February 2011
Volume 52, Issue 2
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Glaucoma  |   February 2011
Trend-Based Analysis of Retinal Nerve Fiber Layer Thickness Measured by Optical Coherence Tomography in Eyes with Localized Nerve Fiber Layer Defects
Author Affiliations & Notes
  • Eun Ji Lee
    From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea;
    the Seoul National University Bundang Hospital, Seongnam, Korea;
  • Tae-Woo Kim
    From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea;
    the Seoul National University Bundang Hospital, Seongnam, Korea;
  • Robert N. Weinreb
    the Hamilton Glaucoma Center and Department of Ophthalmology, University of California San Diego, La Jolla, California; and
  • Ki Ho Park
    From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea;
  • Seok Hwan Kim
    From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea;
    the Seoul National University Boramae Hospital, Seoul, Korea.
  • Dong Myung Kim
    From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea;
  • 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 463-707, Korea; twkim7@snu.ac.kr
Investigative Ophthalmology & Visual Science February 2011, Vol.52, 1138-1144. doi:10.1167/iovs.10-5975
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      Eun Ji Lee, Tae-Woo Kim, Robert N. Weinreb, Ki Ho Park, Seok Hwan Kim, Dong Myung Kim; Trend-Based 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(2):1138-1144. doi: 10.1167/iovs.10-5975.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To evaluate the rate of change in retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) in eyes with stable and progressive localized RNFL defects and to investigate, in a trend-based approach, the diagnostic capability of OCT in the detection of progressive RNFL thinning.

Methods.: The study included 153 glaucomatous eyes with localized RNFL defects. The patients were divided into nonprogressors (n = 77) and progressors (n = 76) on the basis of an evaluation of serial red-free photographs. The rates of progressive thinning in global, quadrant, and clock-hour OCT RNFL thicknesses were determined, by linear regression, and were compared between groups. Areas under receiver operating characteristic curves and sensitivities at fixed specificities were calculated for each parameter.

Results.: The rate of progressive RNFL thinning was significantly faster in progressors than in nonprogressors globally; in the inferior quadrant; in the 10, 11, 6, and 7 o'clock sectors; and in the affected quadrant and clock-hour sector thicknesses (all P ≤ 0.001). The rate of RNFL thinning in affected clock-hour sectors had the highest ability to discriminate between stable and progressive RNFL thinning with a sensitivity of 62% (95% confidence interval, 50%–73%) at a specificity ≥80%. Agreement between OCT and red-free photography was strongest when the criterion of −3.6 μm/year with P < 0.1 was used for each clock hour.

Conclusions.: The rate of OCT RNFL thinning was significantly greater in patients with progressive localized RNFL defects than in those with stable localized defects. The data suggest that trend-based analysis of OCT RNFL thickness may be useful in glaucoma progression analysis and may complement other diagnostic tests.

Monitoring of glaucoma progression is essential in glaucoma management. To date, such monitoring has been principally conducted with standard automated perimetry (SAP) and optic disc examination. 
Recently, several investigators have shown that serial evaluation of retinal nerve fiber layer (RNFL) thickness, as measured by optical coherence tomography (OCT), may be useful in detection of glaucoma progression. Wollstein et al. 1 studied RNFL progression in an event-based approach, using a prototype OCT. When progression was defined as thinning of global RNFL thickness by at least 20 μm, OCT was more effective in detection of glaucomatous progression than was SAP. We have previously shown that the Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA) detects progressive RNFL atrophy with high sensitivity and moderate specificity in patients who show localized progressive loss of retinal nerve fibers in red-free fundus photographs, using criteria derived from test–retest variability. 2  
Recently, a new RNFL progression analysis algorithm, termed guided progression analysis (GPA), has been incorporated into Stratus OCT software (ver. 5.0; Carl Zeiss Meditec, Inc.). GPA employs trend-based analysis, and progression is evaluated and reported as a change over time, according to serial RNFL measurements. Leung et al. 3 demonstrated that OCT GPA was able to detect progressive RNFL loss and permitted the rate of change of RNFL thickness to be measured in glaucoma patients. 
The purpose of the present study was to evaluate the rate of change in RNFL thickness, as measured by OCT, in eyes with either stable or progressive localized RNFL defects, and, in a trend-based approach, to investigate the diagnostic capability of OCT in the detection of progressive RNFL thinning observed by red-free fundus photography. 
Methods
This investigation was a retrospective analysis of serial red-free fundus photographs and OCT printouts. The study was approved by the Seoul National University Bundang Hospital Institutional Review Board and conformed to the principles of the Declaration of Helsinki. 
Study Subjects
The patient database of Seoul National University Bundang Hospital was screened for patients with glaucoma who visited our glaucoma clinic between June 2008 and January 2010, and the latest red-free fundus photographs of such patients were reviewed. Patients with localized RNFL atrophy clearly visible on the latest red-free fundus photographs and who had been evaluated by at least four serial OCT measurements (of which the first and last measurements were separated by at least 3 years) were consecutively enrolled. All red-free fundus photographs and OCT scans had been obtained within an interval of 1 month on each occasion. 
Before the study, each patient underwent a complete ophthalmic examination, including measurement of visual acuity and refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, and dilated stereoscopic examination of the optic disc. Each patient was also evaluated by red-free fundus photography, OCT, and SAP (Humphrey Field Analyzer II 750; 24-2 Swedish interactive threshold algorithm; Carl Zeiss Meditec, Inc.). 
An eye was excluded if there was concurrent diffuse atrophy or ambiguity regarding the coexistence of diffuse atrophy on the latest red-free fundus photograph, based on evaluations made by two independent observers (EJL and TWK) masked to the patient's clinical information, including OCT data. When either observer flagged concurrent diffuse atrophy or there was ambiguity in that respect, the eye was excluded. This examination was performed to increase the probability that progressors were effectively discriminated from nonprogressors by red-free fundus photography. Unlike what is possible when defects are localized, it is often difficult to clearly define the borders of diffuse atrophy in red-free fundus photography, 4 which may cause problems when defect expansion is to be measured. 
Patients were also excluded if they had a best corrected visual acuity worse than 20/40; spherical refraction greater than ± 5.0 D or cylinder correction greater than ± 3.0 D; a history of any retinal disease, neurologic diseases, ocular surgery or laser procedures; or a disease that could affect the peripapillary area where OCT measurements were obtained. A history of cataract extraction before baseline examination was not an exclusion criterion, but patients from whom cataracts were extracted during the study period were excluded. If both eyes of a patient were eligible for the study, only one eye was randomly chosen for inclusion. 
For the purpose of the present study, patients were divided into groups on the basis of an evaluation of red-free fundus photographs: a stable group in whom RNFL defects showed no change during follow-up (nonprogressors) and a progressive group in whom RNFL change was observed over the study period (progressors). 
Red-Free Fundus Photography
Progression was determined primarily by evaluation of red-free fundus photographs, which were taken with a digital camera (EOS D60; Canon, Utsunomiyashi, Tochigiken, Japan) after maximum pupil dilation. Sixty-degree, wide-angle optic disc photographs, centered between the superior and inferior RNFL regions, were obtained and reviewed on an LCD monitor. Localized RNFL defects were identified when the defect width at a position one disc diameter distant from the disc edge was larger than that of a major retinal vessel; an arcuate- or wedge-shaped divergence was evident; and/or the defect attained the disc edge. 5  
Serial red-free fundus photographs of included patient eyes were collected and evaluated by two observers (EJL and TWK). Each observer classified each eye into one of three categories: nonprogressor, progressor, and ambiguous. Eyes classified as ambiguous were sometimes poorly imaged or showed changes that were too subtle to be considered as accurately reflecting progression, which was defined as clear widening of preexisting localized defect borders on red-free fundus photography, or development of a new localized defect. If no change was found in the width of a localized defect during follow-up, the eye was considered to be a nonprogressor. If progressive widening of a defect was seen at any follow-up visit, the eye was classified as a progressor. Any discrepancy between observers was resolved by consensus. 
The two observers also recorded the locations of RNFL defects in the red-free fundus photographs in which the defects were first evident, to allow topographic comparison with OCT RNFL thickness change data. In this assessment, the directional angle of the RNFL defect was measured in a manner that allowed alignment of OCT images with photographs. The method has been described in detail elsewhere. 2,6 Briefly, a clock-face circle was drawn around the optic nerve head on the red-free fundus photograph, and the diameter and location of the circle corresponded as closely as possible to those of the circle displayed in the video mode of the RNFL thickness analysis report (Fig. 1). The two points where the borders of a defect met the circle were next identified, and the clock-hour location of the defect was determined. Clock hours were numbered clockwise for right eyes and counterclockwise for left eyes. The quadrant or clock-hour with a localized defect was defined as the affected quadrant or the affected clock hour. 
Figure 1.
 
Determination of clock-hour location of a localized defect as seen on red-free fundus photography. A clock-face circle was placed around the optic nerve head. The circle location and diameter corresponded as closely as possible to those of the circle displayed in the video mode of the Stratus OCT RNFL thickness analysis report (inset) (Carl Zeiss Meditec, Inc., Dublin, CA). The clock-hour location of the localized defect (arrowheads) was then determined. The defect was located in the 7 o'clock sector in this patient.
Figure 1.
 
Determination of clock-hour location of a localized defect as seen on red-free fundus photography. A clock-face circle was placed around the optic nerve head. The circle location and diameter corresponded as closely as possible to those of the circle displayed in the video mode of the Stratus OCT RNFL thickness analysis report (inset) (Carl Zeiss Meditec, Inc., Dublin, CA). The clock-hour location of the localized defect (arrowheads) was then determined. The defect was located in the 7 o'clock sector in this patient.
Optical Coherence Tomography
Subjects were assessed by using the peripapillary Fast RNFL program of the 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 tests. The imaging lens was positioned 1 cm from the eye to be examined and adjusted independently until the retina came into focus. The internal fixation target was used because it offers greater reproducibility. 7 An image was defined as satisfactory if good centration on the optic disc was apparent, and the signal strength was ≥6 (maximum, 10). 8 10 Data were analyzed with the version 5.0 software. With the Fast RNFL program, RNFL thickness was determined three times at each of 256 points at a set diameter (3.4 mm) around the center of the optic disc, during a single scan. These values were averaged to yield 12 clock-hour thicknesses, four quadrant thicknesses, and a global (360°) RNFL thickness measurement. 
Data Analysis
Interobserver agreement in discrimination of progressors from nonprogressors was evaluated with the κ statistic. Scores ≥0.75, between 0.40 and 0.75, and ≤0.4 were considered excellent, fair-to-good, and poor, respectively. 11 Linear regression of RNFL thickness over time was performed for global thickness, all quadrant thicknesses, and all clock-hour thicknesses, in each subject. The slope of each regression equation represented the rate of change of RNFL thickness. When multiple sectors were affected, the quadrant or clock-hour sector showing the fastest rate of progressive thinning was designated the affected quadrant or clock-hour. 
The ability of individual trend-based analysis of various OCT parameters to differentiate progressive from stable eyes was assessed with receiver operating characteristic curves and by calculation of sensitivities at fixed specificities. Raw data were subjected to Bonferroni correction on the basis of the number of comparisons within each analysis (SPSS 17 software; SPSS, Inc., Chicago, IL). 
Results
The study involved 583 subjects who had been examined on at least four occasions by OCT and red-free fundus photography. Of these, 315 showed localized RNFL atrophy on their latest red-free fundus photographs and were initially enrolled. However, 32 patients were excluded because of concurrent diffuse atrophy (n = 15) or ambiguity regarding the coexistence of diffuse atrophy (n = 17). 
Of the remaining 283 subjects, 127 were excluded because of refractive errors exceeding the exclusion criterion (n = 22), a history of retinal or neurologic disease (n = 32), a history of intraocular surgery (including cataract extraction) during the follow-up period (n = 46), a large peripapillary atrophy (n = 7), or an unacceptable OCT scan (n = 20). Of the remaining 156 patients, 3 were further excluded because of difficulty in determining progressive change by red-free fundus photography. Thus, 153 eyes of 153 subjects were finally enrolled (147 patients had open-angle and 6 angle-closure glaucoma). 
Of these, 77 subjects were classified as nonprogressors and 76 as progressors, based on evaluation of serial red-free fundus photographs. Interobserver agreement in discriminating progressors from nonprogressors was excellent (κ = 0.895). In three patients, no RNFL defect was observed at baseline. In the remaining 150 patients, RNFL defects were evident on the first red-free fundus photographs. 
The baseline demographics of all patients are shown in Table 1. There were no differences between the two groups in age (60.1 ± 10.7 vs. 59.2 ± 13.6 years), refractive error, mean deviation (MD), pattern standard deviation (PSD), or baseline average RNFL thickness. The average number of OCT scans, the mean interval between scans, and follow-up duration, were also similar in the two groups (P > 0.05). Figure 2 shows the frequency distribution of clock-hour sectors in which localized defects were identified by red-free fundus photography (the affected clock-hour sectors). Of the 153 eyes, 106 had single defects (of which 45 involved multiple clock-hour sectors), 44 had two defects (29 defects involved multiple clock-hour sectors), and 3 had three or more defects (two defects involved multiple clock-hour sectors). RNFL defects were most commonly identified in the 7 and 11 o'clock sectors. 
Table 1.
 
Clinical Demographics
Table 1.
 
Clinical Demographics
Nonprogressors (n = 77) Progressors (n = 76) P
Sex, female/male 38/39 46/30 0.165*
Age, y 60.1 ± 10.7 59.2 ± 13.6 0.658†
Spherical error, D −0.65 ± 2.60 −1.25 ± 2.76 0.177†
Baseline MD, dB −3.71 ± 4.60 −3.27 ± 3.84 0.523†
Baseline PSD, dB 5.33 ± 4.54 5.63 ± 4.31 0.679†
Baseline average RNFL thickness, μm 91.93 ± 15.06 89.07 ± 12.24 0.199†
Average number of OCT scans per eye, n 4.4 ± 0.8 4.5 ± 0.8 0.500†
Mean interval between OCT scans, mo 10.9 ± 2.2 10.5 ± 1.7 0.343†
Mean follow-up duration, y 3.9 ± 0.8 3.9 ± 0.8 0.919†
Figure 2.
 
Frequency distribution of defects by clock-hour sector. Localized defects were identified in 153 study subjects by red-free fundus photography.
Figure 2.
 
Frequency distribution of defects by clock-hour sector. Localized defects were identified in 153 study subjects by red-free fundus photography.
Table 2 and Figure 3 compare the rates of RNFL thinning and the area under the receiver operating characteristic curve (AUROC) for discrimination between nonprogressors and progressors. The rate of progressive RNFL thinning was significantly faster in progressors than in nonprogressors globally; in the inferior quadrant; in the 10, 11, 6, and 7 o'clock sectors; and in the affected quadrant and clock-hour sector thicknesses (all P < 0.0026; corrected for multiple comparisons, 0.05/19). The best parameter of Stratus OCT trend analysis discriminating between nonprogressors and progressors was the rate of change in affected clock-hour thickness (sensitivity of 62% at a specificity of 80%, AUROC = 0.78). The rate of change in affected quadrant thickness was the second-best parameter, with a sensitivity of 52% at a specificity of 80% (AUROC = 0.76). 
Table 2.
 
Comparison of the Rates of RNFL Thickness Change, with AUROC Values and Sensitivities at Fixed Specificities, When Used to Discriminate between Nonprogressors and Progressors
Table 2.
 
Comparison of the Rates of RNFL Thickness Change, with AUROC Values and Sensitivities at Fixed Specificities, When Used to Discriminate between Nonprogressors and Progressors
Location Rate of RNFL Thickness Change (μm/y) P * AUROC† Sensitivity at ≥95% Specificity (%)† Sensitivity at ≥80% Specificity (%)†
Nonprogressors (n = 77) Progressors (n = 76)
Global −0.34 ± 1.41 −1.58 ± 2.24 <0.001 0.68 (0.60–0.77) 6 (2–15) 32 (22–44)
Temporal quadrant 0.01 ± 1.87 −0.97 ± 2.40 0.005 0.62 (0.53–0.71) 9 (4–18) 22 (13–34)
Superior quadrant −0.38 ± 2.45 −1.75 ± 3.13 0.003 0.64 (0.55–0.73) 9 (4–18) 29 (19–40)
Nasal quadrant −0.54 ± 3.34 −0.66 ± 3.64 0.838 0.50 (0.41–0.60) 5 (1–13) 21 (12–32)
Inferior quadrant −0.44 ± 2.16 −2.76 ± 2.91 <0.001 0.74 (0.66–0.82) 16 (8–26) 45 (34–57)
Affected quadrant‡ −1.02 ± 1.83 −3.26 ± 2.69 <0.001 0.76 (0.68–0.83) 13 (6–23) 52 (40–64)
9 o'clock 0.22 ± 2.14 −0.21 ± 2.53 0.262 0.55 (0.46–0.64) 6 (2–15) 25 (16–36)
10 o'clock −0.25 ± 2.51 −1.61 ± 2.64 0.001 0.64 (0.55–0.73) 13 (6–23) 38 (27–50)
11 o'clock −0.21 ± 3.22 −2.99 ± 4.33 <0.001 0.71 (0.63–0.80) 8 (3–16) 48 (37–60)
12 o'clock −0.16 ± 2.72 −1.66 ± 3.69 0.005 0.62 (0.54–0.71) 5 (1–13) 29 (19–40)
1 o'clock −0.86 ± 3.63 −1.05 ± 4.33 0.774 0.50 (0.41–0.59) 5 (2–13) 14 (8–24)
2 o'clock −1.14 ± 4.07 −0.21 ± 4.54 0.184 0.45 (0.36–0.55) 0 (0–5) 7 (2–15)
3 o'clock −0.36 ± 3.59 −1.10 ± 4.08 0.235 0.55 (0.46–0.64) 5 (1–13) 31 (21–43)
4 o'clock −0.22 ± 3.77 −0.99 ± 3.99 0.221 0.56 (0.47–0.65) 12 (5–21) 19 (11–30)
5 o'clock −0.81 ± 3.28 −1.96 ± 3.64 0.042 0.59 (0.50–0.68) 4 (1–11) 36 (26–48)
6 o'clock −0.58 ± 2.94 −2.82 ± 3.56 <0.001 0.68 (0.60–0.77) 12 (6–21) 36 (26–48)
7 o'clock 0.03 ± 3.27 −3.71 ± 4.39 <0.001 0.75 (0.67–0.83) 30 (20–41) 51 (39–62)
8 o'clock 0.13 ± 2.24 −0.98 ± 3.07 0.012 0.61 (0.52–0.70) 6 (2–15) 29 (19–40)
Affected clock-hour§ −1.41 ± 2.82 −5.08 ± 3.79 <0.001 0.78 (0.71–0.86) 18 (10–29) 62 (51–73)
Figure 3.
 
Comparison of the rate of RNFL thickness change determined by Stratus OCT for each OCT clock-hour sector. Progressors showed a faster rate of OCT-assessed RNFL deterioration in the 10, 11, 6, and 7 o'clock sectors (shown with asterisks), compared with nonprogressors, and the 7 o'clock sector showed the most significant difference. Error bar, ±1 SD.
Figure 3.
 
Comparison of the rate of RNFL thickness change determined by Stratus OCT for each OCT clock-hour sector. Progressors showed a faster rate of OCT-assessed RNFL deterioration in the 10, 11, 6, and 7 o'clock sectors (shown with asterisks), compared with nonprogressors, and the 7 o'clock sector showed the most significant difference. Error bar, ±1 SD.
The frequency distribution of the global RNFL change rate in nonprogressors and progressors is shown in Figure 4. In progressors, negative slopes were more often evident than was the case for nonprogressors (P = 0.008). 
Figure 4.
 
Histograms showing the global rates of RNFL change in nonprogressors and progressors.
Figure 4.
 
Histograms showing the global rates of RNFL change in nonprogressors and progressors.
The frequency distribution of clock-hour RNFL measurements showing a significant negative trend (progression) or a positive trend (improvement) is shown in Figure 5
Figure 5.
 
Frequency distribution of clock-hour RNFL measurements showing a significant negative (progression) or positive trend (improvement).
Figure 5.
 
Frequency distribution of clock-hour RNFL measurements showing a significant negative (progression) or positive trend (improvement).
In addition to sensitivity at a fixed specificity, the agreement between OCT trend-based analysis and the grading of each observer was tested, using the parameter which showed the best sensitivity at fixed specificity (i.e., the rate of RNFL thinning at any clock-hour). In this analysis, −3.6 μm/year with P < 0.1 was chosen as a cutoff. The evaluations of both observers were in fair to good agreement with the OCT data (κ = 0.48 and 0.46). 
Figure 6 shows serial red-free fundus photographs of a progressor and linear regression graphs for global thickness and the two thickness measures with the highest AUROC values (affected clock-hour and affected quadrant thickness). 
Figure 6.
 
Serial red-free fundus photographs (AD) of a progressor; overlay of serial RNFL thickness profiles (E); and linear regression graphs of global (F), affected quadrant (G), and affected clock-hour (H) thickness with age. The RNFL defects shown in both the superotemporal and inferotemporal quadrants displayed progressive change. Arrowheads: The defect borders which have expanded compared with prior examination are indicated. In this patient, the inferior quadrant and the 7 o'clock sector were considered to be the affected quadrant and the affected clock-hour sector, respectively, as these areas showed the fastest rate of thinning of the several affected quadrants and clock-hour sectors.
Figure 6.
 
Serial red-free fundus photographs (AD) of a progressor; overlay of serial RNFL thickness profiles (E); and linear regression graphs of global (F), affected quadrant (G), and affected clock-hour (H) thickness with age. The RNFL defects shown in both the superotemporal and inferotemporal quadrants displayed progressive change. Arrowheads: The defect borders which have expanded compared with prior examination are indicated. In this patient, the inferior quadrant and the 7 o'clock sector were considered to be the affected quadrant and the affected clock-hour sector, respectively, as these areas showed the fastest rate of thinning of the several affected quadrants and clock-hour sectors.
Discussion
Our results demonstrate that eyes showing progression of localized RNFL defects, as assessed by red-free fundus photography, had significantly higher rates of RNFL loss over time, as measured by OCT trend-based analysis, than did eyes that remained stable. 
The results of the present study are consistent with previous work that evaluated trend-based progression analysis of OCT RNFL thickness. Medeiros et al. 12 reported that serial analysis of Stratus OCT RNFL parameters served to discriminate eyes that progressed, as assessed by visual field evaluation or optic disc photography, from eyes that remained stable. Leung et al. 3 evaluated the OCT GPA program and suggested that the modality was a useful new contribution to glaucoma progression analysis. 
In progressors, the fastest rate of RNFL thinning was observed in affected clock hours. This may reflect the widening of a very early defect less than 1 clock hour in width and/or the deepening of an existing defect, and it fits our criteria for progression which included expansion of a localized defect. The good topographic correspondence between trend-based analysis of OCT-measured RNFL thickness and red-free fundus photography validates the ability of OCT to detect progressive changes in localized RNFL defects. In addition, it is worth noting that progressive defect widening was rare in both the nasal (between 1 and 5 o'clock) and the temporal (8 and 9 o'clock) sectors. In these regions, between-group differences in the rates change in RNFL thickness were not significant. This finding is in agreement with the observation that glaucoma patients retain temporal or central visual fields until the end stage of the disease. 13  
In the present study, the rates of RNFL thinning in particular clock hours or quadrants were more useful than was the rate of global thickness change in discriminating progressors from nonprogressors. This result indicates that localized RNFL loss may not always cause a detectable change in global RNFL thickness, and the data agree with the observations of Leung et al., 3 to the effect that analysis of both global and sector RNFL thicknesses (quadrant and clock-hour thicknesses) is important. 
We used red-free fundus photography as the reference standard to determine progression. It is common to define progression using visual field tests or stereo disc photographs when studying glaucoma progression. However, these methods have recognized limitations. The former technique yields highly variable results and has low agreement with structural progression. 1,12,14 Stereo disc photography suffers from low interobserver agreement (κ = 0.20). 15 In contrast, both red-free fundus photography and OCT evaluate the same anatomic structure, the RNFL. Further, it is known that RNFL loss can, but does not always, precede measurable optic nerve head and visual field damage in glaucoma patients. 16 19 Thus, red-free fundus photography is a useful standard by which to evaluate the performance of OCT used to detect glaucoma progression, although this technique may not be entirely appropriate (discussed later). Finally, interobserver agreement on progressors and nonprogressors, based on evaluation of red-free fundus photographs, was excellent in our present study. 
Progression of an RNFL defect was defined as widening of a preexisting defect or development of a new defect. However, it is possible that progressive changes occur in a different manner (i.e., by deepening of an existing defect). As it is difficult to accurately detect this type of progression with red-free fundus photography, we used only defect widening or appearance of a new defect as criteria for progression. This method may lower the apparent specificity of OCT. It is possible that deepening of existing defects occurred in eyes classified as nonprogressors. Indeed, nonprogressors show a decline in Stratus OCT measurements over time, with a faster rate of global RNFL thickness deterioration (−0.34 ± 1.41 μm/year) than the known age-related RNFL change in the normal population (−0.16 to −0.20 μm/year). 20,21 Stratus OCT can detect this degree of progression. At present, this possibility cannot be tested, because no reference standard is available that can be used to definitively indicate progressive glaucomatous structural change. 2 A prospective longitudinal study is needed to explore this question. 
The agreement between OCT trend-based analysis and the grading of each observer was fair to good (κ = 0.48 and 0.46). The rather low agreement may be explained in two ways. Although the statistics may suggest that OCT trend-based analysis is less than excellent when used to detect progression of localized RNFL defects, it is also possible that some proportion of the disagreement between the two diagnostic modalities is attributable to the ability of OCT to detect progressive changes that are not seen in red-free fundus photographs, as discussed earlier. 
When intertest agreement was analyzed, −3.6 μm/year with P < 0.1 was chosen as a cutoff value. This choice was based on repeated trials. Using this criterion, the best agreement was obtained. These data suggest that both rate and statistical significance are important when diagnosing progressive RNFL thinning using OCT trend-based analysis. When P < 0.05 was chosen as a cutoff, agreement was poor, because of a low progressor detection rate, suggesting that such a criterion is too strict when linear regression analysis based on four to five measurements is performed. 
Because of the study design, our data on the ability of OCT trend analysis to predict progression are valid only for eyes with localized defects, and the utility of such trend analysis in eyes with diffuse atrophy remains to be determined. However, we recently reported an excellent quantitative correlation between OCT RNFL thickness and the extent of diffuse RNFL atrophy. 22 This result suggests that trend-based analysis using OCT may also be valuable in eyes with diffuse atrophy, although a further study, longitudinal in design, is needed to assess the true performance of OCT trend analysis when used to predict progression of diffuse atrophy. 
It is known that measures of the rate of deterioration may be influenced by baseline RNFL thickness or signal strength at each examination. 3 Thus, it would be ideal if calculated rates of deterioration could be adjusted to consider such factors. However, the current version of OCT GPA does not include such refinements. Further work is needed to evaluate whether OCT trend analysis adjusted for potential confounding variables might increase the detection reliability of glaucoma progression. 
Interestingly, no difference in baseline RNFL thickness between progressors and nonprogressors was evident 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 true in all circumstances. For example, Leung et al. 3 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 early-stage glaucoma patients, whereas the reverse is true when the disease is more advanced. 23,24 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. Our data suggest that the rate of RNFL thinning is not associated with baseline RNFL thickness in the early stages of glaucoma. 
A limitation of our present study is that we used time-domain OCT (TD-OCT), which is rapidly being supplanted by spectral-domain OCT (SD-OCT). As SD-OCT scans are more reproducible than are those of TD-OCT, 23 it may be expected that SD-OCT will better discriminate between progressive and stable eyes. However, evaluation of the usefulness of the trend-based analysis using SD-OCT may not become available for several years. 
In conclusion, the rate of OCT RNFL thinning was significantly greater in patients with progressive localized RNFL defects observed by red-free fundus photography than in those with stable localized defects. These data suggest that trend-based analysis of OCT RNFL thickness has the potential to be useful in evaluating glaucoma progression and that such an approach may complement other diagnostic modalities. 
Footnotes
 Supported by a grant from the Seoul National University Bundang Hospital Research Fund. The funding organization had no role in the design or conduct of this research.
Footnotes
 Disclosure: E.J. Lee, None; T.-W. Kim, None; R.N. Weinreb, Carl Zeiss Meditec, Inc. (F, C); K.H. Park, None; S.H. Kim, None; D.M. Kim, None
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Figure 1.
 
Determination of clock-hour location of a localized defect as seen on red-free fundus photography. A clock-face circle was placed around the optic nerve head. The circle location and diameter corresponded as closely as possible to those of the circle displayed in the video mode of the Stratus OCT RNFL thickness analysis report (inset) (Carl Zeiss Meditec, Inc., Dublin, CA). The clock-hour location of the localized defect (arrowheads) was then determined. The defect was located in the 7 o'clock sector in this patient.
Figure 1.
 
Determination of clock-hour location of a localized defect as seen on red-free fundus photography. A clock-face circle was placed around the optic nerve head. The circle location and diameter corresponded as closely as possible to those of the circle displayed in the video mode of the Stratus OCT RNFL thickness analysis report (inset) (Carl Zeiss Meditec, Inc., Dublin, CA). The clock-hour location of the localized defect (arrowheads) was then determined. The defect was located in the 7 o'clock sector in this patient.
Figure 2.
 
Frequency distribution of defects by clock-hour sector. Localized defects were identified in 153 study subjects by red-free fundus photography.
Figure 2.
 
Frequency distribution of defects by clock-hour sector. Localized defects were identified in 153 study subjects by red-free fundus photography.
Figure 3.
 
Comparison of the rate of RNFL thickness change determined by Stratus OCT for each OCT clock-hour sector. Progressors showed a faster rate of OCT-assessed RNFL deterioration in the 10, 11, 6, and 7 o'clock sectors (shown with asterisks), compared with nonprogressors, and the 7 o'clock sector showed the most significant difference. Error bar, ±1 SD.
Figure 3.
 
Comparison of the rate of RNFL thickness change determined by Stratus OCT for each OCT clock-hour sector. Progressors showed a faster rate of OCT-assessed RNFL deterioration in the 10, 11, 6, and 7 o'clock sectors (shown with asterisks), compared with nonprogressors, and the 7 o'clock sector showed the most significant difference. Error bar, ±1 SD.
Figure 4.
 
Histograms showing the global rates of RNFL change in nonprogressors and progressors.
Figure 4.
 
Histograms showing the global rates of RNFL change in nonprogressors and progressors.
Figure 5.
 
Frequency distribution of clock-hour RNFL measurements showing a significant negative (progression) or positive trend (improvement).
Figure 5.
 
Frequency distribution of clock-hour RNFL measurements showing a significant negative (progression) or positive trend (improvement).
Figure 6.
 
Serial red-free fundus photographs (AD) of a progressor; overlay of serial RNFL thickness profiles (E); and linear regression graphs of global (F), affected quadrant (G), and affected clock-hour (H) thickness with age. The RNFL defects shown in both the superotemporal and inferotemporal quadrants displayed progressive change. Arrowheads: The defect borders which have expanded compared with prior examination are indicated. In this patient, the inferior quadrant and the 7 o'clock sector were considered to be the affected quadrant and the affected clock-hour sector, respectively, as these areas showed the fastest rate of thinning of the several affected quadrants and clock-hour sectors.
Figure 6.
 
Serial red-free fundus photographs (AD) of a progressor; overlay of serial RNFL thickness profiles (E); and linear regression graphs of global (F), affected quadrant (G), and affected clock-hour (H) thickness with age. The RNFL defects shown in both the superotemporal and inferotemporal quadrants displayed progressive change. Arrowheads: The defect borders which have expanded compared with prior examination are indicated. In this patient, the inferior quadrant and the 7 o'clock sector were considered to be the affected quadrant and the affected clock-hour sector, respectively, as these areas showed the fastest rate of thinning of the several affected quadrants and clock-hour sectors.
Table 1.
 
Clinical Demographics
Table 1.
 
Clinical Demographics
Nonprogressors (n = 77) Progressors (n = 76) P
Sex, female/male 38/39 46/30 0.165*
Age, y 60.1 ± 10.7 59.2 ± 13.6 0.658†
Spherical error, D −0.65 ± 2.60 −1.25 ± 2.76 0.177†
Baseline MD, dB −3.71 ± 4.60 −3.27 ± 3.84 0.523†
Baseline PSD, dB 5.33 ± 4.54 5.63 ± 4.31 0.679†
Baseline average RNFL thickness, μm 91.93 ± 15.06 89.07 ± 12.24 0.199†
Average number of OCT scans per eye, n 4.4 ± 0.8 4.5 ± 0.8 0.500†
Mean interval between OCT scans, mo 10.9 ± 2.2 10.5 ± 1.7 0.343†
Mean follow-up duration, y 3.9 ± 0.8 3.9 ± 0.8 0.919†
Table 2.
 
Comparison of the Rates of RNFL Thickness Change, with AUROC Values and Sensitivities at Fixed Specificities, When Used to Discriminate between Nonprogressors and Progressors
Table 2.
 
Comparison of the Rates of RNFL Thickness Change, with AUROC Values and Sensitivities at Fixed Specificities, When Used to Discriminate between Nonprogressors and Progressors
Location Rate of RNFL Thickness Change (μm/y) P * AUROC† Sensitivity at ≥95% Specificity (%)† Sensitivity at ≥80% Specificity (%)†
Nonprogressors (n = 77) Progressors (n = 76)
Global −0.34 ± 1.41 −1.58 ± 2.24 <0.001 0.68 (0.60–0.77) 6 (2–15) 32 (22–44)
Temporal quadrant 0.01 ± 1.87 −0.97 ± 2.40 0.005 0.62 (0.53–0.71) 9 (4–18) 22 (13–34)
Superior quadrant −0.38 ± 2.45 −1.75 ± 3.13 0.003 0.64 (0.55–0.73) 9 (4–18) 29 (19–40)
Nasal quadrant −0.54 ± 3.34 −0.66 ± 3.64 0.838 0.50 (0.41–0.60) 5 (1–13) 21 (12–32)
Inferior quadrant −0.44 ± 2.16 −2.76 ± 2.91 <0.001 0.74 (0.66–0.82) 16 (8–26) 45 (34–57)
Affected quadrant‡ −1.02 ± 1.83 −3.26 ± 2.69 <0.001 0.76 (0.68–0.83) 13 (6–23) 52 (40–64)
9 o'clock 0.22 ± 2.14 −0.21 ± 2.53 0.262 0.55 (0.46–0.64) 6 (2–15) 25 (16–36)
10 o'clock −0.25 ± 2.51 −1.61 ± 2.64 0.001 0.64 (0.55–0.73) 13 (6–23) 38 (27–50)
11 o'clock −0.21 ± 3.22 −2.99 ± 4.33 <0.001 0.71 (0.63–0.80) 8 (3–16) 48 (37–60)
12 o'clock −0.16 ± 2.72 −1.66 ± 3.69 0.005 0.62 (0.54–0.71) 5 (1–13) 29 (19–40)
1 o'clock −0.86 ± 3.63 −1.05 ± 4.33 0.774 0.50 (0.41–0.59) 5 (2–13) 14 (8–24)
2 o'clock −1.14 ± 4.07 −0.21 ± 4.54 0.184 0.45 (0.36–0.55) 0 (0–5) 7 (2–15)
3 o'clock −0.36 ± 3.59 −1.10 ± 4.08 0.235 0.55 (0.46–0.64) 5 (1–13) 31 (21–43)
4 o'clock −0.22 ± 3.77 −0.99 ± 3.99 0.221 0.56 (0.47–0.65) 12 (5–21) 19 (11–30)
5 o'clock −0.81 ± 3.28 −1.96 ± 3.64 0.042 0.59 (0.50–0.68) 4 (1–11) 36 (26–48)
6 o'clock −0.58 ± 2.94 −2.82 ± 3.56 <0.001 0.68 (0.60–0.77) 12 (6–21) 36 (26–48)
7 o'clock 0.03 ± 3.27 −3.71 ± 4.39 <0.001 0.75 (0.67–0.83) 30 (20–41) 51 (39–62)
8 o'clock 0.13 ± 2.24 −0.98 ± 3.07 0.012 0.61 (0.52–0.70) 6 (2–15) 29 (19–40)
Affected clock-hour§ −1.41 ± 2.82 −5.08 ± 3.79 <0.001 0.78 (0.71–0.86) 18 (10–29) 62 (51–73)
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