Microstructure of b-Zone Parapapillary Atrophy and Rate of Retinal Nerve Fiber Layer Thinning in Primary Open-Angle Glaucoma Yong Woo Kim, MD,1 Eun Ji Lee, MD,2 Tae-Woo Kim, MD,2 Mijin Kim, MD,2 Hyunjoong Kim, PhD3 Objective: To investigate whether the rate of retinal nerve fiber layer (RNFL) thinning differs according to the microstructure of b-zone parapapillary atrophy (PPA) as evaluated by spectral-domain (SD) optical coherence tomography (OCT) in primary open-angle glaucoma (POAG). Design: Prospective, observational, comparative study. Participants: A total of 195 eyes with POAG that had been evaluated by serial SD-OCT RNFL thickness measurements for 2 years. Methods: On the basis of the extent of Bruch’s membrane (BM) within the b-zone PPA (area without retinal pigment epithelium [RPE]), as shown in the infrared fundus images, PPA was divided into PPAþBM (PPA with intact BM) and PPAeBM (PPA devoid of BM). Eyes were categorized into group A (having PPAþBM only, n¼64), group B (having both PPAþBM and PPAeBM, n¼58), group C (having PPAeBM only, n¼32), and group D (without b-zone PPA, n¼41). The rate of progressive OCT RNFL thinning was determined by linear regression and compared between groups. Factors influencing the rate of RNFL thinning were evaluated, including age, sex, follow-up duration, history of filtering surgery, baseline RNFL thickness, baseline intraocular pressure (IOP), mean IOP and IOP fluctuation during follow-up, PPA types, baseline PPA width, PPA width increase, axial length (AXL), central corneal thickness, and visual field mean deviation (MD). Main Outcome Measures: Rate of thinning of OCT RNFL thicknesses over time. Results: Patients in groups B and C were significantly younger and more myopic, and had a greater AXL, than those in groups A and D (all P < 0.001). The rate of global RNFL thinning was significantly faster in group A (1.662.94 mm/year) than in the other groups (group B, 0.871.28 mm/year; group C, 0.201.86 mm/year; group D, 0.281.74 mm/year; P ¼ 0.001). Multivariate regression showed a significant association of shorter follow-up period (P ¼ 0.016), greater baseline global RNFL thickness (P ¼ 0.035), type of b-zone PPA (group A, P ¼ 0.023), and greater baseline PPAþBM width (P ¼ 0.034) with a faster rate of RNFL thinning. Conclusions: The rate of RNFL thinning differed according to the microstructure of b-zone PPA. It was faster for eyes with b-zone PPA with intact BM than for eyes without b-zone PPA or with b-zone PPA devoid of BM. Ophthalmology 2014;-:1e9 ª 2014 by the American Academy of Ophthalmology.
b-Zone parapapillary atrophy (PPA) has long been associated with glaucoma progression.1,2,3 Not only the presence of the b-zone PPA3,4 but also its size2,3 and enlargement5,6 have been recognized as significant risk factors for glaucoma progression. Recent studies have shown that b-zone PPA also is associated with the rate of glaucoma progression, as assessed by the trend-based analysis of visual field mean deviation (MD) or optical coherence tomography (OCT)emeasured retinal nerve fiber layer (RNFL) thickness. Teng et al3 demonstrated that glaucomatous eyes with b-zone PPA had faster rates of visual field progression and that the size of b-zone PPA was a significant risk factor for visual field progression. Consistent with this finding, it has been shown that the presence or enlargement of b-zone PPA is associated with a faster rate of RNFL thinning, as determined by OCT.7 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
The b-zone PPA is characterized histologically by the absence or marked atrophy of the retinal pigment epithelium (RPE), thus exposing the sclera and choroidal vessels.8,9 The development of enhanced depth imaging (EDI) spectral-domain OCT (SD-OCT) has rendered it possible to examine the microstructure of optic nerve and peripapillary connective tissues in more detail. With the use of EDI SDOCT images, it has recently been shown that within some b-zone PPA, there is an area that is devoid of Bruch’s membrane (BM), whereby the end of BM does not reach the optic disc border.10e12 Jonas et al13 characterized this area histologically and defined it as “zone g” because the area did not fulfill the definition of the a-zone or b-zone. They found that cases of PPA devoid of BM were associated with axial elongation and were independent of the presence of glaucoma. Dai et al14 subsequently visualized ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2014.01.008
1
Ophthalmology Volume -, Number -, Month 2014 areas of PPA that were devoid of BM clinically, corresponding to the histologic g-zone, using EDI SDOCT. In that study, PPA devoid of BM was associated with the absence of glaucoma. In line with previous observations, our group recently suggested that the PPA could be classified morphologically using EDI SD-OCT according to the extent of BM termination within the b-zone PPA area.15 In that study, we proposed that PPA with an intact BM is likely an agerelated atrophic change, whereas PPA without a BM may be attributable to the axial elongation of the eyes that occurs at an early age. Considering the diverse pathogenesis of PPA (agerelated atrophy vs. axial elongation), the authors of this study hypothesized that the influence of each type of PPA on the development and progression of glaucoma may differ. The purpose of the present study was to determine whether the rate of glaucoma progression as assessed by OCT-measured RNFL thinning differs according to the PPA microstructure.
Methods The participants in this study comprised patients from the Investigating Glaucoma Progression Study (IGPS), which is an ongoing prospective study on patients with glaucoma at the Seoul National University Bundang Hospital Glaucoma Clinic. They were consecutive patients who met the eligibility criteria and provided written informed consent to participate. This study was approved by the Seoul National University Bundang Hospital Institutional Review Board and followed the tenets of the Declaration of Helsinki.
Study Subjects Patients who were enrolled in the IGPS underwent a comprehensive ophthalmic examination, including visual acuity assessment, refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, and dilated stereoscopic examination of the optic disc, disc photographs (EOS D60 digital camera; Canon, Utsunomiya-shi, Tochigi-ken, Japan), SD-OCT (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany), standard automated perimetry (24-2 Swedish interactive threshold algorithm; Humphrey Field Analyzer II 750; Carl Zeiss Meditec, Dublin, CA), and measurements of corneal curvature (KR-1800; Topcon, Tokyo, Japan), central corneal thickness (Orbscan II; Bausch & Lomb Surgical, Rochester, NY), and axial length (AXL) (IOL Master ver. 5; Carl Zeiss Meditec). The IGPS excluded subjects with a history of intraocular surgery other than cataract extraction and glaucoma surgery, an intraocular disease (e.g., diabetic retinopathy or retinal vein occlusion) or a neurologic disease (e.g., pituitary tumor) that could cause visual field loss, and visual acuities worse than 20/40. All patients included in the IGPS were followed up every 3 to 6 months, with regular follow-up SD-OCT RNFL thickness measurements performed at intervals of 6 months to 1 year. Optic disc scanning using EDI SD-OCT was performed at 1- to 2-year intervals. To be included in the present study, patients were required to have primary open-angle glaucoma (POAG), have been followed up for at least 2 years, and have undergone at least 4 serial OCT measurements.7,16,17 Primary open-angle glaucoma was defined as the presence of glaucomatous optic nerve damage (e.g., the presence of focal thinning, notching, and an RNFL defect), an
2
associated glaucomatous visual field defect, and open angle, as revealed by gonioscopy. A glaucomatous visual field defect was defined as (1) values outside the normal limits on the glaucoma hemifield test or (2) 3 abnormal points, with a probability of being normal of P < 5%, 1 point with a pattern deviation of P < 1%, or (3) a pattern standard deviation of 5%. Those visual field defects were confirmed on 2 consecutive reliable tests (fixation loss rate 20%, false-positive and false-negative error rates 25%). Subjects with any abnormalities (including a large PPA) in the circumpapillary region that affected the scan ring where the OCT RNFL thickness measurements were obtained were excluded from this study. A history of cataract or glaucoma surgery before the baseline examination was not an exclusion criterion, but patients who received such procedures during the study period were excluded because (1) cataract extraction affects the signal quality of OCT scans and thus may influence the RNFL thickness data; (2) the large intraocular pressure (IOP) reduction after glaucoma surgery may influence the architecture of the optic nerve head and peripapillary tissue, which could bias the measurements of PPA width18; and (3) the transient increase in the RNFL thickness that can occur in the early postoperative period may affect the results of linear regression analyses.19 The baseline IOP was defined as the mean of the 2 measurements before IOP-lowering treatment. The mean follow-up IOP measurement was gained by averaging the IOP measured at 6month intervals, and IOP fluctuation was obtained using the standard deviation of these values.
Spectralis Optical Coherence Tomography Imaging of the Parapapillary Area The optic disc including the parapapillary area was scanned by the Spectralis OCT using the EDI technique, as reported by Spaide et al.20 The imaging scan covered a rectangular area of the optic disc (10 15 ) that included approximately 65 sections separated by 30 to 34 mm. In total, 42 OCT frames were averaged for each section. This is the standard optic disc scan protocol for imaging the lamina cribrosa. This study used 3 B-scans from the midcentral area (see “Measurement of Parapapillary Atrophy Width”). The value of corneal curvature was entered into the Spectralis OCT system before the scan to remove the magnification error. Eyes were categorized into 2 groups according to the presence or absence of temporal b-zone PPA, which was visible on infrared fundus imaging. The PPA margin shown in the infrared image essentially was the same as the one shown in the disc photograph.15 Eyes without b-zone PPA did not have visible b-zone PPA on infrared fundus image or disc photograph. Subjects with b-zone PPA had to have a temporal b-zone PPA visible on infrared fundus imaging, with a width of 100 mm on at least 1 horizontal OCT scan image within the central one third of the optic nerve, as measured using the built-in caliper tool of the Spectralis OCT system.15 The temporal PPA margin and the disc margin were determined in the infrared fundus imaging. The structure of b-zone PPA was evaluated using the Spectralis viewer (Heidelberg Eye Explorer software version 1.7.0.0; Heidelberg Engineering), which enables synchronous viewing of the selected location on the OCT scan image and the infrared fundus image.15 On the basis of the location of BM termination within the b-zone PPA area, eyes with b-zone PPA were further categorized into PPAþBM (PPA with intact BM, the area between the BM opening to the beginning of RPE) and PPAeBM (PPA devoid of BM, the area between the temporal disc margin to the beginning of BM). Eyes were categorized into 3 groups: (1) group A (having PPAþBM only), (2) group B (having both PPAþBM and PPAeBM),
Kim et al
Microstructure of b-Zone PPA and Rate of RNFL Thinning
and (3) group C (having PPAeBM only) (Fig 1). Eyes without bzone PPA were categorized as group D. The presence or absence of the b-zone PPA on infrared fundus imaging and the classification of each type of PPA were determined independently by 2 experienced ophthalmologists (Y.W.K. and E.J.L.) who were masked to patients’ clinical information, and the interobserver agreements were calculated. Disagreements were resolved by consensus between the 2 ophthalmologists or a third adjudicator (T-W.K.). Circumpapillary RNFL scans with RNFL thickness measurement were performed at intervals of 6 months to 1 year. The global average and 6-sectoral (superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal) peripapillary RNFL thicknesses were recorded for each follow-up measurement to evaluate the rate of RNFL thinning over time.
Measurement of Parapapillary Atrophy Width The distances from the temporal disc margin to the temporal b-zone PPA margin and to the boundary of BM termination were defined as PPA width and PPAeBM width, respectively. The distance from the temporal b-zone PPA margin to the boundary of BM termination was defined as PPAþBM width. Each parameter was measured by an observer who was masked to the condition (Y.W.K.), as described previously.15 Measurements were performed on initial and final B-scans, in a random sequence, obtained from 3 of the 5 horizontal meridians, equally placed within the vertical diameter of the optic disc, and the means of the measured values were analyzed. Excellent interobserver reproducibility for the measurement of PPA width and PPAeBM width have been reported by Kim et al15 (intraclass correlation coefficients ¼ 0.962 and 0.977, respectively).
Statistical Analysis Interobserver agreements in the determination of PPA presence and types were assessed using the kappa statistic. Scores 0.75, between 0.40 and 0.75, and 0.40 were considered excellent, fair to
good, and poor, respectively.21 Continuous variables were compared among the 4 groups using 1-way analysis of variance with Scheffé’s post hoc test. Categoric variables were compared using the chi-square test. Linear regression analysis against time was performed for the global average and each of the 6-sectoral RNFL thicknesses for each subject to determine the rate of change of RNFL thickness (micrometers/year). The PPA width parameters obtained at the initial and final examinations were compared using the paired-samples t test. General linear model was used to investigate the influence of several factors (age, sex, follow-up period, history of filtering surgery, baseline global RNFL thickness, baseline IOP, mean follow-up IOP, IOP fluctuation, type of PPA, baseline width of the b-zone PPA, PPAeBM and PPAþBM, increase in the widths of b-zone PPA, PPAeBM and PPAþBM, AXL, central corneal thickness, and baseline visual field MD) on the rate of global RNFL thinning, first with a univariate model and then with a multivariate model that included variables from the univariate model with P < 0.10. Analyses were performed using the Statistical Package for the Social Sciences version 20.0 (SPSS Inc., Chicago, IL). Except where stated otherwise, the data are presented as mean standard deviation, and the level of statistical significance was set at P < 0.05.
Results Baseline Characteristics The study included 195 eyes of 195 patients with POAG who met the eligibility criteria, of whom 154 eyes had temporal b-zone PPA and were further classified into groups A (having PPAþBM only; n¼64), B (having both PPAþBM and PPAeBM; n¼58), and C (having PPAeBM only; n¼32). The remaining 41 eyes did not have b-zone PPA and were categorized as group D (lacking b-zone PPA). The interobserver agreement of determining the presence or absence of b-zone PPA on infrared fundus imaging was excellent
Figure 1. Classification of parapapillary atrophy (PPA) based on the location of Bruch’s membrane (BM) termination within the b-zone PPA area. The temporal margin of the b-zone PPA and the optic disc are indicated as red and white arrowheads, respectively. The red and blue dotted lines indicate retinal pigment epithelium (RPE) and BM, respectively. The b-zone PPA was defined as the area without RPE (areas between the red and white arrowheads). On the basis of the presence of BM within the b-zone PPA, PPAþBM (PPA with intact BM, the area between the BM opening to the beginning of RPE) and PPAeBM (PPA devoid of BM, the area between the temporal disc margin to the beginning of BM) were further defined. A, Example of group A (PPAþBM only). The BM is present on the entire b-zone PPA bed between the disc margin (white arrowhead) and PPA margin (red arrowhead). B, Example of group B (both PPAþBM and PPAeBM). The BM terminates in the middle of the b-zone PPA (green arrowhead). C, Example of group C (PPAeBM only). The BM does not present on the entire PPA bed throughout the disc margin (white arrowhead) to PPA margin (red arrowhead).
3
Ophthalmology Volume -, Number -, Month 2014 Table 1. Comparison of Variables among Parapapillary Atrophy Groups Variable Age, yrs Female, n (%) SE, diopters AXL, mm Mean follow-up duration, yrs Average OCT scans per eye, n History of filtering surgery, n Baseline IOP, mmHg Mean follow-up IOP, mmHg IOP fluctuation, mmHg CCT, mm Baseline visual field MD, dB Baseline global RNFL thickness, mm
Group A: PPADBM Group B: Both PPADBM and Group C: PPAeBM Group D: without b-zone Only (64 Eyes) Only (32 Eyes) PPAeBM (58 Eyes) PPA (41 Eyes)
P Value
Post Hoc Test
41.812.7 26 (44.8) 4.53.5 26.11.3 2.50.6
44.812.4 12 (37.5) 6.83.8 27.01.6 2.40.4
58.011.7 24 (58.5) 0.31.9 23.80.9 2.40.6
b-Zone parapapillary atrophy (PPA) has long been associated with glaucoma progression.1,2,3 Not only the presence of the b-zone PPA3,4 but also its size2,3 and enlargement5,6 have been recognized as significant risk factors for glaucoma progression. Recent studies have shown that b-zone PPA also is associated with the rate of glaucoma progression, as assessed by the trend-based analysis of visual field mean deviation (MD) or optical coherence tomography (OCT)emeasured retinal nerve fiber layer (RNFL) thickness. Teng et al3 demonstrated that glaucomatous eyes with b-zone PPA had faster rates of visual field progression and that the size of b-zone PPA was a significant risk factor for visual field progression. Consistent with this finding, it has been shown that the presence or enlargement of b-zone PPA is associated with a faster rate of RNFL thinning, as determined by OCT.7 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
The b-zone PPA is characterized histologically by the absence or marked atrophy of the retinal pigment epithelium (RPE), thus exposing the sclera and choroidal vessels.8,9 The development of enhanced depth imaging (EDI) spectral-domain OCT (SD-OCT) has rendered it possible to examine the microstructure of optic nerve and peripapillary connective tissues in more detail. With the use of EDI SDOCT images, it has recently been shown that within some b-zone PPA, there is an area that is devoid of Bruch’s membrane (BM), whereby the end of BM does not reach the optic disc border.10e12 Jonas et al13 characterized this area histologically and defined it as “zone g” because the area did not fulfill the definition of the a-zone or b-zone. They found that cases of PPA devoid of BM were associated with axial elongation and were independent of the presence of glaucoma. Dai et al14 subsequently visualized ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2014.01.008
1
Ophthalmology Volume -, Number -, Month 2014 areas of PPA that were devoid of BM clinically, corresponding to the histologic g-zone, using EDI SDOCT. In that study, PPA devoid of BM was associated with the absence of glaucoma. In line with previous observations, our group recently suggested that the PPA could be classified morphologically using EDI SD-OCT according to the extent of BM termination within the b-zone PPA area.15 In that study, we proposed that PPA with an intact BM is likely an agerelated atrophic change, whereas PPA without a BM may be attributable to the axial elongation of the eyes that occurs at an early age. Considering the diverse pathogenesis of PPA (agerelated atrophy vs. axial elongation), the authors of this study hypothesized that the influence of each type of PPA on the development and progression of glaucoma may differ. The purpose of the present study was to determine whether the rate of glaucoma progression as assessed by OCT-measured RNFL thinning differs according to the PPA microstructure.
Methods The participants in this study comprised patients from the Investigating Glaucoma Progression Study (IGPS), which is an ongoing prospective study on patients with glaucoma at the Seoul National University Bundang Hospital Glaucoma Clinic. They were consecutive patients who met the eligibility criteria and provided written informed consent to participate. This study was approved by the Seoul National University Bundang Hospital Institutional Review Board and followed the tenets of the Declaration of Helsinki.
Study Subjects Patients who were enrolled in the IGPS underwent a comprehensive ophthalmic examination, including visual acuity assessment, refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, and dilated stereoscopic examination of the optic disc, disc photographs (EOS D60 digital camera; Canon, Utsunomiya-shi, Tochigi-ken, Japan), SD-OCT (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany), standard automated perimetry (24-2 Swedish interactive threshold algorithm; Humphrey Field Analyzer II 750; Carl Zeiss Meditec, Dublin, CA), and measurements of corneal curvature (KR-1800; Topcon, Tokyo, Japan), central corneal thickness (Orbscan II; Bausch & Lomb Surgical, Rochester, NY), and axial length (AXL) (IOL Master ver. 5; Carl Zeiss Meditec). The IGPS excluded subjects with a history of intraocular surgery other than cataract extraction and glaucoma surgery, an intraocular disease (e.g., diabetic retinopathy or retinal vein occlusion) or a neurologic disease (e.g., pituitary tumor) that could cause visual field loss, and visual acuities worse than 20/40. All patients included in the IGPS were followed up every 3 to 6 months, with regular follow-up SD-OCT RNFL thickness measurements performed at intervals of 6 months to 1 year. Optic disc scanning using EDI SD-OCT was performed at 1- to 2-year intervals. To be included in the present study, patients were required to have primary open-angle glaucoma (POAG), have been followed up for at least 2 years, and have undergone at least 4 serial OCT measurements.7,16,17 Primary open-angle glaucoma was defined as the presence of glaucomatous optic nerve damage (e.g., the presence of focal thinning, notching, and an RNFL defect), an
2
associated glaucomatous visual field defect, and open angle, as revealed by gonioscopy. A glaucomatous visual field defect was defined as (1) values outside the normal limits on the glaucoma hemifield test or (2) 3 abnormal points, with a probability of being normal of P < 5%, 1 point with a pattern deviation of P < 1%, or (3) a pattern standard deviation of 5%. Those visual field defects were confirmed on 2 consecutive reliable tests (fixation loss rate 20%, false-positive and false-negative error rates 25%). Subjects with any abnormalities (including a large PPA) in the circumpapillary region that affected the scan ring where the OCT RNFL thickness measurements were obtained were excluded from this study. A history of cataract or glaucoma surgery before the baseline examination was not an exclusion criterion, but patients who received such procedures during the study period were excluded because (1) cataract extraction affects the signal quality of OCT scans and thus may influence the RNFL thickness data; (2) the large intraocular pressure (IOP) reduction after glaucoma surgery may influence the architecture of the optic nerve head and peripapillary tissue, which could bias the measurements of PPA width18; and (3) the transient increase in the RNFL thickness that can occur in the early postoperative period may affect the results of linear regression analyses.19 The baseline IOP was defined as the mean of the 2 measurements before IOP-lowering treatment. The mean follow-up IOP measurement was gained by averaging the IOP measured at 6month intervals, and IOP fluctuation was obtained using the standard deviation of these values.
Spectralis Optical Coherence Tomography Imaging of the Parapapillary Area The optic disc including the parapapillary area was scanned by the Spectralis OCT using the EDI technique, as reported by Spaide et al.20 The imaging scan covered a rectangular area of the optic disc (10 15 ) that included approximately 65 sections separated by 30 to 34 mm. In total, 42 OCT frames were averaged for each section. This is the standard optic disc scan protocol for imaging the lamina cribrosa. This study used 3 B-scans from the midcentral area (see “Measurement of Parapapillary Atrophy Width”). The value of corneal curvature was entered into the Spectralis OCT system before the scan to remove the magnification error. Eyes were categorized into 2 groups according to the presence or absence of temporal b-zone PPA, which was visible on infrared fundus imaging. The PPA margin shown in the infrared image essentially was the same as the one shown in the disc photograph.15 Eyes without b-zone PPA did not have visible b-zone PPA on infrared fundus image or disc photograph. Subjects with b-zone PPA had to have a temporal b-zone PPA visible on infrared fundus imaging, with a width of 100 mm on at least 1 horizontal OCT scan image within the central one third of the optic nerve, as measured using the built-in caliper tool of the Spectralis OCT system.15 The temporal PPA margin and the disc margin were determined in the infrared fundus imaging. The structure of b-zone PPA was evaluated using the Spectralis viewer (Heidelberg Eye Explorer software version 1.7.0.0; Heidelberg Engineering), which enables synchronous viewing of the selected location on the OCT scan image and the infrared fundus image.15 On the basis of the location of BM termination within the b-zone PPA area, eyes with b-zone PPA were further categorized into PPAþBM (PPA with intact BM, the area between the BM opening to the beginning of RPE) and PPAeBM (PPA devoid of BM, the area between the temporal disc margin to the beginning of BM). Eyes were categorized into 3 groups: (1) group A (having PPAþBM only), (2) group B (having both PPAþBM and PPAeBM),
Kim et al
Microstructure of b-Zone PPA and Rate of RNFL Thinning
and (3) group C (having PPAeBM only) (Fig 1). Eyes without bzone PPA were categorized as group D. The presence or absence of the b-zone PPA on infrared fundus imaging and the classification of each type of PPA were determined independently by 2 experienced ophthalmologists (Y.W.K. and E.J.L.) who were masked to patients’ clinical information, and the interobserver agreements were calculated. Disagreements were resolved by consensus between the 2 ophthalmologists or a third adjudicator (T-W.K.). Circumpapillary RNFL scans with RNFL thickness measurement were performed at intervals of 6 months to 1 year. The global average and 6-sectoral (superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal) peripapillary RNFL thicknesses were recorded for each follow-up measurement to evaluate the rate of RNFL thinning over time.
Measurement of Parapapillary Atrophy Width The distances from the temporal disc margin to the temporal b-zone PPA margin and to the boundary of BM termination were defined as PPA width and PPAeBM width, respectively. The distance from the temporal b-zone PPA margin to the boundary of BM termination was defined as PPAþBM width. Each parameter was measured by an observer who was masked to the condition (Y.W.K.), as described previously.15 Measurements were performed on initial and final B-scans, in a random sequence, obtained from 3 of the 5 horizontal meridians, equally placed within the vertical diameter of the optic disc, and the means of the measured values were analyzed. Excellent interobserver reproducibility for the measurement of PPA width and PPAeBM width have been reported by Kim et al15 (intraclass correlation coefficients ¼ 0.962 and 0.977, respectively).
Statistical Analysis Interobserver agreements in the determination of PPA presence and types were assessed using the kappa statistic. Scores 0.75, between 0.40 and 0.75, and 0.40 were considered excellent, fair to
good, and poor, respectively.21 Continuous variables were compared among the 4 groups using 1-way analysis of variance with Scheffé’s post hoc test. Categoric variables were compared using the chi-square test. Linear regression analysis against time was performed for the global average and each of the 6-sectoral RNFL thicknesses for each subject to determine the rate of change of RNFL thickness (micrometers/year). The PPA width parameters obtained at the initial and final examinations were compared using the paired-samples t test. General linear model was used to investigate the influence of several factors (age, sex, follow-up period, history of filtering surgery, baseline global RNFL thickness, baseline IOP, mean follow-up IOP, IOP fluctuation, type of PPA, baseline width of the b-zone PPA, PPAeBM and PPAþBM, increase in the widths of b-zone PPA, PPAeBM and PPAþBM, AXL, central corneal thickness, and baseline visual field MD) on the rate of global RNFL thinning, first with a univariate model and then with a multivariate model that included variables from the univariate model with P < 0.10. Analyses were performed using the Statistical Package for the Social Sciences version 20.0 (SPSS Inc., Chicago, IL). Except where stated otherwise, the data are presented as mean standard deviation, and the level of statistical significance was set at P < 0.05.
Results Baseline Characteristics The study included 195 eyes of 195 patients with POAG who met the eligibility criteria, of whom 154 eyes had temporal b-zone PPA and were further classified into groups A (having PPAþBM only; n¼64), B (having both PPAþBM and PPAeBM; n¼58), and C (having PPAeBM only; n¼32). The remaining 41 eyes did not have b-zone PPA and were categorized as group D (lacking b-zone PPA). The interobserver agreement of determining the presence or absence of b-zone PPA on infrared fundus imaging was excellent
Figure 1. Classification of parapapillary atrophy (PPA) based on the location of Bruch’s membrane (BM) termination within the b-zone PPA area. The temporal margin of the b-zone PPA and the optic disc are indicated as red and white arrowheads, respectively. The red and blue dotted lines indicate retinal pigment epithelium (RPE) and BM, respectively. The b-zone PPA was defined as the area without RPE (areas between the red and white arrowheads). On the basis of the presence of BM within the b-zone PPA, PPAþBM (PPA with intact BM, the area between the BM opening to the beginning of RPE) and PPAeBM (PPA devoid of BM, the area between the temporal disc margin to the beginning of BM) were further defined. A, Example of group A (PPAþBM only). The BM is present on the entire b-zone PPA bed between the disc margin (white arrowhead) and PPA margin (red arrowhead). B, Example of group B (both PPAþBM and PPAeBM). The BM terminates in the middle of the b-zone PPA (green arrowhead). C, Example of group C (PPAeBM only). The BM does not present on the entire PPA bed throughout the disc margin (white arrowhead) to PPA margin (red arrowhead).
3
Ophthalmology Volume -, Number -, Month 2014 Table 1. Comparison of Variables among Parapapillary Atrophy Groups Variable Age, yrs Female, n (%) SE, diopters AXL, mm Mean follow-up duration, yrs Average OCT scans per eye, n History of filtering surgery, n Baseline IOP, mmHg Mean follow-up IOP, mmHg IOP fluctuation, mmHg CCT, mm Baseline visual field MD, dB Baseline global RNFL thickness, mm
Group A: PPADBM Group B: Both PPADBM and Group C: PPAeBM Group D: without b-zone Only (64 Eyes) Only (32 Eyes) PPAeBM (58 Eyes) PPA (41 Eyes)
P Value
Post Hoc Test
41.812.7 26 (44.8) 4.53.5 26.11.3 2.50.6
44.812.4 12 (37.5) 6.83.8 27.01.6 2.40.4
58.011.7 24 (58.5) 0.31.9 23.80.9 2.40.6
