- Email: [email protected]
Rates of Neuroretinal Rim and Peripapillary Atrophy Area Change
Rates of Neuroretinal Rim and Peripapillary Atrophy Area Change A Comparative Study of Glaucoma Patients and Normal Controls Jovina L. S. See, FRCS, Marcelo T. Nicolela, MD, Balwantray C. Chauhan, PhD Objective: To compare the rates of global and sectoral neuroretinal rim area (NRA) and peripapillary atrophy area (PPAA) change in open-angle glaucoma patients and normal control subjects and to determine the relationship between rates of NRA and PPAA change. Design: Prospective, longitudinal cohort study of cases and controls. Participants and Controls: Ninety-four patients with open-angle glaucoma and 54 control subjects. Methods: Patients and controls were imaged with confocal scanning laser tomography every 6 months. The NRA and PPAA in 1 eye were analyzed to determine the rate of change globally and in 12 30° sectors by regression analysis. Rates of global NRA and PPAA change were correlated. Sectors were ranked from 1 to 12 each according to the magnitude of NRA and PPAA change and were compared between patients and controls using rank-order correlation. Spatial concordance between rates of NRA and PPAA change was calculated as sector rank distance between correspondingly ranked sectors. Main Outcome Measures: Rates of global and sectoral NRA and PPAA change. Results: The mean (⫾standard deviation) follow-up was 8.6⫾2.9 years for patients and 7.1⫾3.6 years for controls. Globally, NRA declined more rapidly in patients compared with controls, expressed either in absolute units (medians, –5.33⫻10⫺3 mm2/year and ⫺1.25⫻10⫺3 mm2/year, respectively; P ⫽ 0.006) or percentage of baseline NRA (medians, ⫺0.42%/year and ⫺0.07%/year, respectively; P ⫽ 0.001). The global rate of PPAA change was not significantly higher in patients compared with controls (12.66⫻10⫺3 mm2/year and 9.43⫻10⫺3 mm2/year, respectively; P ⫽ 0.173). Rates of global and sectoral NRA and PPAA change were correlated poorly in either group. There was a high correlation between ranked sectors of NRA change in patients and controls (Pⱕ0.001), indicating similar patterns of NRA decline in patients and controls; however, this was not the case for rates of PPAA change. Conclusions: These findings indicate an age-related regional susceptibility of the optic disc that may be accelerated in glaucoma. The poor relationship between rates of NRA and PPAA change suggests their temporal dynamics are uncoupled. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2009;116:840 – 847 © 2009 by the American Academy of Ophthalmology.
The hallmarks of glaucomatous progression are visual field deterioration and morphologic changes of the optic disc, including narrowing of the neuroretinal rim accompanied with deepening or widening of the optic cup, or both.1 Understanding the rates and pattern of neuroretinal rim area (NRA) loss may provide an insight into the underlying glaucomatous process and help the clinician in the management of individual patients. Earlier research indicates that the rate of NRA loss in patients with glaucomatous visual field loss, expressed as percentage of baseline NRA, is between ⫺2.1% and ⫺3.5% per year.2,3 Peripapillary atrophy has been associated with glaucoma since the early 1900s.4 The atrophy is more prevalent and more extensive in glaucoma patients compared with healthy nonglaucomatous individuals.5 It is thought that peripapillary atrophy may be of value in identifying those patients at
840
© 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
risk of converting to manifest glaucoma from ocular hypertension6 and those with manifest glaucoma at risk for visual field deterioration.7–9 Relatively little is known about the rate of change of NRA or peripapillary atrophy area (PPAA) in healthy nonglaucomatous individuals, or the contribution of these effects to the acquired neuropathy in glaucoma. Evidence on whether NRA changes with age comes mostly from single or cross-sectional observations10 –13 and has yielded conflicting results. The use of such cross-sectional data to extrapolate the rate of NRA change over time has limitations.13 Actual longitudinal data from a limited number of studies suggest that NRA decreases with age,2,14 although this is not universally accepted.15 The present study had 2 purposes: first, to compare the global and sectoral rates of NRA and PPAA change in ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2008.12.005
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls open-angle glaucoma patients and normal control subjects followed up prospectively with confocal scanning laser tomography (CSLT), and second, to determine the spatial relationship between NRA and PPAA changes.
Patients and Methods
Intraoperator variability in demarking the PPAA was assessed in single optic disc images of a subgroup of 5 glaucoma patients and 5 normal controls chosen randomly. In these 10 images, PPAA was analyzed as described above 5 times on 5 separate days. Global and sectoral NRA and PPAA measurements were exported for analysis. All eyes were converted to right eye format before analysis.
Subjects
Statistical Analysis
Glaucoma patients and normal control subjects participated in a longitudinal, prospective study on visual field and optic disc change. Patients were recruited consecutively from the glaucoma clinics of Capital Health District Authority, Halifax, Nova Scotia, Canada, with the following inclusion criteria: (1) clinical diagnosis of open-angle glaucoma with notching or progressive thinning of the neuroretinal rim, (2) baseline visual field mean deviation between ⫺2 and ⫺10 dB, (3) open angles by gonioscopy, and (4) best-corrected visual acuity of 6/12 or better. Normal control subjects were recruited among spouses of patients and other volunteers with the following inclusion criteria: (1) clinically normal appearance of the optic disc and fundus, (2) intraocular pressure of less than 22 mmHg, and (3) best-corrected visual acuity of 6/12 or better. Common exclusion criteria were: (1) systemic disease or systemic medication known to affect the visual field, (2) refractive error exceeding 5 diopters (D; equivalent sphere) of myopia or hyperopia or 3 D of astigmatism, and (3) contact lens wear. Additionally, patients were excluded if there was concomitant ocular disease, and controls were excluded if there was any ocular disease. One eye was chosen randomly as the study eye for the controls and also for the patients if both eyes were eligible. In accordance with the Declaration of Helsinki, all participants gave informed consent to participate in the study and the protocol was approved by the Capital Health Research Ethics Board.
Rates of global and sectoral NRA and PPAA change were computed for each subject using regression analysis. Rates of change were ranked independently each for NRA and PPAA within the 12 sectors such that the sector with highest decreasing rate of NRA was ranked first and the sector with the highest increasing rate of PPAA was ranked first, and so on. Comparison of spatial patterns of NRA change between patients and controls was performed using the Spearman nonparametric rank-order correlation analysis for corresponding disc sectors. This analysis also was performed for spatial patterns of PPAA change. The spatial concordance between rates of NRA change and PPAA change was calculated as sector rank distance between correspondingly ranked sectors for ranks 1, 2, and 3. For example, if the sector ranked 1 for NRA change was not the same one ranked for PPAA change, but the neighboring one, then the rank distance was 1. The rank distance therefore varied from 0 to 6. Figure 1 illustrates an example of rank distance calculation. Intraoperator variability of PPAA was analyzed with the coefficient of variation. Distributions of group variables were examined for normality using the Kolmogorov Smirnov 1-sample test. Comparisons between glaucoma patients and controls then were made with a group t test if the distributions were normal and the Kolmogorov Smirnov 2-sample test when a nonparametric test had to be used. Categorical variables were compared with the chisquared test. Associations were analyzed using the Pearson correlation coefficient.
Testing Protocol At baseline and every 6 months thereafter, CSLT was performed with the Heidelberg Retina Tomograph I (Heidelberg Engineering GmbH, Heidelberg, Germany). At each session, several images were obtained with the 10° scan angle with the optic disc centered in the image frame. After carefully examining the image quality for evenness in illumination, optic disc centration, and fixation stability, 3 of the best quality images were used to compute the mean topography and reflectance image.
Analysis of Images Images were imported to the Heidelberg Retina Tomograph 3 software (Heidelberg Engineering GmbH) for processing and analysis. The quality of alignment of the longitudinal image series was checked manually with the movie feature of the software, which displays each of the aligned mean serial reflectance or topography images in quick succession. Poor quality and misaligned images (constituting ⬍5% of the images) were removed. A contour line demarking the optic disc boundary was drawn in the baseline image by a single operator (J.L.S.S.) with the aid of conventional stereo disc photographs when necessary. The contour line was imported automatically to the follow-up images for analysis. The total extent of PPAA then was identified and demarcated by the same operator using the custom Atrophy Zone Analysis software16 (Heidelberg Engineering GmbH). The software computed several parameters, including the global and sectoral (12 equal-sized sectors of 30° each) PPAA. To minimize operator bias, the images were processed in random sequence for both subject and examination date.
Results There were 94 glaucoma patients and 54 normal control subjects in the study. The mean baseline age⫾standard deviation was 61.3⫾12.2 years and 54.0⫾12.1 years, respectively, whereas the mean follow-up was 8.6⫾2.9 years and 7.1⫾3.6 years, respectively. The median (interquartile range) baseline visual field mean deviation was ⫺4.86 dB (⫺6.89, ⫺3.56 dB) and ⫺1.05 dB (⫺2.23, ⫺0.32 dB), respectively. Patients were older at baseline and had a longer follow-up and worse baseline mean deviation (P⬍0.010). The mean (⫾standard deviation) baseline and followup intraocular pressure in patients was 18.8 (⫾4.4) mmHg and 17.4 (⫾2.8) mmHg, respectively. The mean coefficient of variation of operator-defined PPAA area was 4.6% in patients and 6.0% in controls. Baseline optic disc parameters and the rates of global NRA and PPAA change are shown in Table 1. These data indicate that although the optic disc area was not significantly different between patients and controls, the baseline NRA was significantly larger in controls. Peripapillary atrophy was present in 86 (91%) patients and 47 (87%) control subjects at baseline. These proportions were not statistically significantly different, although baseline PPAA was significantly larger in patients (Table 1). The rate of NRA change was significantly higher in patients compared with controls (4.2 times higher expressed in square millimeters per year and 6 times higher expressed in percentage of rim area per year); however, there was considerable variation in rates in both groups. The
841
Ophthalmology Volume 116, Number 5, May 2009
Figure 1. Example of the rank distance calculation. The 30° sector with the highest decreasing neuroretinal rim area (NRA; rank ⫽ 1) is also the one with the highest increasing peripapillary atrophy area (PPAA; rank ⫽ 1) area. Hence for rank ⫽ 1, rank distance ⫽ 0. Similarly, for rank ⫽ 2, the rank distance ⫽ 1, and for rank ⫽ 3, rank distance ⫽ 6. I ⫽ inferior; N ⫽ nasal; S ⫽ superior; T ⫽ temporal.
rate of PPAA change was not statistically significantly higher in patients. The rates of global PPAA and NRA change were poorly correlated in both patients and controls (r ⫽ ⫺0.010 and P ⫽ 0.949; and r ⫽ ⫺0.122 and P ⫽ 0.260, respectively; Fig 2). Sectoral analysis showed that the highest rates of NRA change in patients occurred in 2 of the 3 inferior temporal sectors, followed by 2 superior temporal sectors (Fig 3). The pattern of sectoral rate of NRA change in controls was remarkably similar; however, the magnitudes of change were lower (Fig 3). This observation was confirmed by the high rank-order correlation (of sectors ranked from highest to lowest rate of NRA change) between patients and controls (r ⫽ 0.910, P⬍0.001; Fig 4). In contrast, the pattern of PPAA change in patients was more diffuse, with the lowest rates of change occurring nasally (Fig 5). The PPAA changes observed in controls largely were restricted to the temporal hemidisc (Fig 5). Unlike the spatial correlation of NRA area change between patients and controls, a similar analysis of PPAA change showed poorer rank-order correlation (r ⫽ 0.531, P ⫽ 0.075; Fig 4). The rank distance analysis for determining spatial correlation between ranked rates of NRA change and PPAA change showed that the proportion of patients or controls with lower rank distance was not obviously higher (Fig 6). These results indicate that the 30° sectors with the highest rate of NRA change usually were not the sectors where the PPAA change was highest. For example, the sector with the highest rate of NRA change was the same as the one with the highest rate of PPAA area change in only 10 (12%)
patients and 11 (23%) controls. Similar results were noted for the second- and third-ranked sectors.
Case Examples The baseline and final CSLT reflectance images of a glaucoma patient with 8 years of follow-up are shown in Figure 7. There is NRA thinning in the inferior temporal portion of the disc and enlargement of the entire PPAA. The sector with the highest rate of NRA change was not the same as the sector with the highest rate of PPAA change (Fig 7), demonstrating the lack of spatial correlation. The baseline and final CSLT reflectance images of a normal control with 10.5 years of follow-up are also shown in Figure 7. In this case, the sector with the highest rate of NRA area change was the same as the sector with the highest rate of PPAA area change.
Discussion There is a surprising paucity of published reports on the rate of NRA loss in glaucoma patients followed up longitudinally. Most previous studies used planimetry of conventional disc photographs to derive these estimates.2,3,15,14 Zeyen and Caprioli3 and Airkasinen et al2 reported the rate of NRA loss in patients with glaucomatous visual field loss to be ⫺2.1%/year
Table 1. Optic Disc Characteristics* in Glaucoma Patients and Normal Control Subjects
2
Optic disc area (mm ) Baseline neuroretinal rim area (mm2) Baseline vertical cup-to-disc ratio Peripapillary atrophy present, n (%) Baseline peripapillary area (mm2) Rate of neuroretinal rim change (mm2⫻10–3/year) Rate of neuroretinal rim change (%) Rate of peripapillary atrophy area change (mm2⫻10–3/year) *Median (interquartile range). † t test. ‡ Two-sample Kolmogorov Smirnov test. § Chi-square test.
842
Glaucoma Patients
Normal Controls
P Value
2.05 (1.79–2.33) 1.14 (0.89–1.35) 0.6 (0.5–0.7) 86 (91) 0.44 (0.26–0.80) –5.33 (–12.52 to 2.90) –0.42 (–1.26 to 0.29) 12.66 (5.58 to 27.93)
1.92 (1.68–2.24) 1.50 (1.28–1.75) 0.3 (0.0–0.5) 47 (87) 0.29 (0.16–0.80) –1.25 (–5.45 to 0.42) –0.07 (–0.39 to 0.04) 9.43 (5.37–19.20)
0.238† ⬍0.001† ⬍0.001‡ 0.407§ 0.043‡ 0.006‡ 0001‡ 0.173‡
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls
Figure 2. Scatterplots showing the relationship between rates of global peripapillary atrophy area (PPAA) and neuroretinal rim area (NRA) change in (left) glaucoma patients and (right) normal control subjects.
and ⫺3.5%/year, respectively. In ocular hypertensive subjects in whom visual field loss developed, the respective figures vary from ⫺0.95%/year14 to ⫺2.8%/year2 using planimetry and ⫺0.75%/year in one study using CSLT.17 Even less is known about the presumed age-related loss of NRA in normal subjects followed up longitudinally. In 2 published reports, the rate of NRA loss was reported to be ⫺0.23%2 and ⫺0.36%,14 respectively. However, in 1 study there were only 5 subjects2 and in the other,14 photographs were available at only 2 time points, making rate estimates tenuous. To the best of the authors’ knowledge, the present study is the first to report the rate of NRA loss in normal subjects followed up with CSLT. The rate of NRA loss in glaucoma patients in the present study (median, ⫺0.42%/year) is considerably lower than that of previous reports. The reason for this difference is not obvious; however, severity of damage at baseline, follow-up, and treatment among these observational studies likely varied. Because patients in this research were in a prospective study with regular and frequent examinations, it is possible that compliance to treatment was higher and possibly resulted in lower rates of NRA loss. In this study, CLST was used, whereas most previous studies used conventional disc photography. Interestingly, the 1 published rate of NRA loss with CSLT17 also was lower than that of previous reports with disc photography. Finally, rate estimates are largely variable among subjects, yielding highly skewed distributions; hence, depending on the sample size, these point estimates may be influenced differentially by the underlying distributions. In the present study, there were also substantial differences in rates of NRA loss among the disc sectors, with the temporal hemidisc showing the highest rate of NRA loss. The apparently lower rate of NRA loss in the nasal hemidisc could be the result of either a lower susceptibility in this area or a nasal shift of the vessel trunk with cup expansion resulting in less NRA change because blood vessels are not excluded in the calculation of NRA. Although patients had a 7-fold higher rate of global NRA loss compared
with controls, the sectoral pattern of change in these 2 groups of subjects was remarkably similar (Fig 3). The similarity in this pattern was confirmed by a highly statistically significant correlation between patients and controls in the ranked sectors. The rate of age-related NRA loss might have been higher than reported if the controls were not significantly younger than the patients. Age-related loss of NRA probably reflects both loss of retinal ganglion cell axons and optic nerve head structural changes.18 Postmortem studies in nonglaucomatous eyes show an age-related decline in axon counts extrapolated from cross-sectional observations.19 –22 Because of the interindividual variation in baseline axon numbers and the induced statistical errors in extrapolating longitudinal trends from cross-sectional data, estimates of rate of axonal loss vary considerably among the published studies. Whether neuronal loss in the optic nerve is a result of age-related structural changes, or vice versa, is not known. Furthermore, it is not known what proportion of NRA loss is attributable to axonal loss compared with possible nonneuronal structural changes, such as displacement or compression of the laminar and prelaminar tissues. The recent availability of imaging techniques such as spectral domain optical coherence tomography23,24 may allow monitoring of deeper optic nerve structures over time and eventually provide insight into these clinically important questions. It is also plausible that the nonneuronal structural changes in the normal optic nerve head are correlated poorly to axonal loss. The similarity in the pattern of NRA loss in glaucoma patients and normal controls suggests that there may be an age-related pattern of regional susceptibility in the optic nerve comprising neuronal or nonneuronal structural components, or both. In glaucoma, the superimposing pathology may result in an increase in the rate of NRA loss in these susceptible areas. Despite the large variation in the rates of NRA loss among patients and controls, the similarity in the spatial patterns of this change still emerged.
843
Ophthalmology Volume 116, Number 5, May 2009
Figure 3. Rates of sectoral neuroretinal rim area (NRA) change in (left) glaucoma patients and (right) normal control subjects. I ⫽ inferior; N ⫽ nasal; S ⫽ superior; T ⫽ temporal.
Figure 4. Scatterplots showing the correlation between ranked sectors in glaucoma patients and normal control subjects according to rate of (left) neuroretinal rim area (NRA) change and (right) peripapillary atrophy area (PPAA) change. These results indicate that the spatial patterns of NRA change, but not PPAA, among the 2 groups was very similar.
Figure 5. Rates of sectoral peripapillary atrophy area (PPAA) change in (left) glaucoma patients and (right) normal control subjects. I ⫽ inferior; N ⫽ nasal; S ⫽ superior; T ⫽ temporal.
844
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls
Figure 6. Histograms showing the rank distances between sectors ranked 1, 2, and 3 according to rate of neuroretinal rim area (NRA) change and peripapillary atrophy area (PPAA) change. These data indicate that there was little spatial correlation between the sectors showing the highest rates of NRA and PPAA area change in either glaucoma patients or normal control subjects.
The rate of PPAA change was nonsignificantly higher in patients compared with controls. There was a poor relationship between the rates of global NRA change and PPAA change in either group (Fig 2). Furthermore, there was little spatial cor-
relation between the sectors showing the highest rates of NRA and PPAA change. Sectors with the largest PPAA were not the same or even necessarily in the vicinity of sectors with the largest NRA change. Finally, PPAA change seemed to be
Figure 7. Confocal scanning laser reflectivity images obtained at (A) baseline and (B) final examination of the right eye of a glaucoma patient followed up for 9 years showing both neuroretinal rim area (NRA) and peripapillary atrophy area (PPAA) changes. The analysis showed that the sector with the highest decreasing rate of NRA (⫹) was not the same as the sector with the highest increasing rate of PPA (*). In this case, rank distance ⫽ 3. Confocal scanning laser reflectivity images obtained at (C) baseline and (D) final examination of the right eye of a normal control subject followed up for 11 years. The sector with the highest decreasing rate of NRA (⫹) also was the sector with the highest increasing rate of PPAA (*). In this case, rank distance ⫽ 0.
845
Ophthalmology Volume 116, Number 5, May 2009 more diffuse compared with NRA change, with little similarity in the pattern of loss between patients and controls. Rates of PPAA change have not been reported before; however, Uchida et al8 demonstrated that patients with progressive optic disc or visual field loss were more likely to have increasing peripapillary atrophy. These results are not directly comparable with the current results because patients were not segregated into progressing or nonprogressing categories, but rather rates of change were examined. This study also was not designed to address whether an increase in peripapillary atrophy preceded loss of the neuroretinal rim. This study had several limitations. Although CSLT has been validated to describe and quantify PPAA16,25 with good agreement between photographically derived and CLST-derived PPAA estimates,26 no meaningful distinction could be made between the inner peripapillary crescent of visible sclera and choroidal vessels (zone 27) and the outer crescent of irregular hyperpigmentation or hypopigmentation (zone ␣27). It is possible that these morphologically distinct zones of peripapillary atrophy had different relationships with NRA loss and hence masked a stronger relationship between the rates of NRA loss and either zone ␣ or zone  PPAA loss. The relationship between NRA and PPAA change in both magnitude and location might have been influenced by the amount of remaining NRA tissue. For example, low rates of NRA change may be the result of genuinely slow progression or little remaining NRA in which further deterioration is less possible, either globally or sectorially. Unfortunately, there are no obvious analytical techniques to account for this inherent limitation. For these reasons and the large interindividual variation in the rate of NRA change in both patients and controls, the findings of this study should not be used to derive statistical limits for the rate of NRA change in normal controls to drive treatment decisions in individual patients. In summary, this study showed that although, as expected, the rates of both global and sectoral NRA area change were higher in glaucoma patients compared with those of control subjects, the sectoral pattern of loss was remarkably similar. These findings indicate an age-related regional susceptibility that may be accelerated in glaucoma. The magnitude and location of PPAA change was correlated poorly to NRA change in both patients and controls, suggesting that the mechanisms governing the temporal dynamics of PPAA change may be different to those of NRA change.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17.
18.
19. 20. 21.
References 22. 1. Pederson JE, Anderson DR. The mode of progressive disc cupping in ocular hypertension and glaucoma. Arch Ophthalmol 1980;98:490 –5. 2. Airaksinen PJ, Tuulonen A, Alanko HI. Rate and pattern of neuroretinal rim area decrease in ocular hypertension and glaucoma. Arch Ophthalmol 1992;110:206 –10. 3. Zeyen TG, Caprioli J. Progression of disc and field damage in early glaucoma. Arch Ophthalmol 1993;111:62–5. 4. Airaksinen PJ, Tuulonen A, Werner EB. Clinical evaluation of the optic disc and retinal nerve fiber layer. In: Ritch R, Shields
846
23.
24.
MB, Krupin T, eds. The Glaucomas. vol. 1. St. Louis, MO: Mosby; 1996:617–57. Jonas JB. Clinical implications of peripapillary atrophy in glaucoma. Curr Opin Ophthalmol 2005;16:84 – 8. Tezel G, Kolker AE, Kass MA, et al. Parapapillary chorioretinal atrophy in patients with ocular hypertension. I. An evaluation as a predictive factor for the development of glaucomatous damage. Arch Ophthalmol 1997;115:1503– 8. Araie M, Sekine M, Suzuki Y, Koseki N. Factors contributing to the progression of visual field damage in eyes with normaltension glaucoma. Ophthalmology 1994;101:1440 – 4. Uchida H, Ugurlu S, Caprioli J. Increasing peripapillary atrophy is associated with progressive glaucoma. Ophthalmology 1998;105:1541–5. Jonas JB, Martus P, Horn FK, et al. Predictive factors of the optic nerve head for development or progression of glaucomatous visual field loss. Invest Ophthalmol Vis Sci 2004;45:2613–8. Britton RJ, Drance SM, Schulzer M, et al. The area of the neuroretinal rim of the optic nerve in normal eyes. Am J Ophthalmol 1987;103:497–504. Jonas JB, Gusek GC, Guggenmoos-Holzmann I, Naumann GO. Correlations of the neuroretinal rim area with ocular and general parameters in normal eyes. Ophthalmic Res 1988;20:298–303. Tsai CS, Ritch R, Shin DH, et al. Age-related decline of disc rim area in visually normal subjects. Ophthalmology 1992;99:29 –35. Garway-Heath DF, Wollstein G, Hitchings RA. Aging changes of the optic nerve head in relation to open angle glaucoma. Br J Ophthalmol 1997;81:840 –5. Laemmer R, Schroeder S, Martus P, et al. Quantification of neuroretinal rim loss using digital planimetry in long-term follow-up of normals and patients with ocular hypertension. J Glaucoma 2007;16:430 – 6. Moya FJ, Brigatti L, Caprioli J. Effect of aging on optic nerve appearance: a longitudinal study. Br J Ophthalmol 1999;83:567–72. Park KH, Tomita G, Liou SY, Kitazawa Y. Correlation between peripapillary atrophy and optic nerve damage in normal-tension glaucoma. Ophthalmology 1996;103:1899 –906. Owen VM, Strouthidis NG, Garway-Heath DF, Crabb DP. Measurement variability in Heidelberg Retina Tomograph imaging of neuroretinal rim area. Invest Ophthalmol Vis Sci 2006;47:5322–30. 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; 17:318 –28. Balazsi AG, Rootman J, Drance SM, et al. The effect of age on the nerve fiber population of the human optic nerve. Am J Ophthalmol 1984;97:760 – 6. Mikelberg FS, Drance SM, Schulzer M, et al. The normal human optic nerve: axon count and axon diameter distribution. Ophthalmology 1989;96:1325– 8. Repka MX, Quigley HA. The effect of age on normal human optic nerve fiber number and diameter. Ophthalmology 1989; 96:26 –32. Jonas JB, Muller-Bergh JA, Schlotzer-Schrehardt UM, Naumann GO. Histomorphometry of the human optic nerve. Invest Ophthalmol Vis Sci 1990;31:736 – 44. Srinivasan VJ, Adler DC, Chen Y, et al. Ultrahigh-speed optical coherence tomography for three-dimensional and en face imaging of the retina and optic nerve head. Invest Ophthalmol Vis Sci 2008;49:5103–10. Kagemann L, Ishikawa H, Wollstein G, et al. Ultrahighresolution spectral domain optical coherence tomography imaging of the lamina cribrosa. Ophthalmic Surg Lasers Imaging 2008;39(suppl):S126 –31.
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls 25. Park KH, Park SJ, Lee YJ, et al. Ability of peripapillary atrophy parameters to differentiate normal-tension glaucoma from glaucomalike disk. J Glaucoma 2001;10:95–101. 26. Kono Y, Jonas JB, Zangwill L, et al. Agreement of measurement of parapapillary atrophy with confocal scanning laser
ophthalmoscopy and planimetry of photographs. J Glaucoma 1999;8:105–10. 27. Jonas JB, Nguyen XN, Gusek GC, Naumann GO. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. I. Morphometric data. Invest Ophthalmol Vis Sci 1989;30:908 –18.
Footnotes and Financial Disclosures Originally received: September 25, 2008. Final revision: October 31, 2008. Accepted: December 3, 2008.
The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2008-1158.
Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. Presented at: Association for Research in Vision and Ophthalmology Annual Meeting, May 2006, Fort Lauderdale, Florida. Financial Disclosure(s):
Supported by the Canadian Institutes of Health Research (grant no.: MOP11357 [BCC]), Ottawa, Ontario, Canada. Correspondence: Balwantray C. Chauhan, Department of Ophthalmology and Visual Sciences, Dalhousie University, 2nd Floor Centennial Building, 1278 Tower Road, Halifax, NS, Canada B3H 2Y9. E-mail: [email protected].
847
The hallmarks of glaucomatous progression are visual field deterioration and morphologic changes of the optic disc, including narrowing of the neuroretinal rim accompanied with deepening or widening of the optic cup, or both.1 Understanding the rates and pattern of neuroretinal rim area (NRA) loss may provide an insight into the underlying glaucomatous process and help the clinician in the management of individual patients. Earlier research indicates that the rate of NRA loss in patients with glaucomatous visual field loss, expressed as percentage of baseline NRA, is between ⫺2.1% and ⫺3.5% per year.2,3 Peripapillary atrophy has been associated with glaucoma since the early 1900s.4 The atrophy is more prevalent and more extensive in glaucoma patients compared with healthy nonglaucomatous individuals.5 It is thought that peripapillary atrophy may be of value in identifying those patients at
840
© 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
risk of converting to manifest glaucoma from ocular hypertension6 and those with manifest glaucoma at risk for visual field deterioration.7–9 Relatively little is known about the rate of change of NRA or peripapillary atrophy area (PPAA) in healthy nonglaucomatous individuals, or the contribution of these effects to the acquired neuropathy in glaucoma. Evidence on whether NRA changes with age comes mostly from single or cross-sectional observations10 –13 and has yielded conflicting results. The use of such cross-sectional data to extrapolate the rate of NRA change over time has limitations.13 Actual longitudinal data from a limited number of studies suggest that NRA decreases with age,2,14 although this is not universally accepted.15 The present study had 2 purposes: first, to compare the global and sectoral rates of NRA and PPAA change in ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2008.12.005
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls open-angle glaucoma patients and normal control subjects followed up prospectively with confocal scanning laser tomography (CSLT), and second, to determine the spatial relationship between NRA and PPAA changes.
Patients and Methods
Intraoperator variability in demarking the PPAA was assessed in single optic disc images of a subgroup of 5 glaucoma patients and 5 normal controls chosen randomly. In these 10 images, PPAA was analyzed as described above 5 times on 5 separate days. Global and sectoral NRA and PPAA measurements were exported for analysis. All eyes were converted to right eye format before analysis.
Subjects
Statistical Analysis
Glaucoma patients and normal control subjects participated in a longitudinal, prospective study on visual field and optic disc change. Patients were recruited consecutively from the glaucoma clinics of Capital Health District Authority, Halifax, Nova Scotia, Canada, with the following inclusion criteria: (1) clinical diagnosis of open-angle glaucoma with notching or progressive thinning of the neuroretinal rim, (2) baseline visual field mean deviation between ⫺2 and ⫺10 dB, (3) open angles by gonioscopy, and (4) best-corrected visual acuity of 6/12 or better. Normal control subjects were recruited among spouses of patients and other volunteers with the following inclusion criteria: (1) clinically normal appearance of the optic disc and fundus, (2) intraocular pressure of less than 22 mmHg, and (3) best-corrected visual acuity of 6/12 or better. Common exclusion criteria were: (1) systemic disease or systemic medication known to affect the visual field, (2) refractive error exceeding 5 diopters (D; equivalent sphere) of myopia or hyperopia or 3 D of astigmatism, and (3) contact lens wear. Additionally, patients were excluded if there was concomitant ocular disease, and controls were excluded if there was any ocular disease. One eye was chosen randomly as the study eye for the controls and also for the patients if both eyes were eligible. In accordance with the Declaration of Helsinki, all participants gave informed consent to participate in the study and the protocol was approved by the Capital Health Research Ethics Board.
Rates of global and sectoral NRA and PPAA change were computed for each subject using regression analysis. Rates of change were ranked independently each for NRA and PPAA within the 12 sectors such that the sector with highest decreasing rate of NRA was ranked first and the sector with the highest increasing rate of PPAA was ranked first, and so on. Comparison of spatial patterns of NRA change between patients and controls was performed using the Spearman nonparametric rank-order correlation analysis for corresponding disc sectors. This analysis also was performed for spatial patterns of PPAA change. The spatial concordance between rates of NRA change and PPAA change was calculated as sector rank distance between correspondingly ranked sectors for ranks 1, 2, and 3. For example, if the sector ranked 1 for NRA change was not the same one ranked for PPAA change, but the neighboring one, then the rank distance was 1. The rank distance therefore varied from 0 to 6. Figure 1 illustrates an example of rank distance calculation. Intraoperator variability of PPAA was analyzed with the coefficient of variation. Distributions of group variables were examined for normality using the Kolmogorov Smirnov 1-sample test. Comparisons between glaucoma patients and controls then were made with a group t test if the distributions were normal and the Kolmogorov Smirnov 2-sample test when a nonparametric test had to be used. Categorical variables were compared with the chisquared test. Associations were analyzed using the Pearson correlation coefficient.
Testing Protocol At baseline and every 6 months thereafter, CSLT was performed with the Heidelberg Retina Tomograph I (Heidelberg Engineering GmbH, Heidelberg, Germany). At each session, several images were obtained with the 10° scan angle with the optic disc centered in the image frame. After carefully examining the image quality for evenness in illumination, optic disc centration, and fixation stability, 3 of the best quality images were used to compute the mean topography and reflectance image.
Analysis of Images Images were imported to the Heidelberg Retina Tomograph 3 software (Heidelberg Engineering GmbH) for processing and analysis. The quality of alignment of the longitudinal image series was checked manually with the movie feature of the software, which displays each of the aligned mean serial reflectance or topography images in quick succession. Poor quality and misaligned images (constituting ⬍5% of the images) were removed. A contour line demarking the optic disc boundary was drawn in the baseline image by a single operator (J.L.S.S.) with the aid of conventional stereo disc photographs when necessary. The contour line was imported automatically to the follow-up images for analysis. The total extent of PPAA then was identified and demarcated by the same operator using the custom Atrophy Zone Analysis software16 (Heidelberg Engineering GmbH). The software computed several parameters, including the global and sectoral (12 equal-sized sectors of 30° each) PPAA. To minimize operator bias, the images were processed in random sequence for both subject and examination date.
Results There were 94 glaucoma patients and 54 normal control subjects in the study. The mean baseline age⫾standard deviation was 61.3⫾12.2 years and 54.0⫾12.1 years, respectively, whereas the mean follow-up was 8.6⫾2.9 years and 7.1⫾3.6 years, respectively. The median (interquartile range) baseline visual field mean deviation was ⫺4.86 dB (⫺6.89, ⫺3.56 dB) and ⫺1.05 dB (⫺2.23, ⫺0.32 dB), respectively. Patients were older at baseline and had a longer follow-up and worse baseline mean deviation (P⬍0.010). The mean (⫾standard deviation) baseline and followup intraocular pressure in patients was 18.8 (⫾4.4) mmHg and 17.4 (⫾2.8) mmHg, respectively. The mean coefficient of variation of operator-defined PPAA area was 4.6% in patients and 6.0% in controls. Baseline optic disc parameters and the rates of global NRA and PPAA change are shown in Table 1. These data indicate that although the optic disc area was not significantly different between patients and controls, the baseline NRA was significantly larger in controls. Peripapillary atrophy was present in 86 (91%) patients and 47 (87%) control subjects at baseline. These proportions were not statistically significantly different, although baseline PPAA was significantly larger in patients (Table 1). The rate of NRA change was significantly higher in patients compared with controls (4.2 times higher expressed in square millimeters per year and 6 times higher expressed in percentage of rim area per year); however, there was considerable variation in rates in both groups. The
841
Ophthalmology Volume 116, Number 5, May 2009
Figure 1. Example of the rank distance calculation. The 30° sector with the highest decreasing neuroretinal rim area (NRA; rank ⫽ 1) is also the one with the highest increasing peripapillary atrophy area (PPAA; rank ⫽ 1) area. Hence for rank ⫽ 1, rank distance ⫽ 0. Similarly, for rank ⫽ 2, the rank distance ⫽ 1, and for rank ⫽ 3, rank distance ⫽ 6. I ⫽ inferior; N ⫽ nasal; S ⫽ superior; T ⫽ temporal.
rate of PPAA change was not statistically significantly higher in patients. The rates of global PPAA and NRA change were poorly correlated in both patients and controls (r ⫽ ⫺0.010 and P ⫽ 0.949; and r ⫽ ⫺0.122 and P ⫽ 0.260, respectively; Fig 2). Sectoral analysis showed that the highest rates of NRA change in patients occurred in 2 of the 3 inferior temporal sectors, followed by 2 superior temporal sectors (Fig 3). The pattern of sectoral rate of NRA change in controls was remarkably similar; however, the magnitudes of change were lower (Fig 3). This observation was confirmed by the high rank-order correlation (of sectors ranked from highest to lowest rate of NRA change) between patients and controls (r ⫽ 0.910, P⬍0.001; Fig 4). In contrast, the pattern of PPAA change in patients was more diffuse, with the lowest rates of change occurring nasally (Fig 5). The PPAA changes observed in controls largely were restricted to the temporal hemidisc (Fig 5). Unlike the spatial correlation of NRA area change between patients and controls, a similar analysis of PPAA change showed poorer rank-order correlation (r ⫽ 0.531, P ⫽ 0.075; Fig 4). The rank distance analysis for determining spatial correlation between ranked rates of NRA change and PPAA change showed that the proportion of patients or controls with lower rank distance was not obviously higher (Fig 6). These results indicate that the 30° sectors with the highest rate of NRA change usually were not the sectors where the PPAA change was highest. For example, the sector with the highest rate of NRA change was the same as the one with the highest rate of PPAA area change in only 10 (12%)
patients and 11 (23%) controls. Similar results were noted for the second- and third-ranked sectors.
Case Examples The baseline and final CSLT reflectance images of a glaucoma patient with 8 years of follow-up are shown in Figure 7. There is NRA thinning in the inferior temporal portion of the disc and enlargement of the entire PPAA. The sector with the highest rate of NRA change was not the same as the sector with the highest rate of PPAA change (Fig 7), demonstrating the lack of spatial correlation. The baseline and final CSLT reflectance images of a normal control with 10.5 years of follow-up are also shown in Figure 7. In this case, the sector with the highest rate of NRA area change was the same as the sector with the highest rate of PPAA area change.
Discussion There is a surprising paucity of published reports on the rate of NRA loss in glaucoma patients followed up longitudinally. Most previous studies used planimetry of conventional disc photographs to derive these estimates.2,3,15,14 Zeyen and Caprioli3 and Airkasinen et al2 reported the rate of NRA loss in patients with glaucomatous visual field loss to be ⫺2.1%/year
Table 1. Optic Disc Characteristics* in Glaucoma Patients and Normal Control Subjects
2
Optic disc area (mm ) Baseline neuroretinal rim area (mm2) Baseline vertical cup-to-disc ratio Peripapillary atrophy present, n (%) Baseline peripapillary area (mm2) Rate of neuroretinal rim change (mm2⫻10–3/year) Rate of neuroretinal rim change (%) Rate of peripapillary atrophy area change (mm2⫻10–3/year) *Median (interquartile range). † t test. ‡ Two-sample Kolmogorov Smirnov test. § Chi-square test.
842
Glaucoma Patients
Normal Controls
P Value
2.05 (1.79–2.33) 1.14 (0.89–1.35) 0.6 (0.5–0.7) 86 (91) 0.44 (0.26–0.80) –5.33 (–12.52 to 2.90) –0.42 (–1.26 to 0.29) 12.66 (5.58 to 27.93)
1.92 (1.68–2.24) 1.50 (1.28–1.75) 0.3 (0.0–0.5) 47 (87) 0.29 (0.16–0.80) –1.25 (–5.45 to 0.42) –0.07 (–0.39 to 0.04) 9.43 (5.37–19.20)
0.238† ⬍0.001† ⬍0.001‡ 0.407§ 0.043‡ 0.006‡ 0001‡ 0.173‡
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls
Figure 2. Scatterplots showing the relationship between rates of global peripapillary atrophy area (PPAA) and neuroretinal rim area (NRA) change in (left) glaucoma patients and (right) normal control subjects.
and ⫺3.5%/year, respectively. In ocular hypertensive subjects in whom visual field loss developed, the respective figures vary from ⫺0.95%/year14 to ⫺2.8%/year2 using planimetry and ⫺0.75%/year in one study using CSLT.17 Even less is known about the presumed age-related loss of NRA in normal subjects followed up longitudinally. In 2 published reports, the rate of NRA loss was reported to be ⫺0.23%2 and ⫺0.36%,14 respectively. However, in 1 study there were only 5 subjects2 and in the other,14 photographs were available at only 2 time points, making rate estimates tenuous. To the best of the authors’ knowledge, the present study is the first to report the rate of NRA loss in normal subjects followed up with CSLT. The rate of NRA loss in glaucoma patients in the present study (median, ⫺0.42%/year) is considerably lower than that of previous reports. The reason for this difference is not obvious; however, severity of damage at baseline, follow-up, and treatment among these observational studies likely varied. Because patients in this research were in a prospective study with regular and frequent examinations, it is possible that compliance to treatment was higher and possibly resulted in lower rates of NRA loss. In this study, CLST was used, whereas most previous studies used conventional disc photography. Interestingly, the 1 published rate of NRA loss with CSLT17 also was lower than that of previous reports with disc photography. Finally, rate estimates are largely variable among subjects, yielding highly skewed distributions; hence, depending on the sample size, these point estimates may be influenced differentially by the underlying distributions. In the present study, there were also substantial differences in rates of NRA loss among the disc sectors, with the temporal hemidisc showing the highest rate of NRA loss. The apparently lower rate of NRA loss in the nasal hemidisc could be the result of either a lower susceptibility in this area or a nasal shift of the vessel trunk with cup expansion resulting in less NRA change because blood vessels are not excluded in the calculation of NRA. Although patients had a 7-fold higher rate of global NRA loss compared
with controls, the sectoral pattern of change in these 2 groups of subjects was remarkably similar (Fig 3). The similarity in this pattern was confirmed by a highly statistically significant correlation between patients and controls in the ranked sectors. The rate of age-related NRA loss might have been higher than reported if the controls were not significantly younger than the patients. Age-related loss of NRA probably reflects both loss of retinal ganglion cell axons and optic nerve head structural changes.18 Postmortem studies in nonglaucomatous eyes show an age-related decline in axon counts extrapolated from cross-sectional observations.19 –22 Because of the interindividual variation in baseline axon numbers and the induced statistical errors in extrapolating longitudinal trends from cross-sectional data, estimates of rate of axonal loss vary considerably among the published studies. Whether neuronal loss in the optic nerve is a result of age-related structural changes, or vice versa, is not known. Furthermore, it is not known what proportion of NRA loss is attributable to axonal loss compared with possible nonneuronal structural changes, such as displacement or compression of the laminar and prelaminar tissues. The recent availability of imaging techniques such as spectral domain optical coherence tomography23,24 may allow monitoring of deeper optic nerve structures over time and eventually provide insight into these clinically important questions. It is also plausible that the nonneuronal structural changes in the normal optic nerve head are correlated poorly to axonal loss. The similarity in the pattern of NRA loss in glaucoma patients and normal controls suggests that there may be an age-related pattern of regional susceptibility in the optic nerve comprising neuronal or nonneuronal structural components, or both. In glaucoma, the superimposing pathology may result in an increase in the rate of NRA loss in these susceptible areas. Despite the large variation in the rates of NRA loss among patients and controls, the similarity in the spatial patterns of this change still emerged.
843
Ophthalmology Volume 116, Number 5, May 2009
Figure 3. Rates of sectoral neuroretinal rim area (NRA) change in (left) glaucoma patients and (right) normal control subjects. I ⫽ inferior; N ⫽ nasal; S ⫽ superior; T ⫽ temporal.
Figure 4. Scatterplots showing the correlation between ranked sectors in glaucoma patients and normal control subjects according to rate of (left) neuroretinal rim area (NRA) change and (right) peripapillary atrophy area (PPAA) change. These results indicate that the spatial patterns of NRA change, but not PPAA, among the 2 groups was very similar.
Figure 5. Rates of sectoral peripapillary atrophy area (PPAA) change in (left) glaucoma patients and (right) normal control subjects. I ⫽ inferior; N ⫽ nasal; S ⫽ superior; T ⫽ temporal.
844
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls
Figure 6. Histograms showing the rank distances between sectors ranked 1, 2, and 3 according to rate of neuroretinal rim area (NRA) change and peripapillary atrophy area (PPAA) change. These data indicate that there was little spatial correlation between the sectors showing the highest rates of NRA and PPAA area change in either glaucoma patients or normal control subjects.
The rate of PPAA change was nonsignificantly higher in patients compared with controls. There was a poor relationship between the rates of global NRA change and PPAA change in either group (Fig 2). Furthermore, there was little spatial cor-
relation between the sectors showing the highest rates of NRA and PPAA change. Sectors with the largest PPAA were not the same or even necessarily in the vicinity of sectors with the largest NRA change. Finally, PPAA change seemed to be
Figure 7. Confocal scanning laser reflectivity images obtained at (A) baseline and (B) final examination of the right eye of a glaucoma patient followed up for 9 years showing both neuroretinal rim area (NRA) and peripapillary atrophy area (PPAA) changes. The analysis showed that the sector with the highest decreasing rate of NRA (⫹) was not the same as the sector with the highest increasing rate of PPA (*). In this case, rank distance ⫽ 3. Confocal scanning laser reflectivity images obtained at (C) baseline and (D) final examination of the right eye of a normal control subject followed up for 11 years. The sector with the highest decreasing rate of NRA (⫹) also was the sector with the highest increasing rate of PPAA (*). In this case, rank distance ⫽ 0.
845
Ophthalmology Volume 116, Number 5, May 2009 more diffuse compared with NRA change, with little similarity in the pattern of loss between patients and controls. Rates of PPAA change have not been reported before; however, Uchida et al8 demonstrated that patients with progressive optic disc or visual field loss were more likely to have increasing peripapillary atrophy. These results are not directly comparable with the current results because patients were not segregated into progressing or nonprogressing categories, but rather rates of change were examined. This study also was not designed to address whether an increase in peripapillary atrophy preceded loss of the neuroretinal rim. This study had several limitations. Although CSLT has been validated to describe and quantify PPAA16,25 with good agreement between photographically derived and CLST-derived PPAA estimates,26 no meaningful distinction could be made between the inner peripapillary crescent of visible sclera and choroidal vessels (zone 27) and the outer crescent of irregular hyperpigmentation or hypopigmentation (zone ␣27). It is possible that these morphologically distinct zones of peripapillary atrophy had different relationships with NRA loss and hence masked a stronger relationship between the rates of NRA loss and either zone ␣ or zone  PPAA loss. The relationship between NRA and PPAA change in both magnitude and location might have been influenced by the amount of remaining NRA tissue. For example, low rates of NRA change may be the result of genuinely slow progression or little remaining NRA in which further deterioration is less possible, either globally or sectorially. Unfortunately, there are no obvious analytical techniques to account for this inherent limitation. For these reasons and the large interindividual variation in the rate of NRA change in both patients and controls, the findings of this study should not be used to derive statistical limits for the rate of NRA change in normal controls to drive treatment decisions in individual patients. In summary, this study showed that although, as expected, the rates of both global and sectoral NRA area change were higher in glaucoma patients compared with those of control subjects, the sectoral pattern of loss was remarkably similar. These findings indicate an age-related regional susceptibility that may be accelerated in glaucoma. The magnitude and location of PPAA change was correlated poorly to NRA change in both patients and controls, suggesting that the mechanisms governing the temporal dynamics of PPAA change may be different to those of NRA change.
5. 6.
7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17.
18.
19. 20. 21.
References 22. 1. Pederson JE, Anderson DR. The mode of progressive disc cupping in ocular hypertension and glaucoma. Arch Ophthalmol 1980;98:490 –5. 2. Airaksinen PJ, Tuulonen A, Alanko HI. Rate and pattern of neuroretinal rim area decrease in ocular hypertension and glaucoma. Arch Ophthalmol 1992;110:206 –10. 3. Zeyen TG, Caprioli J. Progression of disc and field damage in early glaucoma. Arch Ophthalmol 1993;111:62–5. 4. Airaksinen PJ, Tuulonen A, Werner EB. Clinical evaluation of the optic disc and retinal nerve fiber layer. In: Ritch R, Shields
846
23.
24.
MB, Krupin T, eds. The Glaucomas. vol. 1. St. Louis, MO: Mosby; 1996:617–57. Jonas JB. Clinical implications of peripapillary atrophy in glaucoma. Curr Opin Ophthalmol 2005;16:84 – 8. Tezel G, Kolker AE, Kass MA, et al. Parapapillary chorioretinal atrophy in patients with ocular hypertension. I. An evaluation as a predictive factor for the development of glaucomatous damage. Arch Ophthalmol 1997;115:1503– 8. Araie M, Sekine M, Suzuki Y, Koseki N. Factors contributing to the progression of visual field damage in eyes with normaltension glaucoma. Ophthalmology 1994;101:1440 – 4. Uchida H, Ugurlu S, Caprioli J. Increasing peripapillary atrophy is associated with progressive glaucoma. Ophthalmology 1998;105:1541–5. Jonas JB, Martus P, Horn FK, et al. Predictive factors of the optic nerve head for development or progression of glaucomatous visual field loss. Invest Ophthalmol Vis Sci 2004;45:2613–8. Britton RJ, Drance SM, Schulzer M, et al. The area of the neuroretinal rim of the optic nerve in normal eyes. Am J Ophthalmol 1987;103:497–504. Jonas JB, Gusek GC, Guggenmoos-Holzmann I, Naumann GO. Correlations of the neuroretinal rim area with ocular and general parameters in normal eyes. Ophthalmic Res 1988;20:298–303. Tsai CS, Ritch R, Shin DH, et al. Age-related decline of disc rim area in visually normal subjects. Ophthalmology 1992;99:29 –35. Garway-Heath DF, Wollstein G, Hitchings RA. Aging changes of the optic nerve head in relation to open angle glaucoma. Br J Ophthalmol 1997;81:840 –5. Laemmer R, Schroeder S, Martus P, et al. Quantification of neuroretinal rim loss using digital planimetry in long-term follow-up of normals and patients with ocular hypertension. J Glaucoma 2007;16:430 – 6. Moya FJ, Brigatti L, Caprioli J. Effect of aging on optic nerve appearance: a longitudinal study. Br J Ophthalmol 1999;83:567–72. Park KH, Tomita G, Liou SY, Kitazawa Y. Correlation between peripapillary atrophy and optic nerve damage in normal-tension glaucoma. Ophthalmology 1996;103:1899 –906. Owen VM, Strouthidis NG, Garway-Heath DF, Crabb DP. Measurement variability in Heidelberg Retina Tomograph imaging of neuroretinal rim area. Invest Ophthalmol Vis Sci 2006;47:5322–30. 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; 17:318 –28. Balazsi AG, Rootman J, Drance SM, et al. The effect of age on the nerve fiber population of the human optic nerve. Am J Ophthalmol 1984;97:760 – 6. Mikelberg FS, Drance SM, Schulzer M, et al. The normal human optic nerve: axon count and axon diameter distribution. Ophthalmology 1989;96:1325– 8. Repka MX, Quigley HA. The effect of age on normal human optic nerve fiber number and diameter. Ophthalmology 1989; 96:26 –32. Jonas JB, Muller-Bergh JA, Schlotzer-Schrehardt UM, Naumann GO. Histomorphometry of the human optic nerve. Invest Ophthalmol Vis Sci 1990;31:736 – 44. Srinivasan VJ, Adler DC, Chen Y, et al. Ultrahigh-speed optical coherence tomography for three-dimensional and en face imaging of the retina and optic nerve head. Invest Ophthalmol Vis Sci 2008;49:5103–10. Kagemann L, Ishikawa H, Wollstein G, et al. Ultrahighresolution spectral domain optical coherence tomography imaging of the lamina cribrosa. Ophthalmic Surg Lasers Imaging 2008;39(suppl):S126 –31.
See et al 䡠 Optic Disc Changes in Glaucoma Patients and Normal Controls 25. Park KH, Park SJ, Lee YJ, et al. Ability of peripapillary atrophy parameters to differentiate normal-tension glaucoma from glaucomalike disk. J Glaucoma 2001;10:95–101. 26. Kono Y, Jonas JB, Zangwill L, et al. Agreement of measurement of parapapillary atrophy with confocal scanning laser
ophthalmoscopy and planimetry of photographs. J Glaucoma 1999;8:105–10. 27. Jonas JB, Nguyen XN, Gusek GC, Naumann GO. Parapapillary chorioretinal atrophy in normal and glaucoma eyes. I. Morphometric data. Invest Ophthalmol Vis Sci 1989;30:908 –18.
Footnotes and Financial Disclosures Originally received: September 25, 2008. Final revision: October 31, 2008. Accepted: December 3, 2008.
The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2008-1158.
Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada. Presented at: Association for Research in Vision and Ophthalmology Annual Meeting, May 2006, Fort Lauderdale, Florida. Financial Disclosure(s):
Supported by the Canadian Institutes of Health Research (grant no.: MOP11357 [BCC]), Ottawa, Ontario, Canada. Correspondence: Balwantray C. Chauhan, Department of Ophthalmology and Visual Sciences, Dalhousie University, 2nd Floor Centennial Building, 1278 Tower Road, Halifax, NS, Canada B3H 2Y9. E-mail: [email protected].
847