-Zone Parapapillary Atrophy and the Rate of Retinal Nerve Fiber Layer Thinning in Glaucoma

Transcription

1 Glaucoma -Zone Parapapillary Atrophy and the Rate of Retinal Nerve Fiber Layer Thinning in Glaucoma Eun Ji Lee, 1,2 Tae-Woo Kim, 1,3 Robert N. Weinreb, 4 Ki Ho Park, 1 Seok Hwan Kim, 1,5 and Dong Myung Kim 1 PURPOSE. To evaluate whether -zone parapapillary atrophy (PPA) is associated with the rate of retinal nerve fiber layer (RNFL) thickness change as assessed by trend-based analysis using time-domain optical coherence tomography (OCT). METHODS. This retrospective cohort study included 202 glaucomatous eyes that were observed for 3 years with serial OCTs and stereo disc photographs. Subjects were divided into two groups according to the presence (n 144) or absence of -zone PPA (n 58). The rates of progressive thinning in global, quadrant, and clock-hour OCT RNFL thicknesses were determined using linear regression and compared between groups. Logistic regression analysis was used to determine the factors associated with the rate of global RNFL thinning. RESULTS. The mean rate for global RNFL thinning over time was m/year. Eyes with -zone PPA showed a significantly faster rate of RNFL thinning than did eyes without -zone PPA in the inferior quadrant and 7 o clock sector (values of P ). Multivariate analysis showed significant influence of the presence of -zone PPA and the percentage increase in the PPA to disc area ratio during the follow-up on the rate of OCT RNFL thinning (odds ratio [OR], 3.314, P 0.007; OR, 2.894, P 0.003, respectively). CONCLUSIONS. Glaucomatous eyes with -zone PPA are at increased risk for progressive RNFL thinning. (Invest Ophthalmol Vis Sci. 2011;52: ) DOI: /iovs A possible relationship between -zone parapapillary atrophy (PPA) and glaucoma progression has been investigated for almost two decades. 1 8 The presence, 4,5,9 11 size, 2 4,9,10 and enlargement of -zone PPA have been demonstrated to be associated with glaucoma progression. Among the features of PPA, breakdown of the blood optic nerve barrier and/or reduced blood supply are considered to contribute to this association. 1,6,7 From the 1 Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea; the 2 Department of Ophthalmology, National Medical Center, Seoul, Korea; the 3 Seoul National University Bundang Hospital, Seongnam, Korea; the 4 Hamilton Glaucoma Center and Department of Ophthalmology, University of California San Diego, La Jolla, California; and the 5 Seoul National University Boramae Hospital, Seoul, Korea. Supported, in part, by a grant from the Seoul National University Bundang Hospital Research Fund. Submitted for publication November 1, 2010; revised February 7, 2011; accepted March 10, Disclosure: E.J. Lee, None; T.-W. Kim, None; R.N. Weinreb, Carl Zeiss Meditec (C, R); K.H. Park, None; S.H. Kim, None; D.M. Kim, None Corresponding author: Tae-Woo Kim, Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 166 Gumi-dong, Bundang-gu, Seongnam, Gyeonggi-do , Korea; twkim7@snu.ac.kr. Until now, the relationship between -zone PPA and glaucoma progression was evaluated, for the most part, by comparing the presence or area of PPA with standard automated perimetry. 2,4,5 Because functional progression and structural progression often are not observed to change similarly, a comparison of PPA with structural glaucoma progression is also of interest. Optical coherence tomography (OCT) has been shown to be capable of documenting and measuring progressive glaucomatous retinal nerve fiber layer (RNFL) atrophy. 15 Budenz et al. 16 reported intersession test retest variability of approximately 7 m for the global RNFL thickness, measured by time-domain OCT (Stratus OCT; Carl Zeiss Meditec AG, Jena, Germany), and suggested that an 8- m decrease in the respective value might be considered as the criterion to define the significant RNFL loss. Our group also reported similar test retest variability and demonstrated that the stratus OCT software detects progressive RNFL atrophy with high sensitivity and moderate specificity, using event-based analysis in cases showing localized progressive RNFL loss in red-free photographs. 17 Studies demonstrated that trend-based analysis could also be performed using the OCT measured RNFL thickness to evaluate glaucoma progression. Such analysis allowed measurement of rate of change in RNFL thickness in glaucoma patients 18 and was able to discriminate eyes progressing by visual fields or optic disc photographs from eyes that remained stable. 19 It has also been shown that analyzing the RNFL may be advantageous for evaluating glaucoma progression compared with optic disc examination. 20 More recently, we reported the performance of OCT-based trend analysis to detect progressive RNFL thinning identified with red-free photography. 21 The rate of RNFL thinning was significantly faster in progressors than that in nonprogressors, with the best parameter showing sensitivity of 62% at a specificity 80% to detect progressive RNFL thinning, only a moderate performance. The purpose of the present study was to evaluate whether the presence, size, and the increase of -zone PPA are associated with the rate of RNFL thickness change as assessed by trend-based analysis of OCT RNFL thickness. METHODS This study was a retrospective cohort study. The patient database of Seoul National University Bundang Hospital was screened for patients with primary open angle glaucoma who were observed for 3 years with serial OCTs and stereo disc photographs, and the patients who were eligible for the study were consecutively enrolled. This study was approved by the Seoul National University Bundang Hospital institutional review board and conformed to the Declaration of Helsinki. Before the study, all patients underwent complete ophthalmic examinations, including visual acuity assessment, refraction test, slitlamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, and dilated stereoscopic examination of the optic disc. They also Investigative Ophthalmology & Visual Science, June 2011, Vol. 52, No Copyright 2011 The Association for Research in Vision and Ophthalmology, Inc.

2 IOVS, June 2011, Vol. 52, No. 7 -Zone PPA and OCT RNFL Thinning 4423 underwent central corneal thickness measurement (Orbscan II; Bausch & Lomb Surgical, Rochester, NY), stereo disc photography, OCT, and standard automated perimetry (Humphrey Field Analyzer II 750; 24 2 Swedish interactive threshold algorithm; Carl Zeiss Meditec Inc., Dublin, CA). The baseline intraocular pressure (IOP) was defined as the average of the two measurements before IOP lowering treatment was administered. Mean follow-up IOP measurement was obtained by averaging the IOP measured at 6-month intervals, and IOP fluctuation was determined using the SD of these values. 4 When patients underwent incisional glaucoma surgery or laser trabeculoplasty, the IOPs measured within 3 months posttreatment were not included in the calculation. To be included, patients were required to have primary open angle glaucoma and have at least four serial OCT measurements (first and the last measurements separated by at least 3 years). Patients were excluded if they had a best-corrected visual acuity worse than 20/40, 6 diopters (D) of myopia, a history of any retinal disease, neurologic diseases, ocular surgery, or laser procedures other than cataract and glaucoma surgery, or the presence of any abnormalities including large PPA that affected the 3.4-mm scan ring where OCT measurements were obtained. The history of cataract extraction before the baseline examination was not an exclusion criterion but patients who received the cataract extraction during the study period were excluded because cataract extraction affects the signal quality of OCT scans and thus may influence the linear regression. If both eyes of the same patient were eligible, one eye of each patient was randomly selected. Primary open angle glaucoma was defined as the presence of glaucomatous optic nerve damage (i.e., vertical cup-to-disc ratio of 0.7, or asymmetry 0.2, or the presence of focal thinning, notching, or a splinter hemorrhage) and an associated visual field defect without ocular disease or conditions that could elevate the IOP. A glaucomatous visual field change was defined as (1) outside a normal limit on the glaucoma hemifield test; or (2) three abnormal points with P 0.05 probability of being normal, one with P 0.01 by pattern deviation; or (3) pattern SD of 0.05 if the visual field was otherwise normal. The criteria were required to be confirmed on two consecutive tests. -Zone Parapapillary Atrophy Area Measurement PPA was defined based on stereo disc photographs that were acquired using a digital camera (EOS D60; Canon, Tochigiken, Japan) after maximal pupil dilation. Optic disc photographs were obtained, digitized, and transferred to a computer workstation and reviewed on a liquid crystal display monitor. The optic disc images were independently evaluated by two authors (EJL and TWK) who were masked in terms of patient clinical information. First, each observer classified photographs into one of the two groups: eyes with -zone PPA and eyes without -zone PPA. Any discrepancy between the observers was resolved by consensus. Then, for the eyes with -zone PPA, their baseline disc photographs were evaluated by one of the authors (EJL) who was masked to patient identity and clinical information. The outlines of the optic disc (inner border of Elschnig s scleral ring) and -zone PPA (an inner crescent of chorioretinal atrophy with visible sclera and choroidal vessels) 22 were plotted using a mouse-driven cursor to trace the disc and PPA margins directly onto the image using ImageJ software (version 1.43u, developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at Then the pixel areas of total optic disc and -zone PPA were measured. The -zone PPA area to disc area ratio (PDR) was obtained as the ratio of the -zone PPA pixel area divided by the total optic disc pixel area. Changes in PDR were calculated by subtracting the follow-up value from the baseline value and dividing by the baseline. Optical Coherence Tomography Subjects were assessed using the peripapillary fast RNFL program (Stratus OCT; Carl Zeiss Meditec Inc.) after pupillary dilation to a minimum diameter of 5 mm. The same stratus OCT instrument was used for all testing sessions. The imaging lens was positioned 1 cm from the eye to be examined and adjusted independently until the retina was in focus. The internal fixation target was used because of its higher reproducibility. 23 Satisfactory quality was defined as: good centration on the optic disc and a signal strength 6 (10 maximum) Data were analyzed using version 5.0 software. Using the fast RNFL program, RNFL thickness was determined at 256 points at a set diameter (3.4 mm) around the center of the optic disc three times during a single scan. These values were averaged to yield 12 clock-hour thicknesses, 4 quadrant thicknesses, and a global average RNFL thickness measurement (360 measure). Statistical Analysis Interobserver agreement in discriminating the presence or absence of -zone PPA was evaluated using kappa statistics. According to Joseph L. Fleiss, 27 scores 0.75, between 0.40 and 0.75, and 0.4 are termed as excellent, fair to good, and poor, respectively. Interobserver variability in measuring the PDR was assessed by estimating the intraclass correlation coefficient (ICC) and its 95% confidence interval (CI). To evaluate this, 50 randomly selected disc photographs of the subjects with -zone PPA were assessed by two independent observers (EJL and TWK) and the ICC was calculated. Values close to 1 indicate high agreement between the observers. Linear regression analysis against time was performed for the global average and the individual quadrant and clock-hour sector thicknesses in each subject. The slope of the regression equation represented the rate of change of RNFL thickness. The slopes for each measurement between the eyes having and not having -zone PPA were compared using the independent-samples t-test and were adjusted to any differences between groups using a general linear model (GLM). A fast progression rate was defined as having the rate of global RNFL thinning within the lowest quartile of the overall subjects. Logistic regression analysis was used to evaluate the influence of several factors (age, central corneal thickness, refractive error, baseline mean deviation [MD], baseline IOP, mean IOP measured at each follow up, IOP fluctuation, the presence of -zone PPA, baseline PDR, and percentage increase in PDR during the follow-up) on a faster rate of global RNFL thinning first with the univariate model. Then, the variables that retained significance at P 0.10 were included in a multivariate model as well as parameters that have been demonstrated to be correlated with the presence of PPA, such as the baseline MD and refractive error. 4,22,28,29 The role of each variable was expressed in odds ratio (OR) and its 95% CIs. Statistical analyses were performed using statistical analysis software (SPSS 17.0; SPSS Inc., Chicago, IL), and raw data were subjected to Bonferroni correction based on the number of comparisons within each analysis. RESULTS The study initially involved 265 patients who had been examined on at least four occasions by OCT. Of these, 63 patients were excluded because of visual acuity worse than 20/40 (n 12); 6 D of myopia (n 11); a history of retinal, neurologic diseases, or abnormalities affecting the OCT scan path (n 9); previous ocular or laser procedures other than glaucoma surgery or laser trabeculoplasty (n 6); and cataract extraction during the study period (n 25). Serial optic disc photographs of the remaining 202 eyes of 202 patients were reviewed. In all, 177 eyes had normal-tension glaucoma (untreated IOP 22 mm Hg) and 25 eyes had high-tension glaucoma (untreated IOP 22 mm Hg). Of these, -zone PPA was observed in 144 eyes (71.3%). There was excellent interobserver agreement in assessing the presence of -zone PPA (kappa 0.920). The mean ICC of observer-defined PDR was (95% CI, from to 0.998).

3 4424 Lee et al. IOVS, June 2011, Vol. 52, No. 7 TABLE 1. Patient Clinical Demographics Variable With -Zone PPA (n 144) Without -Zone PPA (n 58) P Value Age, y * Sex, female/male 68/76 35/ Central corneal thickness, m * Diagnosis, NTG/HTG 128/16 49/ Spherical equivalent, D * Mean follow-up duration, y * Number of subjects that underwent trabeculectomy, n Number of subjects that underwent laser trabeculoplasty, n Baseline IOP, mm Hg * Mean follow-up IOP, mm Hg * IOP fluctuation, mm Hg * Baseline MD, db * Baseline average RNFL thickness, m * Average number of OCT scans per eye, n * Average number of disc photography per eye, n * Baseline -zone PPA area/disc area ratio N/A N/A * Comparisons were performed using the independent-samples t-test. Significant value (P 0.05) is shown in bold. Comparisons were performed using the 2 test. NTG, normal-tension glaucoma; HTG, high-tension glaucoma. There was no difference between the eyes with and without -zone PPA in the baseline characteristics except baseline average RNFL thickness. The baseline characteristics of the patients with and without -zone PPA are shown in Table 1. In patients with -zone PPA, the mean initial and final PDR values were (range, 0.08 to 1.98) and (range, 0.08 to 2.15), respectively. The mean change in PDR during the follow-up period was 9.97% 9.44% (range, 11.66% to 35.70%). Table 2 and Figure 1 show the comparison of the rate of RNFL thinning between the eyes with and without -zone PPA. After adjusting for the baseline global RNFL thickness using a GLM, the rate of progressive RNFL thinning was significantly faster in eyes with -zone PPA than TABLE 2. Comparison of Mean ( SD) Values of the Rate of RNFL Thickness Change between the Patients with and without -Zone PPA Location Rate of RNFL Thickness Change, m/y With -Zone PPA (n 144) Without -Zone PPA (n 58) P Value* Global average Temporal quadrant Superior quadrant Nasal quadrant Inferior quadrant < o clock o clock o clock o clock o clock o clock o clock o clock o clock o clock o clock o clock * Comparisons were performed using the independent-samples t-test. Significant values after Bonferroni correction (P ; 0.05/ 17) are shown in bold. that in eyes without it in the inferior quadrant and 7 o clock sector (values of P ; corrected for multiple comparisons, 0.05/17). The mean rate for global RNFL thinning over time was m/year. A faster rate of global RNFL thinning (the rate within the lowest quartile [26/202]) of overall subjects) was defined as the rate of global RNFL thinning of 2.04 m/year. In a comparison of the global rate of RNFL thinning, there were more patients who showed faster rates of RNFL thinning in eyes with -zone PPA (46 of 144) than in eyes without -zone PPA (7 of 58; P 0.001). Risk factors for a faster rate of OCT RNFL thinning were older age (OR, 1.034; P 0.030), the presence of -zone PPA (OR, 3.420; P 0.005) and percentage increase in PDR (OR, 3.059; P 0.001) in the univariate analysis (Table 3). The multivariate analysis, which was performed including the variables with a value of P 0.10 by univariate analysis (i.e., presence of -zone PPA, percentage increase in PDR, and age), as well as those that have been demonstrated to be correlated with the presence of PPA (i.e., the baseline MD and refractive error), demonstrated that the presence of -zone PPA and the FIGURE 1. Comparison of Stratus OCT rate of RNFL thickness change ( m/year) for each OCT clock-hour sector. The eyes with -zone PPA showed a significantly faster rate of OCT-measured RNFL deterioration at the 7 o clock sector (shown with asterisk). Each error bar represents mean 1 SD.

4 IOVS, June 2011, Vol. 52, No. 7 -Zone PPA and OCT RNFL Thinning 4425 TABLE 3. Factors Associated with the Rate of Global RNFL Thinning in Glaucomatous Eyes Univariate Analysis Multivariate Analysis* Variable OR 95% CI P Value OR 95% CI P Value Age (for each year older) Sex, male Central corneal thickness ( 525 m) Spherical equivalent, D Mean follow-up duration, y Baseline IOP, mm Hg Mean follow-up IOP, mm Hg IOP fluctuation, mm Hg Baseline MD, db Baseline average RNFL thickness, m Average number of OCT scans per eye, n Mean interval between OCT scans, mo Presence of PPA Baseline PDR (per 0.1 increase) Change in PDR (per 1% increase) * Variables with a value of P 0.10 in the univariate analysis as well as parameters that have been demonstrated to be correlated with the presence of PPA, such as the baseline MD and refractive error, were included in the multivariate model. Logistic regression analysis using a global rate of RNFL thinning of lowest quartile ( 2.04 m/y) as an end point. OR, odds ratio; CI, confidence interval. percentage increase in PDR were significantly associated with faster global RNFL thinning (OR, 3.314; P 0.007; OR, 2.894; P 0.003, respectively) (Table 3). The MD was marginally different between the eyes with or without -zone PPA ( db vs db) at the end of the follow-up (P 0.080). DISCUSSION Our study demonstrates that -zone PPA is associated with a faster rate of RNFL thinning as evaluated by OCT. These data add new information regarding the role of PPA in glaucoma progression and provide additional support for an association between PPA and glaucoma progression. In the present study, the presence and the enlargement of PPA, as assessed by an increase in PDR, was associated with a faster rate of RNFL thinning. These data are consistent with previous findings. 4,5,9,10,13,14 Association between the presence of PPA and glaucoma progression have been demonstrated in ocular hypertension 10 and open angle glaucoma. 4,5,9 In addition, Uchida et al. 13 and Budde and Jonas 14 demonstrated the association of PPA enlargement and glaucoma progression. However, the present study found no association between the initial PDR and the rate of OCT RNFL thinning. This finding differs from that of previous studies where glaucoma progression was associated with initial PPA size or PDR. 2 4,9,30 Although the discrepancy may be attributable to factors including the different study populations with respect to ethnicity, type of glaucoma, differing definitions of PPA and the methods of measuring its area, and length of follow-up, it is notable that our study excluded patients with large PPA, which could affect the scan path of OCT. This exclusion should have eliminated the effect derived from very large PPA, thereby leading to a false-negative association. Indeed, both initial and final PDR values in our study ( and , respectively) are smaller than those reported by Uchida et al. 13 ( and , respectively). It is notable that this result suggests that the presence of -zone PPA might be a more important marker for glaucoma progression than the size of -zone PPA. This is consistent with findings reported in the study by Teng et al., 4 where the presence of -zone PPA was a stronger predictor of future visual field progression than the size of -zone PPA (hazard ratio, 2.27 vs. 1.03, respectively). Once -zone PPA has developed, it is possible that the ensuing, continued insult to optic disc results in a greater susceptibility to progression and thus the presence of -zone PPA is relatively more important than its size. The rate of thinning at 7 o clock and inferior quadrant were the only parameters that showed statistical significance. This result is in agreement with that of previous studies that 7 o clock was the most frequent location that showed progression in RNFL thickness by stratus OCT, and that inferior average thickness measured by stratus OCT had the best performance to discriminate progressors from nonprogressors. 18,19 Meanwhile, the group difference in the rate of RNFL thickness change was not significant at nasal sectors (from 1 to 4 o clock) and temporal sector (9 o clock). This result accords with the observation that glaucoma patients retain their temporal or central visual field until the end stage of the disease. 31 In the present study, no IOP-related factors, including baseline IOP, mean follow-up IOP, and the fluctuation of IOP, were associated with a faster rate of RNFL thinning. The absence of such associations had been reported in several studies. In the study reported by Prata et al., 32 the baseline IOP and the amount of IOP reduction were not risk factors for a faster rate of visual field loss after disc hemorrhage. In the study reported by Sung et al., 33 none of the IOP-related parameters including baseline IOP, mean 24-hour admission value, follow-up average, or follow-up IOP fluctuation, was associated with visual field progression. However, these data including ours are in contrast with data from many previous studies, where an association between IOP and glaucoma progression was found. The discrepancy between studies on the effect of IOP on glaucoma progression may be explained by variations in patient populations under study and IOP levels seen during follow-up. The majority (87.6%) of our study patients had normaltension glaucoma and all our patients were medically or surgically treated and maintained a relatively low mean follow-up IOP of 12.4 mm Hg. We believe that lowering of IOP is important to slow glaucoma progression. However, lowering IOP may not be equally effective in each individual glaucoma patient. Although it is evident that IOP is one of the strong risk

5 4426 Lee et al. IOVS, June 2011, Vol. 52, No. 7 factors for glaucoma progression, it may be possible that the absolute IOP level may be less important for the rate of progressive RNFL thinning in normotensive eyes, since low IOP could still be above the threshold of injury for individual optic nerve head tissue. 42 The baseline RNFL thickness was not related with a faster rate of RNFL loss in our study. Although it is generally acknowledged that baseline disease severity is related to further glaucoma progression, such observations are based on visual field analysis and may not be correct in all circumstances. For example, Leung et al. 18 reported that a higher baseline RNFL measurement was associated with an increased rate of RNFL reduction. This finding is in agreement with the curvilinear structure function relationship observed in previous cross-sectional studies, suggesting that progression as measured by a decrease in RNFL thickness is more noticeable than is progression assessed by visual field measurements in patients with early-stage glaucoma, whereas the reverse is true when the disease is more advanced. 43,44 Thus, the relationship between baseline status and rate of progression may vary, depending on the stage of disease in enrolled patients and the method used to evaluate progressive change. Studies have shown that disc hemorrhage is associated with PPA. 45,46 Because disc hemorrhage is a known significant risk factor for glaucoma progression, it is possible that the association of PPA with RNFL progression shown in the present study was mediated by more frequent disc hemorrhage in the PPA group. Due to the retrospective study design, however, the accurate frequency of disc hemorrhage and, thus, the influence of disc hemorrhage could not be evaluated. A prospective, longitudinal study is needed to address the influence of disc hemorrhage on glaucoma progression in eyes with PPA. Although our data support the previous findings that determined the PPA as a risk factor for glaucoma progression, the result of the present study also validates the usefulness of trend-based approach of OCT RNFL thickness to monitor glaucoma progression. Our data show that OCT-based trend analysis is able to discriminate the eyes where the disease progresses faster, being associated with known risk factors for faster progression. The MD was marginally significant between the groups at the end of the follow-up, whereas they were comparable at baseline. This finding indirectly suggests that the rate of visual field progression was faster in eyes with -zone PPA, which is consistent with results reported in the study by Teng et al. 4 They reported a significantly faster rate of visual field progression in eyes with -zone PPA than that in eyes without -zone PPA. Taken together, both structural and functional evaluations indicate that -zone PPA is a risk factor for faster glaucoma progression. However, the coexistence of the structural and functional progression may not be observed when evaluated in other study populations with different stages of disease because the change is often dependent on the stage of disease. The present study has several limitations. First, we did not measure the PPA size in absolute units. Because of the retrospective study design, Heidelberg retina tomographic images were not available in many patients. Further, the patients did not receive keratometric readings and axial length measurement at each occasion of disc photography. Thus, it was not possible to correct the magnification factor in many patients. Nonetheless, we have shown that the increase in PDR is associated with structural glaucoma progression. Because optic disc size most likely is not changing, it is reasonable to consider that the change in PDR is derived from the increase of PPA. Thus, the result of our study may be interpreted to support earlier studies that demonstrated the association between the increase in PPA size and glaucoma progression. Second, patients were scanned using the same diameter scan ring without consideration of their disc size. This may affect the outcome because the RNFL thickness measurement can be affected by the disc size However, we measured the rate of change based on the measurement on the same location as closely as possible; thus, the effect of using the same diameter scan ring should be much less than when the measurement of RNFL thickness is used for diagnostic purposes, which is often the case in clinical practice. In conclusion, the presence and enlargement of -zone PPA were significantly associated with the rate of progressive RNFL thinning as measured by OCT. Detailed examination of PPA in glaucoma may enable the clinician to obtain clinically relevant information about the possibility of future glaucoma progression. References 1. Best M, Toyofuku H. Ocular hemodynamics during induced ocular hypertension in man. Am J Ophthalmol. 1972;74: Jonas JB, Martus P, Horn FK, Junemann A, Korth M, Budde WM. Predictive factors of the optic nerve head for development or progression of glaucomatous visual field loss. Invest Ophthalmol Vis Sci. 2004;45: Jonas JB, Martus P, Budde WM, Junemann A, Hayler J. Small neuroretinal rim and large parapapillary atrophy as predictive factors for progression of glaucomatous optic neuropathy. Ophthalmology. 2002;109: Teng CC, De Moraes CG, Prata TS, Tello C, Ritch R, Liebmann JM. Beta-Zone parapapillary atrophy and the velocity of glaucoma progression. Ophthalmology. 2010;117: Daugeliene L, Yamamoto T, Kitazawa Y. Risk factors for visual field damage progression in normal-tension glaucoma eyes. Graefes Arch Clin Exp Ophthalmol. 1999;237: Cohen AI. Is there a potential defect in the blood-retinal barrier at the choroidal level of the optic nerve canal? Invest Ophthalmol. 1973;12: Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117: Quigley HA, Katz J, Derick RJ, Gilbert D, Sommer A. An evaluation of optic disc and nerve fiber layer examinations in monitoring progression of early glaucoma damage. Ophthalmology. 1992;99: Araie M, Sekine M, Suzuki Y, Koseki N. Factors contributing to the progression of visual field damage in eyes with normal-tension glaucoma. Ophthalmology. 1994;101: Tezel G, Kolker AE, Wax MB, Kass MA, Gordon M, Siegmund KD. Parapapillary chorioretinal atrophy in patients with ocular hypertension. II. An evaluation of progressive changes. Arch Ophthalmol. 1997;115: Quigley HA, Enger C, Katz J, Sommer A, Scott R, Gilbert D. Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol. 1994;112: Tezel G, Siegmund KD, Trinkaus K, Wax MB, Kass MA, Kolker AE. Clinical factors associated with progression of glaucomatous optic disc damage in treated patients. Arch Ophthalmol. 2001;119: Uchida H, Ugurlu S, Caprioli J. Increasing peripapillary atrophy is associated with progressive glaucoma. Ophthalmology. 1998;105: Budde WM, Jonas JB. Enlargement of parapapillary atrophy in follow-up of chronic open-angle glaucoma. Am J Ophthalmol. 2004;137: Sehi M, Greenfield DS. Assessment of retinal nerve fiber layer using optical coherence tomography and scanning laser polarimetry in progressive glaucomatous optic neuropathy. Am J Ophthalmol. 2006;142: Budenz DL, Fredette MJ, Feuer WJ, Anderson DR. Reproducibility of peripapillary retinal nerve fiber thickness measurements with stratus OCT in glaucomatous eyes. Ophthalmology. 2008;115: 661.e4 666.e4.

6 IOVS, June 2011, Vol. 52, No. 7 -Zone PPA and OCT RNFL Thinning Lee EJ, Kim TW, Park KH, Seong M, Kim H, Kim DM. Ability of Stratus OCT to detect progressive retinal nerve fiber layer atrophy in glaucoma. Invest Ophthalmol Vis Sci. 2009;50: Leung CK, Cheung CY, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma: a study on optical coherence tomography guided progression analysis. Invest Ophthalmol Vis Sci. 2010;51: Medeiros FA, Zangwill LM, Alencar LM, et al. Detection of glaucoma progression with stratus OCT retinal nerve fiber layer, optic nerve head, and macular thickness measurements. Invest Ophthalmol Vis Sci. 2009;50: Alencar LM, Zangwill LM, Weinreb RN, et al. A comparison of rates of change in neuroretinal rim area and retinal nerve fiber layer thickness in progressive glaucoma. Invest Ophthalmol Vis Sci. 2010;51: Lee EJ, Kim T-W, Weinreb RN, Park KH, Kim SH, Kim DM. Trendbased analysis of retinal nerve fiber layer thickness measured by optical coherence tomography in eyes with localized nerve fiber layer defects. Invest Ophthalmol Vis Sci. 2011;52: Jonas JB. Clinical implications of peripapillary atrophy in glaucoma. Curr Opin Ophthalmol. 2005;16: Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography. Ophthalmology. 1996;103: Li G, Fansi AK, Boivin JF, Joseph L, Harasymowycz P. Screening for glaucoma in high-risk populations using optical coherence tomography. Ophthalmology. 2010;117: Vizzeri G, Weinreb RN, Gonzalez-Garcia AO, et al. Agreement between spectral-domain and time-domain OCT for measuring RNFL thickness. Br J Ophthalmol. 2009;93: Moreno-Montanes J, Anton A, Garcia N, Olmo N, Morilla A, Fallon M. Comparison of retinal nerve fiber layer thickness values using stratus optical coherence tomography and Heidelberg retina tomograph-iii. J Glaucoma. 2009;18: Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. 3rd ed. Hoboken, NJ: Wiley; 2003: Jonas JB, Nguyen XN, Gusek GC, Naumann GO. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. I. Morphometric data. Invest Ophthalmol Vis Sci. 1989;30: Jonas JB, Naumann GO. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. II. Correlations. Invest Ophthalmol Vis Sci. 1989;30: Tezel G, Kolker AE, Kass MA, Wax MB, Gordon M, Siegmund KD. Parapapillary chorioretinal atrophy in patients with ocular hypertension. I. An evaluation as a predictive factor for the development of glaucomatous damage. Arch Ophthalmol. 1997;115: Hart WM Jr, Becker B. The onset and evolution of glaucomatous visual field defects. Ophthalmology. 1982;89: Prata TS, De Moraes CG, Teng CC, Tello C, Ritch R, Liebmann JM. Factors affecting rates of visual field progression in glaucoma patients with optic disc hemorrhage. Ophthalmology. 2010;117: Sung KR, Lee S, Park SB, et al. Twenty-four hour ocular perfusion pressure fluctuation and risk of normal-tension glaucoma progression. Invest Ophthalmol Vis Sci. 2009;50: Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126: Collaborative Normal-Tension Glaucoma Study Group. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am J Ophthalmol. 1998;126: Nakagami T, Yamazaki Y, Hayamizu F. Prognostic factors for progression of visual field damage in patients with normal-tension glaucoma. Jpn J Ophthalmol. 2006;50: Miglior S, Torri V, Zeyen T, Pfeiffer N, Vaz JC, Adamsons I. Intercurrent factors associated with the development of open-angle glaucoma in the European glaucoma prevention study. Am J Ophthalmol. 2007;144: Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol. 2003;121: O Brien C, Schwartz B, Takamoto T, Wu DC. Intraocular pressure and the rate of visual field loss in chronic open-angle glaucoma. Am J Ophthalmol. 1991;111: The Advanced Glaucoma Intervention Study (AGIS). The AGIS Investigators. 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000; 130: Stewart WC, Kolker AE, Sharpe ED, et al. Factors associated with long-term progression or stability in primary open-angle glaucoma. Am J Ophthalmol. 2000;130: Burgoyne CF, Downs JC. Premise and prediction: how optic nerve head biomechanics underlies the susceptibility and clinical behavior of the aged optic nerve head. J Glaucoma. 2008;17: Leung CK-S, Chan W-M, Chong KK-L, et al. Comparative study of retinal nerve fiber layer measurement by StratusOCT and GDx VCC, I: Correlation analysis in glaucoma. Invest Ophthalmol Vis Sci. 2005;46: Schlottmann PG, De Cilla S, Greenfield DS, Caprioli J, Garway- Heath DF. Relationship between visual field sensitivity and retinal nerve fiber layer thickness as measured by scanning laser polarimetry. Invest Ophthalmol Vis Sci. 2004;45: Hayakawa T, Sugiyama K, Tomita G, et al. Correlation of the peripapillary atrophy area with optic disc cupping and disc hemorrhage. J Glaucoma. 1998;7: Sugiyama K, Tomita G, Kitazawa Y, Onda E, Shinohara H, Park KH. The associations of optic disc hemorrhage with retinal nerve fiber layer defect and peripapillary atrophy in normal-tension glaucoma. Ophthalmology. 1997;104: Savini G, Zanini M, Carelli V, Sadun AA, Ross-Cisneros FN, Barboni P. Correlation between retinal nerve fibre layer thickness and optic nerve head size: an optical coherence tomography study. Br J Ophthalmol. 2005;89: Savini G, Barboni P, Carbonelli M, Zanini M. The effect of scan diameter on retinal nerve fiber layer thickness measurement using stratus optic coherence tomography. Arch Ophthalmol. 2007;125: Budenz DL, Anderson DR, Varma R, et al. Determinants of normal retinal nerve fiber layer thickness measured by Stratus OCT. Ophthalmology. 2007;114: