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1From the Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea; the 2Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea; the 3Department of Ophthalmology, Hanyang University College of Medicine, Guri Hospital, Guri, Korea; and the 4Department of Applied Statistics, Yonsei University, Seoul, Korea
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Abstract |
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METHODS. Intersession test–retest variability of each clock hour, quadrant, and average RNFL thickness was determined in 53 control subjects. The sensitivity and specificity of OCT for identification of progressive RNFL atrophy were tested on subjects in whom this condition was clearly observed in red-free RNFL photographs (n = 27) and in another control group (n = 62), according to criteria derived from test–retest variability.
RESULTS. The sensitivity of Stratus OCT RNFL measurement ranged from 14.8% (for average RNFL thickness) to 85.2% (for clock hour thickness) when tested at the 95% confidence level. The specificity of Stratus OCT RNFL measurement was approximately 95% for average RNFL thickness, but decreased considerably with clock hour (59.7%) and quadrant thickness (77.4%). This is presumably because multiple testing was used for multiple clock hours and quadrants. When calculated based on two consecutive follow-up examinations, the specificity for the clock hour measurements increased to 86.6% and that for quadrant thickness increased to 92.5%. The OCT-measured RNFL thickness change showed excellent topographic agreement with the progressive RNFL atrophy observed using RNFL photography.
CONCLUSIONS. Within the limits of retest variability, Stratus OCT detects progressive RNFL atrophy with high sensitivity and moderate specificity in cases showing localized progressive loss of retinal nerve fibers in red-free photographs. The specificity can be improved by use of multiple measurements. Stratus OCT is a potentially useful technique for detection of glaucoma progression.
New-generation imaging devices such as the Stratus OCT must be able to detect progressive changes if it is to assist in better management of patients with glaucoma. Currently, limited information is available regarding the ability of OCT to detect progressive glaucomatous change. Wollstein et al.9 compared OCT and automated perimetry for detection of glaucoma progression. They suggested that OCT is more sensitive but could not exclude the possibility of a higher number of OCT-related type I errors (false positives).
Sehi et al.10 reported that both OCT and scanning laser polarimetry were capable of documenting and measuring progressive glaucomatous RNFL atrophy. However, that study involved only one case. Moreover, that patient had not been compliant with antiglaucoma therapy for 4 years, resulting in an intraocular pressure > 30 mm Hg, which led to marked visual field defect progression. Therefore, although that study demonstrated that OCT has the potential to detect progressive glaucomatous RNFL atrophy, it remains unclear whether this new imaging device can accurately detect small progressive changes. This is a critical issue because early detection of progressive change and proper management provide the best prospect for preventing significant visual function loss since glaucomatous damage is irreversible.
In the present study, we investigated the ability of Stratus OCT to detect small progressive glaucomatous changes.
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Methods |
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For the purpose of the present study, three subject groups meeting defined eligibility requirements were used: (1) a stable glaucoma group to establish test–retest limits, (2) a stable glaucoma group to test OCT specificity at baseline and at one or two follow-ups, and (3) a progressive glaucoma group to test OCT sensitivity at baseline and at one or two follow-ups.
Patients with Stable Glaucoma
Eligible patients with glaucoma were consecutively enrolled in the study during regular follow-up visits and were divided into two groups: control group 1, whose data were used to measure OCT reproducibility, and control group 2, whose data were used to evaluate OCT specificity in the detection of progressive glaucomatous RNFL atrophy. Only patients with IOP 
18 mm Hg on the last three consecutive visits were included. Exclusion criteria were best corrected visual acuity worse than 20/40; spherical refraction greater than ±5.0 D; cylinder correction greater than ±3.0 D; history of ocular surgery (including cataract extraction between examinations); or presence of a disease that could affect the peripapillary area (where OCT measurements are obtained).
All subjects were assessed with the peripapillary Fast RNFL program of the Stratus OCT, either twice for control group 1 or three times for control group 2; all measurements were 3 to 30 days apart. The same Stratus OCT instrument was used by the same operator for all testing sessions.
Patients with Progressive Glaucomatous Change
Eyes showing progressive glaucomatous change that met the eligibility criteria were consecutively enrolled from a database of patients examined for glaucoma between February 2006 and April 2008 in the Department of Ophthalmology, Seoul National University Bundang Hospital.
Before the study, all patients underwent a complete ophthalmic examination including visual acuity, refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, and dilated stereoscopic examination of the optic disc. They also underwent red-free fundus photography, OCT and standard automated perimetry (SAP), each of which was performed by the same operator.
Patients having a localized RNFL defect and showing definite progressive RNFL atrophy between visits according to red-free RNFL photography were enrolled. To be included, patients should have OCT results obtained taken within 1 month of red-free photography on each occasion. Exclusion criteria were a best corrected visual acuity worse than 20/40, a spherical refraction greater than ±5.0 D, cylinder correction greater than ±3.0 D, a history of ocular surgery including cataract extraction between examinations, and the presence of disease that may affect the peripapillary area (where OCT measurements are obtained).
The sensitivity of OCT for detection of progressive glaucomatous atrophy was tested by single and repeated testing. When a patient underwent only one OCT examination after the first detection of a progressive change in the RNFL photography, the patient was invited into the study and underwent repeated OCT examinations.
Defining Progression
Progression was primarily determined based on red-free RNFL photographs, which were acquired with a digital camera (EOS D60; Canon, Utsunomiyashi, Tochigiken, Japan) after maximum pupil dilation. Sixty degree, wide-angle views of the optic disc focusing on the retina with the built-in split-lines focusing device and centered between the fovea and the optic disc11 were obtained and reviewed on an LCD monitor. Red-free RNFL photographs were independently evaluated by two authors (EJL and TWK) who were masked to the patient’s clinical information including OCT results. Each examiner classified eyes into one of the following three categories: no change, progressed, or ambiguous (which may have been due to poor image quality or a change too subtle to be considered progression). Progression was defined as clearly visible widening of the preexisting localized defect borders according to red-free photography and the development of new localized defects. The quadrant where the progression was detected was recorded. Subjects were enrolled when both observers classified the defect as progression, and identified it in the same quadrant. Any discrepancy between the observers was resolved by consensus.
After patients were enrolled, the two observers together reviewed the RNFL photographs to agree on a clock location of the progression, which enabled a topographic comparison with the OCT-measured RNFL thickness change. For this assessment, the directional angle of the expanded RNFL defect was measured in a way that allowed alignment of the OCT images with the RNFL photographs. This method has been described in detail elsewhere.8 12 13 Briefly, a clock-face circle was drawn around the optic nerve head on the red-free photograph, the diameter and location of which corresponded as closely as possible to the circle displayed in the video mode of the RNFL thickness analysis report (Fig. 1) . The expanded portion of the defect was identified and its clock hour location was determined. To determine the angular width of the expansion, the two points where the borders of the defect met the circle (small arrows in Fig. 1 ) were then identified, and the directional angle of the border points with respect to the center of the circle was then measured. The angular width of the expansion was calculated based on that measurement. The clock hour was assessed in a clockwise direction for right eyes and a counterclockwise direction for left eyes, with the temporal sector at 9 o’clock to correspond with the OCT.
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6 (10 = maximum). Data were analyzed (Stratus version 4.0 software; Carl-Zeiss Meditec, Inc.). With the Fast RNFL program, RNFL thickness was determined at 256 points at a set diameter (3.4 mm) around the center of the optic disc three times during a single scan. These values were averaged to yield 12-clock-hour thicknesses (represented by clock hours, with the 9-o’clock (3-o’clock for the left eyes) value representing the segment between 345° and 15° for the right eyes), four-quadrant thicknesses, and a global average RNFL thickness measurement (360° measure).
Data Analysis
For control group 1, we obtained data on intraclass correlation coefficients (ICCs), coefficients of variation (COVs), and inter-session test–retest variability for clock hour thickness, quadrant thickness, and 360° average thickness. The ICC was defined as the ratio of the intersubject component of variance to the total variance. For the purpose of the present study, intersession test–retest variability was defined at the 95% and 80% confidence level. It was calculated as 1.96-fold greater than the intervisit SD for the 95% level14 and was calculated as 1.28-fold greater than the intervisit SD for the 80% level. For control group 2, we measured OCT specificity. The sensitivity and specificity of the Stratus OCT were tested using the following parameters (each of which had an upper 95% confidence limit of test–retest variability defined at the 95% and 80% level): (1) RNFL thickness decrease beyond the limit in more than 1 clock hour; (2) RNFL thickness decrease beyond the limit in more than one quadrant; and (3) 360° average RNFL thickness decrease beyond the limit. The number of subjects and measurements allowed us to establish the lower 95% confidence limit for an ICC of 0.85 as not lower than 0.75, which is considered an acceptable lower cutoff level for good reproducibility.15
Statistical analyses were performed with commercial software (SPSS, ver. 15.0; SPSS Inc, Chicago, IL) and R package 2.7.0 (http://www.r-project.org). P < 0.05 was considered to indicate a significant difference.
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Results |
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After the first grading, there was disagreement between the two observers on approximately 21 eyes. Disagreements regarding no change versus ambiguity were the most common (n = 19), followed by progression versus ambiguity (n = 2). Cases in which there was disagreement regarding no change versus ambiguity were finally classified as either no change or ambiguity and excluded from further analysis. Cases in which there was disagreement regarding progression versus ambiguity were classified as ambiguous and also excluded from further analysis. In cases initially classified as progression by both graders, both agreed on the location of the defect expansion or of the new defect. Of 29 eyes classified as progressive, either the baseline or follow-up OCT scans from 2 (6.9%) subjects were deemed unacceptable owing to an inadequate signal strength (<6 dB) or to the presence of an uncentered circular ring around the optic disc. These measurements were excluded from further analyses. The final sample consisted of 27 eyes of 27 patients.
The mean age of the 27 patients who showed progressive change in RNFL photographs was 53.3 ± 13.4 years, and 14 were women. The visual field mean deviation and pattern standard deviation at baseline were –3.95 ± 6.02 dB and 6.54 ± 4.97 dB, respectively (Table 1) . Of the 27 eyes, 26 showed expansion of one preexisting RNFL defect, and 1 eye showed expansion of two preexisting RNFL defects. The mean angular width of the expanded defect was 7.5 ± 3.2° (range, 2.5–12.5°) on red-free photography. The mean interval between the baseline red-free photography and the follow-up red-free photography where the progressive RNFL atrophy was noted was 20.1 ± 7.2 months. Although progression was determined primarily using RNFL photographs, progression was also observed in 19 (70.4%) eyes by using SDP, and in 14 (51.9%) eyes with SAP (according to criteria suggested by the European Glaucoma Society,16 which was modified from the Hoddap-Parrish-Anderson criteria17 ). Sixteen eyes showed progression at 7 o’clock, four eyes at 11 o’clock, two eyes each at 6 and 8 o’clock, and one eye each at 5 and 10 o’clock. One eye showed progression at both 7 and 11 o’clock (Fig. 2) .
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Reproducibility of OCT RNFL Thickness Measurements
Table 2 shows the intersession ICCs, COVs, and test–retest variability for RNFL tests performed on two separate days during a 3- to 30-day period. The test–retest variability defined at the 95% level for average thickness was 6.4 µm. The quadrant and clock-hour measurements had higher test–retest variability. The test–retest variabilities of the temporal and inferior quadrant seemed to be less than that of the nasal and superior quadrant.
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0.0012). Table 3 shows the sensitivity and specificity of OCT, which were tested using criteria corresponding to the upper 95% limit of test–retest variability defined at the 95% level. The sensitivity was highest for the criterion based on clock-hour thickness (85.2% [CI, 71.8–98.6%]) and lowest (14.8% [CI, 1.4–28.2%]) for the criterion based on average RNFL thickness. The specificity was highest (98.4% [CI, 95.3–100.0%]) for the criterion based on average RNFL thickness, followed by quadrant thickness (77.4% [CI, 70.0–87.8%]) and clock-hour thickness (59.7% [CI, 47.5–71.9%]). The specificities for the criteria based on clock hour and quadrant measurement increased to 86.6% (CI, 78.1–95.1%) and 92.5% (CI, 85.9–99.1%), respectively, when calculations were based on the two consecutive follow-up examinations.
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Discussion |
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The reproducibility of Status OCT and several other findings of the present study are similar to those reported recently by Budenz et al.18 They reported a test–retest variability of 6.7 µm for average RNFL thickness, as measured by the Fast RNFL program. The reproducibility was variable depending on the size and location of the area that was measured. Specifically, we found less test–retest variability for average thickness than for quadrants and less test–retest variability in quadrants than in their respective clock-hour sectors. In addition, for both studies, the measurement was least reproducible (lowest ICCs and highest COVs) in the nasal quadrant and in the respective clock-hour sectors.
We tested the sensitivity and specificity of Stratus OCT for detection of glaucoma progression using criteria corresponding to the upper 95% limit of test–retest variability defined at the 95% and 80% confidence level. These criteria used different thickness values for individual clock hours or quadrants. It seemed unreasonable to use identical criteria for all clock hours (e.g., >15 µm decrease from the baseline measurement) or quadrants owing to the considerable variation between clock hour measurements and quadrant measurements. This was also the case when the test–retest variability was converted to percentages (data not presented).
For the criteria we tested, the clock-hour criterion appeared to be the most sensitive. This is somewhat contrary to our expectations based on measurements of test–retest variability. The ability to detect changes due to disease depends largely on the test–retest variability of measurements. When variability is low, small changes can be detected with confidence. Our test–retest variability was lowest for average RNFL thickness followed by quadrant thickness, and so we expected that the criteria for average RNFL thickness would have the highest sensitivity, followed by quadrant criterion. However, this was the opposite of our observations. To explain this, we propose that glaucoma progression occurred focally, at least in subjects who had expansion of a localized RNFL defect, and this had little affect on average RNFL thickness and quadrant thickness. Indeed, the difference in average RNFL thickness between the baseline and follow-up examinations in patients with progressive RNFL atrophy (4.3 ± 6.5 µm) was far less than the 95% upper limit of test–retest variability defined at the 95% confidence level (7.9 µm). Even when tested with the test–retest variability defined at the 80% confidence level, the sensitivity was still approximately 40%.
We expected that the RNFL thickness would change by no more than the upper 95% limit of our test–retest variability defined at 95% confidence level 95% of the time (assuming there was no change in patient age or disease progression). This means that, with the criteria corresponding to the upper 95% limit of test–retest variability, there should be a specificity of 95%. However, this expectation is applicable only to cases where the specificity is tested once. In the present study, the specificity for criterion based on average RNFL thickness (which needs a single test) was 98.4%. However, for the criteria based on clock-hour and quadrant thickness, the specificities were 59.7% and 77.4%, respectively. This decrease in specificity is in agreement with our statistical considerations. If parameters for each sector are set at the 95% confidence level, 12 simultaneous tests for 12 different clock-hour measurements and four simultaneous tests for four quadrant measurements may have the confidence level of 54.0% (0.9512 ) and 81.5% (0.954 ), respectively.
In clinical practice, the inherent limitations of simultaneous multiple testing can be overcome by repeat OCT testing. Given that the specificity of a diagnostic device is 60% for a single test, the specificity should increase to 84% (1–0.42) when the test is performed twice and to 93.6% (1–0.43) when it is performed three times. The specificity calculated from two consecutive examinations in the present study agrees with this expectation. Meanwhile, the sensitivity of OCT did not change considerably when calculated from two consecutive examinations and maintained acceptable sensitivity for the clock-hour criterion.
In the present study, test–retest variability as well as sensitivity and specificity were measured in patients with early-to-moderate glaucoma. It is possible that the test–retest variability determined in the present study would not be valid for evaluating the ability of OCT to detect progressive change in patients with advanced glaucoma who have a much thinner RNFL at baseline. Moreover, the test–retest variability in such patients may significantly differ from that observed in the present patients. Thus, further studies may be required to evaluate the ability of OCT to detect progressive glaucomatous change in patients with advanced damage.
In the present study, progressive change in glaucoma was defined primarily based on changes identified in RNFL photographs. It is common to define progression based on VF changes when studying glaucoma progression. However, VF data may fluctuate, leading to incorrect conclusions. In addition, detectable functional change does not occur simultaneously with structural changes in glaucoma.16 17 18 Thus, it is inappropriate to consider VF change as the gold standard when investigating the ability of a diagnostic instrument to detect progressive structural change. In contrast, both OCT RNFL thickness analysis and RNFL photography evaluate the same anatomic structure, the RNFL. As such, it is reasonable to assume that any RNFL change should be detected by OCT if OCT can accurately measure RNFL thickness. Furthermore, by defining progression based on RNFL photography, we were able to evaluate the topographic relationship between the OCT-measured RNFL thickness change location and the progressive RNFL atrophy location based on red-free RNFL photography.
We should note that the video image acquisition of the Stratus OCT is recorded after the actual scan has been taken and may not represent the exact location of the acquired scan. If this disparity is substantial, it may lead to a weak topographical relationship between the RNFL photography and OCT. In the present study, we noted an excellent topographical correlation in subjects who showed progressive atrophy in the photography. This observation suggests that the disparity between the actual scan and the true location of acquired scan in OCT is likely to be minimal.
The present study included only eyes with localized defects and with an obvious border. Although localized RNFL defects are easily identified with red-free photography, it is sometimes difficult to define clearly the diffuse atrophy borders using RNFL photography,19 which may lead to problems in measuring any defect expansion. As such, the present study excluded eyes with diffuse atrophy.
Owing to the design of our study, our results provide information regarding the ability of OCT to detect progressive RNFL atrophy only of patients who have localized RNFL defects. The performance of OCT for the detection of glaucoma progression of patients with diffuse RNFL damage remains to be determined.
Progression of the RNFL defect was defined as the widening of the preexisting defect or development of a new defect. However, it is possible that progressive changes occur in a different fashion. Remnant nerve fibers in a region previously defined as defective may be further damaged without any change in the defect border (i.e., deepening of the defect). It is difficult to accurately detect this type of progression, and the inclusion of such change in the definition of progression may provide a source of bias. Thus, the present study considered only defect widening or a new defect as the criteria for progression.
In eyes in which we detected progressive OCT change, we often observed the progressive change even in clock hour sectors where progression was not noted in the photography. It is possible that OCT-detected changes represent true RNFL loss that can only be detected using OCT. At present, it is impossible to test this, as there is no reference standard that can be used to definitively indicate progressive structural changes in glaucoma. A prospective longitudinal study could investigate this question.
In the present study, we included only the subjects who had high-quality OCT measurements (that is, good centration on the optic disc of the scan and signal strength 6). These inclusion criteria may have biased our results toward a better performance of OCT for detection of glaucoma progression than typically occurs in clinical practice.
In summary, the present study demonstrated that within the limits of retest variability, Stratus OCT can detect progressive RNFL atrophy with high sensitivity and moderate specificity in cases showing localized progressive loss of retinal nerve fibers in red-free photographs. The OCT-measured RNFL thickness change showed excellent topographic agreement with the progressive RNFL atrophy observed using RNFL photography. We also demonstrated that the specificity of Stratus OCT can be improved by repeated testing. Stratus OCT is a potentially useful method for detection of glaucoma progression.
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Footnotes |
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Submitted for publication January 4, 2008; revised June 14 and August 11, 2008; accepted December 8, 2008.
Disclosure: E.J. Lee, None; T.-W. Kim, None; K.H. Park, None; M. Seong, None; H. Kim, None; D.M. Kim, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Tae-Woo Kim, Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea; twkim7{at}snu.ac.kr.
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This article has been cited by other articles:
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  M J Kim, E J Lee, and T-W Kim Peripapillary retinal nerve fibre layer thickness profile in subjects with myopia measured using the Stratus optical coherence tomography Br J Ophthalmol, January 1, 2010; 94(1): 115 - 120. [Abstract] [Full Text] [PDF]
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