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 structural marker for the more time-consuming and expensive MRI imaging in directing clinical response to pharmacotherapy, as well as primary outcomes in drug trials (7). Stratus time-domain OCT (TD-OCT, Carl Zeiss Meditech, Inc, Dublin, CA) has historically been used to quantitate RNFL thinning in patients with multiple sclerosis (MS) and/or optic neuritis, and acceptable reproducibility has been reported with this instrument (2,4,5,8-12).
Until recently, widespread applications of OCT technology 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, eliminating the need for a moving reference mirror, and allowing for more efficient data acquisition (15-17). FD-OCT instruments 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 instruments 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 reported. Furthermore, it is important to determine if measurements from early generation TD-OCT technologies and new generation FD-OCT technologies are compatible and consistent (17-19). Thus, in this study, cross-sectional comparisons of RNFL and CMT measurement were made in patients with MS and/or optic neuritis using 5 different commercially available OCT instruments, including the traditional TD-OCT (Stratus OCT) and 4 different FD-OCT instruments.
Forty-six patients diagnosed with optic neuritis and/or MS were enrolled from the Neuro-ophthalmology Clinic at the University 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 measurements 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, laterality, 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 gross motion 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.
Table 1 summarizes the features of the 5 different commercially available OCT instruments used in this study. 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 protocol, 3 scans, each composed of 256 A-scans, were acquired consecutively using a 3.46-mm diameter circular scan and an automated computer algorithm delineating 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 × 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 × 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 × 6 mm area (2.5 seconds). The optic nerve RNFL 200 × 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 × 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.
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 identify where differences occurred among the instruments. These post hoc tests were corrected for multiple comparisons 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 repeated measures models 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.
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 included in our final analysis. Demographic information and clinical diagnoses for included patients are shown in Table 2. The mean ± 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 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 comparisons), except for RTVue-100 and Cirrus (P = 0.12, corrected). In the right eye, all instruments were significantly 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 individual, 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 difference 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).
The recent advances in OCT in clinical management and research trials have led to the need for investigating differences 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 instruments 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 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 experience 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 measurement 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 μm 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 measured 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 thickness 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 instruments for mean average RNFL. The clinical significance of such findings is unknown. Ultimately, differences in data acquisition and software among the various OCT instruments should be carefully compared and eventually standardized 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 significant difference in RNFL and CMT measurements among commercially available TD- and FD-OCT instruments in patients with optic neuritis and/or MS. As retinal thickness measurements among OCT instruments have 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 necessarily 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.
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 acquisition. Special thanks also to Norman Siu (Heidelberg) and Eugene Huang, PhD, (Topcon) for making available the FD-OCT instruments used in this study. The authors also thank Jack Werner, PhD, for his valuable advice regarding this study.
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