSION Normal-tension glaucoma has been reported to share clinical similarities with POAG. The arbitrary difference between NTG and POAG is the level of IOP, determined mainly by diurnal IOP measurements. Previous studies reported that NTG showed slower progression, deeper and more localized VF defect, thinner neuroretinal rim, and greater prevalence of disc hemorrhage than POAG.22,29,30 In addition, although there is still controversy over the structural difference between NTG and POAG, several studies reported that NTG showed more localized inferior or inferotemporal RNFL defects compared with POAG.21,31,32 Ahrlich et al.33 reported that VF progression in NTG was more localized and concentrated within the central and superotemporal fields, whereas VF progression in POAG was more randomly distributed in the superotemporal and inferotemporal fields. Recently, Kim et al.34 compared the thickness of the macular ganglion cell complex (GCC) in NTG and POAG using spectral
FIGURE 1. The AROCs of the best parameters. (A) POAG; (B) NTG. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al. TABLE 6.
Correlation between Cirrus HD-OCT parameters and the MD values of VF tests
Parameters
r
mGCIPL thickness, Km Average 0.29 Minimum 0.44 Superior 0.05 Superotemporal 0.16 Superonasal 0.02 Inferior 0.42 Inferotemporal 0.39 Inferonasal 0.31 pRNFL thickness, Km Average 0.45 Superior 0.22 Inferior 0.41 Temporal j0.01 Nasal j0.02
NTG
POAG
MD
MD p
r
p
0.021 0.002 0.910 0.262 0.963 0.007 0.010 0.029
0.318 0.451 0.430 0.425 0.363 0.370 0.374 0.308
0.011 G0.001 0.021 0.001 0.041 0.031 0.029 0.051
0.44 0.41 0.35 0.29 0.11
G0.001 0.001 0.009 0.299 0.418
G0.001 0.265 0.004 0.918 0.489
p values were calculated using the Pearson correlation test. r, Pearson coefficient of correlation.
1325
domain OCT and found that macular GCC loss was localized in the inferior hemifield in NTG but was diffusely distributed in POAG. Firat et al.35 showed that macular GCC was significantly thicker in patients with NTG than in patients with POAG. These studies suggest that there is a difference between NTG and POAG in structural damage of macular GCC. However, little is known about changes in the mGCIPL thickness in NTG. To the best of our knowledge, this is the first study to evaluate the mGCIPL thickness in NTG and POAG subgroups according to glaucoma severity. We investigated correlations between the mGCIPL parameters and VF indices. The inferotemporal, inferior, and inferonasal thickness of mGCIPL significantly correlated with MD in the NTG group, whereas the superior, superotemporal, superonasal, inferior, and inferotemporal thickness of mGCIPL showed significant correlations with MD in the POAG group. These findings imply that, as glaucoma severity increases, the mGCIPL thickness decreases in a localized area (especially in the inferior hemifield) in NTG but diffusely decreases in POAG (Fig. 2). To assess the diagnostic ability of each parameter, we calculated the AROCs of all parameters. A number of studies reported that the glaucoma diagnostic ability of macular GCC (the sum of the innermost retinal layer, RNFL, RGC layer, and IPL) or mGCIPL is comparable or superior to that of pRNFL.9,36Y45 In our study, the minimum mGCIPL thickness and average pRNFL thickness showed the highest AROCs. In line with previous studies,44,45
FIGURE 2. Representative mGCIPL images obtained using Cirrus HD-OCT in patients with glaucoma. The mGCIPL loss in POAG (A, C) was diffuse, whereas the mGCIPL loss in NTG (B, D) was localized and mainly concentrated in the inferior portion. Optometry and Vision Science, Vol. 91, No. 11, November 2014
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1326 Macular Inner Plexiform and Retinal Nerve Fiber Layer Thickness in GlaucomaVJung et al.
our study showed that the diagnostic ability of these two best parameters was comparable in both groups. Of the topographical parameters of the mGCIPL thickness, the parameter with the highest AROC in patients with NTG was the inferotemporal thickness. In particular, the AROC of the inferotemporal mGCIPL thickness showed statistically significant differences when compared with those of superior, superotemporal, and superonasal mGCIPL thicknesses in patients with NTG (p = 0.031, 0.048, and 0.004, respectively), whereas the parameter with the highest AROC in patients with POAG was the superior thickness. In contrast with NTG, the AROC of the superior mGCIPL thickness showed no significant differences with the inferotemporal, inferior, and inferonasal mGCIPL thickness in the POAG group. Shin et al.46 reported that the mGCIPL thickness can be a more valuable diagnostic parameter than the pRNFL thickness in patients with a central field defect. In the present study, because we included a considerable number of subjects who had a mixed pattern of paracentral and peripheral scotoma, the comparison between an isolated parafoveal scotoma group and an isolated peripheral scotoma group was unsuitable. Therefore, our subjects were classified into the paracentral scotoma group or nonparacentral scotoma group. No significant difference in proportion of patients was found between the NTG and POAG groups. On the basis of our results, we suppose that a possibility of bias from subject selection is little. Further studies considering the pattern of VF defect will be needed to more accurately assess the diagnostic ability of mGCIPL in NTG or POAG. Our study has several limitations. First, our study included only a Korean population, and it cannot be excluded that the results of similar studies with patients of different ethnicities may be different. Second, our sample size was relatively small. Third, our study evaluated the data from patients with different severities of glaucoma in a cross-sectional way. As glaucoma progresses, there may be a different pattern of changes in the mGCIPL thickness in patients with NTG and POAG. Therefore, a prospective longitudinal study will also be needed to confirm our results. Fourth, because the participants who underwent glaucoma filtering surgery were excluded, there might be a possibility of selection bias. For instance, patients with deep paracentral scotoma who underwent trabeculectomy could be excluded in POAG. However, because this type of patient was uncommon in our database, it is less likely to affect our results. Moreover, in light of previous studies that glaucoma filtering surgery can affect the measurement of retinal thickness by OCT,47,48 our exclusion criteria may be reasonable. In conclusion, the diagnostic ability of the mGCIPL thickness was comparable to that of the pRNFL thickness in patients with either NTG or POAG. The mGCIPL loss in NTG was localized and mainly concentrated on the inferior portion compared with diffuse mGCIPL loss in POAG. Paying more attention to the inferior portion of the mGCIPL would be helpful in managing patients with NTG.
ACKNOWLEDGMENTS None of the authors has any financial/conflicting interests to disclose. Received October 26, 2013; accepted July 2, 2014.
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Sang Woo Park Department of Ophthalmology Chonnam National University Medical School and Hospital, 8 Hak-Dong, Dong-Gu Gwangju 501-757 Korea e-mail: [email protected]
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