Optical coherence tomography (OCT) is a noninvasive,

Transcription

1 Ability of Stratus OCT to Detect Progressive Retinal Nerve Fiber Layer Atrophy in Glaucoma Eun Ji Lee, 1,2 Tae-Woo Kim, 1,2 Ki Ho Park, 2 Mincheol Seong, 3 Hyunjoong Kim, 4 and Dong Myung Kim 2 PURPOSE. To evaluate the ability of Stratus optical coherence tomography (OCT version 4.0; Carl Zeiss Meditec, Inc., Dublin, CA) to detect progressive glaucomatous retinal nerve fiber layer (RNFL) atrophy observed by red-free RNFL photography. 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 redfree 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. (Invest Ophthalmol Vis Sci. 2009;50: ) DOI: /iovs From the 1 Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea; the 2 Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea; the 3 Department of Ophthalmology, Hanyang University College of Medicine, Guri Hospital, Guri, Korea; and the 4 Department of Applied Statistics, Yonsei University, Seoul, Korea Supported by a grant from the Seoul National University Bundang Hospital Research Fund. Submitted for publication January 4, 2008; revised June 14 and August 11, 2008; accepted December 8, 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 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 , Korea; twkim7@snu.ac.kr. Optical coherence tomography (OCT) is a noninvasive, high-resolution, cross-sectional imaging technique that allows in vivo measurement of tissue thickness. 1 The Stratus OCT (Carl Zeiss Meditec, Inc., Dublin, CA) is a third-generation machine that has a resolution of 8 to 10 m and is capable of differentiating between healthy eyes and eyes with glaucoma. 2 6 Several recent studies have demonstrated the high sensitivity and specificity of the Stratus OCT with its internal normative database for diagnosing glaucoma. 7,8 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 OCTrelated 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. METHODS The study was approved by the Seoul National University Bundang Hospital institutional review board, and conformed to the Declaration of Helsinki. Informed consent was obtained from all subjects. 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 Investigative Ophthalmology & Visual Science, February 2009, Vol. 50, No Copyright Association for Research in Vision and Ophthalmology

2 IOVS, February 2009, Vol. 50, No. 2 Stratus OCT in Progressive Glaucoma 663 FIGURE 1. Determination of the clock hour location of the expanded defect on red-free fundus photographs. A clock face circle was placed around the optic nerve head, the location and the diameter of which corresponded as closely as possible to the circle displayed in the video mode of the OCT RNFL thickness analysis report (inset). The clock hour location of the expanded portion of the defect was then determined. Note the progression in the 7 o clock sector in this patient. To determine the angular width of the expansion, the two points where the borders of the defect met the circle (small arrows) 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. Expansion of the defect was more obvious in the more peripheral area (large arrows). 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 disc 11 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

3 664 Lee et al. IOVS, February 2009, Vol. 50, No. 2 TABLE 1. Demographic Characteristics of Study Subjects Subjects with Progression (n 27) Control Group 1 (n 53) Control Group 2 (n 62) Age (y), mean SD Male/female 13/14 26/7 31/31 MD (db), mean SD PSD (db), mean SD counterclockwise direction for left eyes, with the temporal sector at 9 o clock to correspond with the OCT. Optical Coherence Tomography Subjects were assessed using the peripapillary Fast RNFL program of the Stratus OCT (Carl-Zeiss Meditec, Inc.) after a pupillary dilation to a minimum diameter of 5 mm. The imaging lens was positioned 1 cm from the eye to be examined and adjusted independently until the retina was in focus. The internal fixation target was used owing to its higher reproducibility. 2 Satisfactory quality was defined as: good centration on the optic disc and a signal strength 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% level 14 and was calculated as 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 ( P 0.05 was considered to indicate a significant difference. RESULTS Subject Characteristics We evaluated 692 eyes of 380 subjects by using red-free photography, stereo disc photography (SDP), SAP-SITA, and Stratus OCT at least twice. All eyes had localized RNFL defects in the baseline red-free photographs and met the other inclusion criteria. Based on RNFL photographs, we identified progressive change in 29 eyes of 29 patients and no progression in 571 eyes of 323 subjects. In 92 eyes of 61 subjects, the diagnosis was ambiguous owing to poor-quality photography (89 eyes of 59 subjects) or to very subtle progression (3 eyes of 2 subjects). 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 years, and 14 were women. The visual field mean deviation and pattern standard deviation at baseline were db and 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 (range, ) 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 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 criteria 17 ). 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). We enrolled 115 patients, the first 53 consecutive patients in control group 1 and the next 62 patients in control group 2. The mean age of control group 1 was years and that of control group 2 was years. The visual field mean deviation and pattern standard deviation at baseline were and , respectively, for control group 1, and and , respectively, for control group 2 (Table 1). 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 m. The quad-

4 IOVS, February 2009, Vol. 50, No. 2 Stratus OCT in Progressive Glaucoma 665 FIGURE 2. Frequency distribution of progressive glaucomatous change in 27 eyes according to RNFL photography. rant 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. Sensitivity and Specificity of OCT RNFL Thickness Parameters for Detection of Glaucoma Progression The OCT global average thickness after progression detected in photographs was m, which was significantly less than the baseline measurement of m (P ). 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, %]) and lowest (14.8% [CI, %]) for the criterion based on average RNFL thickness. The specificity was highest (98.4% [CI, %]) for the criterion based on average RNFL thickness, followed by quadrant thickness (77.4% [CI, %]) and clock-hour thickness (59.7% [CI, %]). The specificities for the criteria based on clock hour and quadrant measurement increased to 86.6% (CI, %) and 92.5% (CI, %), respectively, when calculations were based on the two consecutive follow-up examinations. Table 4 shows the sensitivity and specificity of OCT using criteria corresponding to the upper 95% limit of test retest variability defined at the 80% confidence level. Again, the sensitivity was highest for the clock hour criterion (100.0% [CI, %]), followed by quadrant (92.6% [CI, %]) and average RNFL thickness criteria (40.7% [CI, %]). The specificity was highest for the average RNFL thickness (85.5% [ %]), followed by quadrant (41.9% [CI, %]) and clock hour (24.2% [CI, %]). The sensitivity of OCT RNFL thickness measurement showed a marginally significant difference depending on the degree of RNFL thickness expansion. For 12 subjects with expansion less than 10, the sensitivity was 75.0%. For 15 subjects with expansion greater than or equal to 10, the sensitivity was 93.3% (P 0.096; Table 5). Topographic Relationship between OCT-Measured Clock-Hour RNFL Thickness Change and Progressive RNFL Atrophy, According to RNFL Photography Of the 23 subjects whose clock hour thickness progressed, we noted progression in the OCT in the same clock hour as in the RNFL photography for 17 patients. Six patients exhibited progressive changes in clock hour that was not observed in the red-free photographs; in one of whom the clock hour determined as having progressed in the OCT examination was just next to the clock hour noted as having expanded in the red-free photography (Table 6). DISCUSSION It has been reported that there is a greater likelihood of detecting glaucomatous progression by OCT than by automated perimetry. 9 However, there is limited information regarding the ability of OCT to detect progressive glaucomatous change. TABLE 2. Intersession Correlations and Test Retest Variability of Fast RNFL Measurements Location ICC* COV Test-Retest Variability 95 ( m) Test-Retest Variability 80 ( m) Global average 0.88 (0.80) ( ) 4.2 ( ) Temporal quadrant 0.86 (0.76) ( ) 5.7 ( ) Superior quadrant 0.91 (0.85) ( ) 6.5 ( ) Nasal quadrant 0.83 (0.73) ( ) 6.9 ( ) Inferior quadrant 0.95 (0.92) ( ) 5.2 ( ) 9 o clock 0.86 (0.76) ( ) 5.4 ( ) 10 o clock 0.91 (0.85) ( ) 7.4 ( ) 11 o clock 0.94 (0.89) ( ) 8.6 ( ) 12 o clock 0.89 (0.82) ( ) 8.1 ( ) 1 o clock 0.80 (0.68) ( ) 9.6 ( ) 2 o clock 0.80 (0.68) ( ) 9.3 ( ) 3 o clock 0.79 (0.66) ( ) 7.6 ( ) 4 o clock 0.83 (0.72) ( ) 8.3 ( ) 5 o clock 0.91 (0.85) ( ) 6.9 ( ) 6 o clock 0.95 (0.92) ( ) 6.5 ( ) 7 o clock 0.97 (0.94) ( ) 6.6 ( ) 8 o clock 0.91 (0.84) ( ) 5.6 ( ) n 53. * Shown with lower 95% confidence interval (CI) in parentheses. Test retest variability defined at the 95% level. Shown with 95% CI in parentheses. Test retest variability defined at the 80% level. Shown with 95% CI in parentheses.

5 666 Lee et al. IOVS, February 2009, Vol. 50, No. 2 TABLE 3. Sensitivity and Specificity of OCT RNFL Thickness Parameters for Detection of Progressive Glaucoma Identified on RNFL Photographs Based on the Upper 95% Limit of Test Retest Variability Defined at the 95% Confidence Level OCT Parameter Sensitivity * Sensitivity Based Specificity * Specificity Based In 1 clock hour ( ) ( ) ( ) ( ) In 1 quadrant ( ) ( ) ( ) ( ) In 360 average thickness ( ) (0 17.3) ( ) ( ) * 95% CI is in parentheses. The present study found that using specific criteria, Stratus OCT detected progressive RNFL atrophy with high sensitivity and moderate specificity. This appears to be the first relatively large study to investigate the use of Stratus OCT for detecting glaucoma progression. 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 m 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 m 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 ( m) was far less than the 95% upper limit of test retest variability defined at the 95% confidence level (7.9 m). 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% ( ) and 81.5% ( ), 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% ( ) when the test is performed twice and to 93.6% ( ) 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 examina- TABLE 4. Sensitivity and Specificity of OCT RNFL Thickness Parameters for Detection of Progressive Glaucomatous Change Identified on RNFL Photography Based on the Upper 95% Limit of Test Retest Variability Defined at the 80% Confidence Level OCT Parameter Sensitivity * Sensitivity Based Specificity * Specificity Based In 1 clock hour ( ) ( ) ( ) ( ) In 1 quadrant ( ) ( ) ( ) ( ) In 360 average thickness ( ) ( ) ( ) ( ) * 95% CI is in parentheses.

6 IOVS, February 2009, Vol. 50, No. 2 Stratus OCT in Progressive Glaucoma 667 tions 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-tomoderate 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 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 TABLE 5. Angular Width of RNFL Defect Expansion and Sensitivity of OCT Angular Width of RNFL Defect Expansion (deg)* Eyes (n) Eyes Showing RNFL Thickness Decrease (n) Sensitivity of OCT The criterion was the RNFL thickness decrease beyond the upper 95% limit of test retest variability defined at the 95% confidence level in more than 1 clock hour. * Measurement based on RNFL photography. TABLE 6. The Relationship of Clock Hour Location of OCT- Determined Progression and RNFL Expansion According to Photography When the OCT Progression Was Determined Clock Hour Location of OCT-Determined Progression 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. References Eyes (n) Only in the same clock hour as in the RNFL photography 4 In the same clock hour as in the RNFL photography, but also in the clock hour where progression was not noted in the RNFL photography 13 Only in the clock hour where progression was not noted in the RNFL photography 6* The criterion was set at the upper 95% limit of test retest variability defined at the 95% confidence level. * In one of the six subjects, the OCT clock hour that was determined as having progressed was just next to the clock hour noted as having expanded in the red-free photography. 1. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254(5035): Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography. Ophthalmology. 1996;103(11): Schuman JS, Hee MR, Puliafito CA, et al. Quantification of nerve fiber layer thickness in normal and glaucomatous eyes using optical coherence tomography. Arch Ophthalmol. 1995;113(5): Bowd C, Weinreb RN, Williams JM, Zangwill LM. The retinal nerve fiber layer thickness in ocular hypertensive, normal, and glauco-

7 668 Lee et al. IOVS, February 2009, Vol. 50, No. 2 matous eyes with optical coherence tomography. Arch Ophthalmol. 2000;118(1): Bowd C, Zangwill LM, Berry CC, et al. Detecting early glaucoma by assessment of retinal nerve fiber layer thickness and visual function. Invest Ophthalmol Vis Sci. 2001;42(9): Williams ZY, Schuman JS, Gamell L, et al. Optical coherence tomography measurement of nerve fiber layer thickness and the likelihood of a visual field defect. Am J Ophthalmol. 2002;134(4): Budenz DL, Michael A, Chang RT, et al. Sensitivity and specificity of the StratusOCT for perimetric glaucoma. Ophthalmology. 2005; 112(1): Jeoung JW, Park KH, Kim TW, et al. Diagnostic ability of optical coherence tomography with a normative database to detect localized retinal nerve fiber layer defects. Ophthalmology. 2005; 112(12): Wollstein G, Schuman JS, Price LL, et al. Optical coherence tomography longitudinal evaluation of retinal nerve fiber layer thickness in glaucoma. Arch Ophthalmol. 2005;123(4): Sehi M, Greenfield DS. Assessment of retinal nerve fiber layer using optical coherence tomography and scanning laser polarimetry in progressive glaucomatous optic neuropathy. Am J Ophthalmol. 2006;142(6): Hoyt WF, Frisen L, Newman NM. Fundoscopy of nerve fiber layer defects in glaucoma. Invest Ophthalmol. 1973;12(11): Hwang JM, Kim TW, Park KH, et al. Correlation between topographic profiles of localized retinal nerve fiber layer defects as determined by optical coherence tomography and red-free fundus photography. J Glaucoma. 2006;15(3): Kim TW, Park UC, Park KH, Kim DM. Ability of Stratus OCT to identify localized retinal nerve fiber layer defects in patients with normal standard automated perimetry results. Invest Ophthalmol Vis Sci. 2007;48(4): Medeiros FA, Doshi R, Zanwill LM, et al. Long-term variability of GDx VCC retinal nerve fiber layer thickness measurements. J Glaucoma. 2007;16(3): Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and Proportions. Hoboken, NJ: John Wiley & Sons, Inc.; European Glaucoma Society. Terminology and guidelines for glaucoma 2nd ed. Sanova, Italy: Dogma Srl; 2003: Hodapp E, Parrish R, Anderson S. Clinical Decisions in Glaucoma. St. Louis: Mosby; Budenz DL, Fredette MJ, Feuer WJ, Anderson DR. Reproducibility of peripapillary retinal nerve fiber thickness measurements with stratus OCT in glaucomatous eyes. Ophthalmology. 2008;115(4): Airaksinen PJ, Tuulonen A, Werner EB. Clinical evaluation of the optic disc and retinal nerve fiber layer. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas. Vol. 1. St. Louis: Mosby; 1996: