This study reports both the rate of segmentation error and the importance of central 1-mm segmentation error on automated retinal thickness measurement errors in OCTs of patients with nAMD in treatment with anti-VEGF agents. In addition, this study suggests that acquiring up to two further optimized scan sets in a single imaging session may help reduce segmentation error but does not completely eliminate the problem. Analysis of our data suggests that evaluating line scans for a central 1-mm zone segmentation error to report a CSES score for patients may be a better way of identifying scan sets with automated retinal thickness measurement errors than using the onboard Stratus low confidence analysis message. Furthermore, patients with two or more line scans with central 1-mm segmentation error (high CSES) have a mean automated retinal thickness measurement error of 20% (median 12%) and in line with our results, we advise performing manual measurements of retinal thickness in this subgroup.
Ray et al.
3 reported the different types of artifact and error in OCT of patients with retinal disease and included a small subgroup of patients with nAMD, although not in a specific cohort undergoing anti-VEGF therapy. They found that 62.2% of scans were affected by retinal thickness measurement errors in patients with retinal disease, although no details were given regarding the 27 patients with nAMD. In addition, no analysis was performed to determine the relationship between segmentation errors and the magnitude of error in automated retinal thickness measurement. Others
4 have suggested that the methodology used by Ray et al. to identify image artifacts may have led to an underestimation of the rate of artifact and error. The study by Sadda et al.
4 characterized the rate and magnitude of segmentation error in OCT scans in a series of patients with a range of retinal disorders. They used a grading system with provision for weighting segmentation errors in the central 1-mm subfield and errors that were longer than 1 or 2 mm in length and a deviation of greater than one third of the true retinal thickness. This group reported a high rate of patients with OCT scans with retinal thickness measurement error (92%). Most scans (72.5%) were obtained with Stratus 4.0 software, with the remainder analyzed with the earlier version (ver. 3.0). Sadda et al. found a strong association between Stratus OCT software low analysis confidence and segmentation error. These results are similar to those obtained in this study although we report a better association between our CSES and retinal thickness measurement error than the Stratus low analysis confidence metric. In addition, we found good agreement between observers in determining segmentation error (κ = 0.73) with repeatable interobserver retinal thickness measurements (95% coefficient of repeatability = 31 μm or 11% of the mean thickness) using the standardized definition used in this study.
Measurement of retinal thickness was not an important consideration in patients with nAMD when the Stratus OCT segmentation software was first developed; however, with the arrival of new intravitreous anti-VEGF therapies, there has been great interest in quantifying changes in retinal thickness in these patients. The quantitative information is used to assess response to treatment, as part of the retreatment criteria for antiangiogenic therapy
2 and as an endpoint in clinical trials.
8 Accurate and repeatable measurements of retinal thickness are now important in this patient group, and segmentation error is an important cause of errors in retinal thickness measurement with Stratus OCT. Identification of the inner retinal boundary is rarely problematic, as there is usually a clear step change in signal between the inner retinal boundary and the low-reflectance vitreous, although epiretinal membrane and signal from the posterior hyaloid face can sometimes lead to segmentation error. Significant problems may arise, however, in the automated identification of the outer retinal boundary where changes in signal may be less definite especially in patients with nAMD with disease affecting the photoreceptor-RPE complex. The Stratus OCT identifies the inner HRB as the outer retinal boundary, even though studies have shown the HRB to correlate better with the photoreceptor inner- and outer-segment junction,
9 Use of the HRB to identify the outer retinal boundary to systematic error in retinal thickness measurement using the proprietary software. However, when disease affects the photoreceptor-RPE complex, there is disruption of the inner HRB, and in these cases the Stratus algorithm often uses the high-reflectance signal from the inner RPE surface to identify the outer retinal boundary. Any moderate-to-highly reflective subretinal lesion components (such as blood, CNV tissue, or fibrosis) in close association with the photoreceptor-RPE complex may lead to further difficulty in identifying the HRB, resulting in erroneous and variable identification of the outer retinal boundary by the segmentation software. In instances in which the Stratus segmentation algorithm uses the signal from the inner surface of the RPE to determine the outer retinal boundary, subretinal fluid may be erroneously included in the retinal thickness measurement.
Furthermore, calibration of OCT for retinal thickness measurements with optical path measurement using glass targets assumes a group index of refraction change that is based on normal tissue and not a mixture of fluid, lipids, and proteins not normally found in the retina, as may be the case in patients with nAMD, and further limits the accuracy of OCT-derived retinal thickness measurements in nAMD.
Since quantitative measures of exudation in nAMD are increasingly driving treatment, it is crucial that OCT measures be made accurate in the presence of exudation, where the index of refraction changes are not always sufficient to generate a strong coherence signal.
Our results suggest that visual acuity and retinal thickness do not influence segmentation error; however, the relationship between scan signal strength and CSES and retinal thickness measurement error is uncertain. Although caution should be applied to conclusions drawn from the subanalysis of factors influencing CSES and retinal thickness measurement error, the data from
Tables 2 and 3suggest a trend for scans with signal strength ≥7 for a higher mean retinal thickness measurement error, despite a lower CSES. This finding suggests that a greater magnitude of retinal thickness measurement error may result from fewer line scans with central 1-mm zone segmentation error (a lower CSES) in scan sets with a mean signal strength of ≥7. This result could be due to large-magnitude errors in retinal thickness resulting from areas of subretinal moderate-to-high reflectance lesion components in a few line scans (low CSES) giving rise to errors in identification of the true HRB and outer retinal boundary.
Fung et al.,
2 who used an OCT-guided variable dosage regimen with intravitreous ranibizumab (Lucentis; Genentech Inc., South San Francisco, CA) for nAMD, comment that OCT scanning was repeated until retinal boundaries were accurately identified by the algorithm. One of the purposes of our study was to see whether elimination of segmentation error was possible with repeat scanning within the limits of patient fatigue and imaging time.
In this study, repeat OCT scanning in patients with central 1-mm zone OCT scan segmentation error led to a further seven patients with central zone segmentation error-free scans after three optimized scans (a total of 40% of patients free of central 1-mm segmentation error). This result suggests that though operator and patient factors may lead to segmentation error in a proportion of patients with nAMD, failure of the Stratus algorithm is the underlying problem in most cases. This conclusion further implies that, although it is an important strategy for reducing segmentation error, repeated scanning may not eliminate the problem. Indeed even after three optimized scan sets were obtained there were still 18 patients (36%) with high CSES requiring manual measurement of retinal thickness. This finding is important, as it contrasts with reports from other studies that suggest that segmentation error may be eliminated with repeated scanning.
2 In addition, this finding is of importance due to the increasing use of quantitative OCT data in the treatment of patients with nAMD with anti-VEGF agents.