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Show Comparison of Retinal Nerve Fiber Layer and Central Macular Thickness Measurements Among Five Different Optical Coherence Tomography Instruments in Patients With Multiple Sclerosis and Optic Neuritis George M. Watson, MD, John L. Keltner, MD, Eric K. Chin, MD, Danielle Harvey, PhD, Audrey Nguyen, MD, Susanna S. Park, MD, PhD Background: To compare the mean central macular thickness (CMT) and the mean average optic nerve retinal nerve fiber layer (RNFL) thickness in the eyes of patients with a history of optic neuritis and/or multiple sclerosis (MS) using 5 commercially available optical coherence tomography (OCT) instruments. Methods: Cross-sectional study including 46 patients (92 eyes) with a history of optic neuritis and/or MS. Both eyes were imaged on the same day with 5 OCT instru-ments: 1 time-domain OCT (Stratus) and 4 different Fourier-domain (spectral-domain) OCT (3D OCT-1000, Cirrus, RTVue-100, and Spectralis). Results: Twenty-five patients (50 eyes) were included in the final analysis after excluding patients with diabetes, glaucoma, ocular hypertension, or retinal pathology and inadequate scan quality. Randomized block analysis of variance revealed statistically significant differences across instruments (P , 0.001) for both eyes for mean CMT and mean average optic nerve RNFL. When testing for significant differences in measurements from instrument to instrument, some difference was noted between the right and left eyes. Conclusions: Statistically significant differences exist among commercially available OCT instruments in mea-suring mean CMT and mean average RNFL thickness in patients with optic neuritis and/or MS. These findings likely result from the differences in data acquisition and segmentation algorithm software among OCT instru-ments. Awareness of these variations among OCT instruments will be important in using these instruments for clinical trials and management of patients with optic neuritis and/or MS. Journal of Neuro-Ophthalmology 2011;31:110-116 doi: 10.1097/WNO.0b013e3181facbbd 2011 by North American Neuro-Ophthalmology Society Optical coherence tomography (OCT) is a quick and noninvasive method of obtaining a cross-sectional image of the retina, aiding clinicians and researchers in understanding numerous pathologic conditions (1). The ability of OCT to quantify retinal nerve fiber layer (RNFL) and macular thickness allows an objective method for monitoring axonal injury and serves as a useful outcome measure in clinical trials of optic nerve disorders (2-6). Accordingly, the neurology community is increasing their reliance on sequential OCT imaging as a potential struc-tural marker for the more time-consuming and expensive MRI imaging in directing clinical response to pharmaco-therapy, as well as primary outcomes in drug trials (7). Stratus time-domain OCT (TD-OCT, Carl Zeiss Medi-tech, Inc, Dublin, CA) has historically been used to quantitate RNFL thinning in patients with multiple sclerosis (MS) and/or optic neuritis, and acceptable Department of Ophthalmology & Vision Science (GMW, JLK, EKC, AN, SSP), University of California Davis Eye Center, Sacramento, California; Department of Neurology and Neurological Surgery (JLK), University of California Davis Medical Center, Sacramento, California; and Division of Biostatistics and Department of Public Health Sciences (DH), University of California Davis, Davis, California. Supported by a grant from the National Center for Research for Medical Research (grant number: UL1 RR024146) and an un-restricted departmental grant from Research to Prevent Blindness, New York, NY. Dr S. S. Park has received honoraria from Optovue for speaking regarding her clinical experience with RTVue. None of the other authors have any financial or proprietary interest to disclose regarding this study. Address correspondence to Susanna S. Park, MD, PhD, Department of Ophthalmology & Vision Science, University of California Davis Eye Center, 4860 Y Street, Suite 2400, Sacramento, CA 95817; E-mail: susanna.park@ucdmc.ucdavis.edu 110 Watson et al: J Neuro-Ophthalmol 2011; 31: 110-116 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. reproducibility has been reported with this instrument (2,4,5,8-12). Until recently, widespread applications of OCT tech-nology used exclusively TD-OCT, named because image resolution is a function of distance and time (13). Stratus OCT is the most widely used TD-OCT instrument; however, the speed of this class of OCT is limited by the need for a movable reference mirror. In contrast, the newer Fourier-domain OCT (FD-OCT) (spectral-domain OCT) technology offers significant advantages over the traditional TD-OCT techniques (14) by gathering depth information from spectral data using Fourier transformation, eliminat-ing the need for a moving reference mirror, and allowing for more efficient data acquisition (15-17). FD-OCT instru-ments provide superior image sampling as a greater number of scans are acquired at a faster rate (15). FD-OCT also provides a significant reduction in motion artifacts and an increased signal-to-noise ratio in comparison to TD-OCT (15,18,19). Recent studies comparing central macular thickness (CMT) measurements, that is, central 1-mm zone of the Early Treatment Diabetic Retinopathy Study (ETDRS) map (Fig. 1), among the various commercially available TD- and FD-OCT instruments have shown that measurement differences exist among machines (20-22). Comparative optic nerve and macular thickness data have been reported in both normal and diseased eyes with various TD- and FD-OCT, including ocular hypertension, diabetic retinopathy, traumatic optic neuropathy, macular edema, and chiasmal lesions (11,23-27). More recently, studies have compared RNFL and CMT measurements using various OCT instruments for eyes with glaucoma (20,28- 34). Although the majority of these studies illustrate that measurements cannot be compared across 2 different OCT instruments, larger studies comparing greater than 3 instruments are limited. In addition, no study thus far has assessed the variability in RNFL and CMT measurements among commercially available TD- and FD-OCT instru-ments in eyes with MS and/or optic neuritis. Before a new diagnostic instrument can be introduced for use in clinical practice, studies aimed at understanding repeatability and reproducibility of measurements, diagnostic accuracy, and ability to detect changes over time must be re-ported. Furthermore, it is important to determine if measure-ments from early generation TD-OCT technologies and new generation FD-OCT technologies are compatible and consis-tent (17-19). Thus, in this study, cross-sectional comparisons of RNFL and CMT measurement were made in patients withMS and/or optic neuritis using 5 different commercially available OCT instruments, including the traditional TD-OCT (Stratus OCT) and 4 different FD-OCT instruments. METHODS Participants Forty-six patients diagnosed with optic neuritis and/orMS were enrolled from the Neuro-ophthalmology Clinic at the Uni-versity of California Davis Eye Center. Written informed consent was obtained from all participants, and the study was conducted according to a protocol approved by the Institutional Review Board Administration, University of California, Davis, and in adherence to the tenets of the Declaration of Helsinki. From September through December 2008, all enrolled patients underwent optic nerve RNFL and CMT meas-urements of both eyes on the following 5 instruments: Stratus TD-OCT and 4 different FD-OCT 3D OCT-1000 (Topcon, Tokyo, Japan), Cirrus (Carl Zeiss Meditec, Inc), RTVue-100 (Optovue Corporation, Fremont, CA), and Spectralis (Heidelberg Engineering, Inc, Heidelberg, Germany) (Table 1). Images were acquired on the same day and setting, by 1 of 3 highly experienced OCT technicians in variable sequence. CMT measurement in this study refers to the thickness of the central 1-mm zone of the macula in the ETDRS macular thickness map (Fig. 1). All participants included in this study had a diagnosis of optic neuritis and/or MS, regardless of disease subtype, later-ality, severity, current activity, or presence of disease-modifying therapy. Participants were excluded if there was a known history of diabetes, glaucoma, ocular hypertension, or other retinal disease that could possibly result in RNFL or macular thickness changes. At the time of image acquisition, OCT scans with grossmotion artifacts and segmentation errors were removed by our OCT technicians, and repeat scanning was performed. OCT data with signal strength less than the minimum standard as published by the Diabetic Retinopathy Clinical Research Network (Table 1) and patients with incomplete scans of either eye were excluded from the final analysis. OCT Instrumentation Table 1 summarizes the features of the 5 different com-mercially available OCT instruments used in this study. FIG. 1. Macular thickness segmented zones as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS). CMT refers to the central 1-mm zone of the ETDRS mac-ular thickness map as shown. Watson et al: J Neuro-Ophthalmol 2011; 31: 110-116 111 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. The following scans were used for each instrument to obtain the RNFL and CMT measurements: Stratus, software version 4.0, fast macular thickness map protocol was acquired consisting of 6 radial line scans (128 A-scans per line) over a 6-mm diameter circle of the macula centered in the fovea. For the fast RNFL pro-tocol, 3 scans, each composed of 256 A-scans, were acquired consecutively using a 3.46-mm diameter circu-lar scan and an automated computer algorithm delin-eating the anterior and posterior margins of the RNFL. Topcon 3D-OCT 1000, software version 3.20, macular and optic nerve protocol consisted of 6 radial line scans (1024 A-scans per line) in a 3-dimensional 6 3 6 mm area (3.6 seconds; 128 raster scans with 512 A-scans per scan). The optic nerve RNFL peripapillary 3.4-mm circle map was centered on the optic nerve. RTVue-100, software version 2.0, MM6 macular map protocol consisted of 12 radial line scans (1024 A-scans per line) in a 3-dimensional 6 3 6 mm area (2.0 seconds). The optic nerve RNFL NHM4 protocol consisted of 12 radial scans (452 A-scans per line) over 3.45-mm diameter centered on the optic disc. Cirrus, software version 3.0, macular cube protocol consisted of 128 radial lines (512 A-scans per line) in a 3-dimensional 6 3 6 mm area (2.5 seconds). The optic nerve RNFL 200 3 200 protocol was utilized generating 200 horizontal scan lines (200 A-scans per line) over a diameter of 3.46 mm. Spectralis, software version 3.2, macular volume protocol consisted of 49 radial lines (512 A-scans per line) in a 3-dimensional 6 3 6 mm area (5 seconds). Optic nerve RNFL measurements consist of 768 A-scans over a 3.45 mm area, however, repeated and averaged over 16 measurements, capable of being performed through eye-tracking software. Statistical Analysis Means and SDs of CMT and RNFL for each eye were calculated for the 5 instruments. To provide a scaling comparison for each instrument, percent differences from the Stratus mean CMT and RNFL were also calculated. As measurements were available on each instrument for each subject, a randomized block analysis of variance (ANOVA) was used to assess differences across instruments in CMT and RNFL. Post hoc pairwise tests were performed if an overall difference was detected across instruments to iden-tify where differences occurred among the instruments. These post hoc tests were corrected for multiple compar-isons using Turkey studentized range (Honestly Significant Differences) test. Because the percent differences are simple linear transformations of the original data, results of the ANOVA and post hoc pairwise comparisons are identical to those for the original data; so results are only presented for the original data. Assumptions of the ANOVA were checked and were met by the data. Analyses were done for each eye separately, because measurements taken from eyes of the same individual cannot be assumed to be independent from one another. In secondary analyses, data from both eyes were used in repeatedmeasuresmodels accounting for the correlation between observations from the same individuals across instruments and eyes to test for differences in CMT or RNFL between eyes. All statistical analyses were performed using SAS, and a P value ,0.05 was considered statistically significant. RESULTS Among 46 patients (92 eyes) imaged and recruited, 21 patients were excluded due to incomplete scans (34 eyes), concurrent retinal disease (6 eyes), or poor signal strength and image quality (2 eyes). Ultimately, 25 patients (50 eyes) were in-cluded in our final analysis. Demographic information and clinical diagnoses for included patients are shown in Table 2. The mean6 SD of the respective CMT (Table 3) and average optic nerve RNFL thickness (Table 4) were measured using each of the 5 OCT instruments. Percent differences for CMT and RNFL from the Stratus mean were calculated for each instrument to provide a comparison of scaling as seen in Tables 5 and 6, respectively. A statistically significant difference was observed for each eye when comparing mean CMT and mean average optic TABLE 1. Summary of specifications of OCT instruments OCT Instrument Macular Thickness Outer Boundary* Optic Nerve RNFL Diameter (mm) Minimal Accepted Signal Strength† Axial Resolution (mm) A-Scan Speed (scans/s) Stratus IS-OS junction 3.46 7 8-10 400-600 3D OCT-1000 Inner RPE 3.40 50 5-6 25,000 RTVue-100 Outer RPE 3.45 40 5-6 26,000 Cirrus Outer RPE 3.46 7 5 27,000 Spectralis Bruch membrane 3.45 30 4-7 40,000 *Macular thickness inner segment boundary is inner limiting membrane for all instruments. †Signal strength recommendations by the Diabetic Retinopathy Clinical Research Network (48-51). IS, inner segment of photoreceptor; OS, outer segment of photoreceptor; RPE, retinal pigment epithelium. 112 Watson et al: J Neuro-Ophthalmol 2011; 31: 110-116 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. nerve RNFL thickness across instruments (P , 0.001). Further investigation into the differences in mean CMT showed that in the left eye, all instruments were different from one another (P , 0.05, corrected for multiple com-parisons), except for RTVue-100 and Cirrus (P = 0.12, corrected). In the right eye, all instruments were signifi-cantly different from one another (P , 0.05, corrected). For RNFL, in the left eye, similarities were seen between 3D OCT-1000 and RTVue-100 (P = 0.99, corrected) and between Cirrus and Spectralis (P = 0.11, corrected), but all other pairings were different (P , 0.05, corrected). In the right eye, RNFL measures obtained from 3D OCT-1000 and RTVue-100 were also similar (P = 0.99, corrected). In addition, Stratus was similar to both of these instruments (P = 0.36, corrected with 3D OCT-1000 and P = 0.17, corrected with RTVue-100). However, Cirrus was different from all other instruments (P , 0.05, corrected) and Spectralis was different from all instruments with the exception of Stratus, which did not quite reach statistical significance in our study (P = 0.052, corrected). In models that used the data from both eyes, accounting for the correlation between the eyes from the same in-dividual, there was a significant difference, on average, between the right and left eye on RNFL (P , 0.001) but not on CMT (P = 0.8). RNFL was significantly lower, on average, in left eyes compared to right eyes. To further investigate differences between the eyes, we assessed the eyes for optic neuritis. Two individuals had optic neuritis in both eyes, 9 had it in the left eye only, and 6 had it in the right eye only. For all instruments except 3D OCT-1000 in the right eye (P = 0.08), eyes with optic neuritis had lower RNFL, on average, than those without optic neuritis (P , 0.01 for all other instruments, right and left eyes analyzed separately). Thus, the lower RNFL measurement noted in the left eye versus the right eye may be partially explained by a differ-ence in the incidence of optic neuritis between the right and left eyes in our study population. There were no differences found on CMT between eyes with and without optic neuritis (P . 0.5 for all instruments, right and left eyes analyzed separately). DISCUSSION The recent advances in OCT in clinical management and research trials have led to the need for investigating dif-ferences among the various instruments, especially between the higher resolution FD-OCT and its predecessor TD-OCT (Stratus). Previous studies have reported statistically significant differences not only between FD and TD classes of OCT instrument but also among the various FD-OCT instruments for both normal and diseased eyes (22,33,35- 37). A majority of these studies are limited in comparing only one OCT instrument to another, and large prospective studies comparing greater than 3 different OCT instru-ments are limited so far. Furthermore, no prior study has compared optic nerve RNFL and CMT measurement among OCT machines in eyes with optic neuritis or MS. Our institution was fortunate to have had access to 5 commercially available OCT machines to compare RNFL and CMT measurements in eyes with optic neuritis or MS. These instruments included Stratus, the prototype TD-OCT, and 4 different commercially available FD-OCT instruments, including Cirrus, TopCon 3D OCT-1000, RTVue, and Spectralis. The results show that both optic TABLE 2. Summary of patient demographics and clinical diagnoses Mean age, years (range) 43 (26-66) No. of women 23 (92%) MS with optic neuritis 14 (56%) MS without optic neuritis 8 (32%) Optic neuritis only 3 (12%) Total no. of patients 25 TABLE 3. Mean CMT 6 SD obtained with each OCT instrument OCT Instrument CMT Right Eye (mm) CMT Left Eye (mm) Stratus 183 6 18 184 6 20 3D OCT-1000 224 6 18 223 6 21 RTVue-100 246 6 19 248 6 21 Cirrus 253 6 21 251 6 23 Spectralis 266 6 20 265 6 20 TABLE 4. Mean average RNFL thickness 6 SD obtained with each OCT instrument OCT Instrument RNFL Right Eye (mm) RNFL Left Eye (mm) Stratus 94 6 13 88 6 15 3D OCT-1000 96 6 11 92 6 12 RTVue-100 97 6 13 92 6 15 Cirrus 86 6 13 83 6 14 Spectralis 91 6 15 85 6 18 TABLE 5. Percent difference of mean CMT 6 SD from Stratus OCT Instrument CMT Right Eye CMT Left Eye Stratus 0.00 6 0.10 0.00 6 0.11 3D OCT-1000 0.23 6 0.10 0.21 6 0.11 RTVue-100 0.34 6 0.10 0.34 6 0.11 Cirrus 0.39 6 0.11 0.36 6 0.12 Spectralis 0.45 6 0.11 0.44 6 0.12 Watson et al: J Neuro-Ophthalmol 2011; 31: 110-116 113 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. nerve RNFL and CMT measurement have statistically significant differences among machines. In this study, we included eyes with optic neuritis and/or MS. While approximately 80% of patients with MS ex-perience visual impairment (38,39), not all patients who have MS have signs of optic neuritis. In our study, we found a statistically lower mean RNFL thickness measurement for the left eye when compared to the right eye (Table 4). No significant difference was noted in CMT between the right and left eyes. This difference in mean RNFL measurement between the right and left eyes may be partly due to the higher incidence of optic neuritis in the left eye compared to the right eye in our study population since RNFL mea-surement tends to be lower in eyes with optic neuritis when compared to eyes with MS without optic neuritis. However, patients with MS and a history of unilateral optic neuritis demonstrate RNFL thinning not only in affected eyes but also in the supposed unaffected eyes as demonstrated by TD-OCT (3,40). Additionally, patients with MS without a history of acute optic nerve inflammation have shown decreased RNFL thickness in comparison to eyes of healthy control subjects, as measured by Stratus TD-OCT, and this decrease has been found to correlate well with low-contrast letter acuity and contrast sensitivity in such patients (5,9). Specifically, 4 mm of RNFL thinning was predictive of 1 line worsening of low-contrast letter acuity (5). These findings support that RNFL thinning in patients with MS occurs on a chronic basis and not exclusively from acute optic neuritis, further warranting the use of OCT to follow disease progression and response to therapy. Quantitative measurements of optic nerve atrophy in patients with MS and optic neuritis with MRI has recently been correlated with optic nerve RNFL thinning as mea-sured by TD-OCT (41,42), further validating RNFL measurement as a potentially more sensitive structural marker for central nervous system imaging in clinical and research investigations in MS. While optic nerve appearance and imaging is of primary interest in evaluating pathology from optic neuritis, the demyelinating damage acts in a retrograde fashion with ultimate retinal ganglion cell loss and subsequent RNFL thinning. As RGCs make up about one third of the total macular thickness, attention has also been placed in following macular thickness reductions in demyelinating disease. An association between optic nerve RNFL thinning and macular volume reduction in patients with optic neuritis with or without MS has been reported with TD-OCT (2). Such findings may be further validated with the superior resolution of FD-OCT, enabling high definition retinal layer segmentation and specific attention to the inner retinal layers. Our study found significant differences in mean CMT and average optic nerve RNFL thickness not only between TD and FD classes of OCT instruments but also within the FD-OCT class of instruments in this population of patients with MS and optic neuritis. Differences in macular thick-ness can be partially explained by the reported differences in segmentation algorithm defining retinal boundaries among OCT machines, as well as differences in sampling density (Table 1). All inner macular thickness boundaries begin at the internal limiting membrane; however, the outer boundary is variable (43-45): Stratus measures to the inner segment-outer segment junction of photoreceptor layer, Topcon to the inner retinal pigment epithelium (RPE) layer, Cirrus and Optovue to the outer RPE layer, and Spectralis to Bruch membrane. Our statistical analysis revealed similar mean CMT values for left eyes between Cirrus and RTVue-100, which may be expected as both instruments measure thickness between the same boundaries. However, this was not a consistent finding when analyzing right eyes as each instrument significantly differed from one another. Similarly, variability in statistically significant differences was found when comparing instru-ments for mean average RNFL. The clinical significance of such findings is unknown. Ultimately, differences in data acquisition and software among the various OCT instru-ments should be carefully compared and eventually stan-dardized to provide more consistent and comparable results among OCT machines. Theoretically, future software development aimed at standardizing data acquisition and segmentation boundaries may allow interchangeability of the thickness measurements across OCT instruments. While our sample size was small, a larger sample would not likely affect our conclusions as differences among instruments are clear and likely resulting from differences in postprocessing algorithms. Our study excluded a large percentage of patients based on incomplete scans or poor signal strength, who otherwise met the inclusion and exclusion criteria. Signal strength has been shown to affect RNFL thickness measurements using Stratus OCT (46,47). Images with lower signal strength were, therefore, excluded from this study. Unfortunately, signal strength scales are not constant across OCT instruments, and this difference among instruments may also have contributed to differences in RNFL and CMT measurements among machines. In summary, our study demonstrated a statistically sig-nificant difference in RNFL and CMT measurements among commercially available TD- and FD-OCT instru-ments in patients with optic neuritis and/or MS. As retinal thickness measurements among OCT instruments have TABLE 6. Percent difference of mean average RNFL thickness 6 SD from Stratus OCT Instrument RNFL Right Eye RNFL Left Eye Stratus 0.00 6 0.14 0.00 6 0.17 3D OCT-1000 0.02 6 0.11 0.04 6 0.13 RTVue-100 0.03 6 0.13 0.04 6 0.17 Cirrus 20.09 6 0.13 20.07 6 0.15 Spectralis 20.03 6 0.16 20.04 6 0.20 114 Watson et al: J Neuro-Ophthalmol 2011; 31: 110-116 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. been found to vary depending on posterior segment disease (35), it is possible that the variation we found among OCT machines is specific to MS or optic neuritis and not nec-essarily applicable to other optic neuropathies. Nonetheless, our study raises awareness in the scientific community relying on OCT measurements for clinical decision making and drug trials. Based on our results, the data from these various OCT instruments do not appear to be freely interchangeable in patients with MS and/or optic neuritis. ACKNOWLEDGMENTS The authors thank Ellen Redenbo, CRA, ROUB, Mark Thomas, CRA (no longer with University of California Davis Eye Center), and Karishma Chandra, COT of the University of California Davis Eye Center, for data ac-quisition. Special thanks also to Norman Siu (Heidelberg) and Eugene Huang, PhD, (Topcon) for making available the FD-OCT instruments used in this study. 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