Measurement of Retinal Vascular Caliber from Optical Coherence Tomography Phase Images

Special Issue Measurement of Retinal Vascular Caliber From Optical Coherence Tomography Phase Images

Klemens Fondi,1 Gerold C. Aschinger,2,3 Ahmed M. Bata,1 Piotr A. Wozniak,1 Liang Liao,1 Gerald Seidel,4 Veronika Doblhoff-Dier,2,3 Doreen Schmidl,1,2 Gerhard Garh¨ofer,1 Rene´ M. Werkmeister,1 and Leopold Schmetterer1,2

1Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria 2Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria 3Institute of Applied Physics, Vienna University of Technology, Vienna, Austria 4Department of Ophthalmology, Medical University of Graz, Graz, Austria

Correspondence: Leopold Schmet- PURPOSE. To compare retinal vessel calibers extracted from phase-sensitive optical coherence terer, Department of Clinical Phar- tomography (OCT) images with vessel calibers as obtained from the Retinal Vessel Analyzer macology, Medical University of (RVA). Vienna, Währinger Gurtel¨ 18-20, 1090 Vienna, Austria; METHODS. Data from previously published studies in 13 healthy subjects breathing room air (n leopold.schmetterer@meduniwien. ¼ 214 vessels) and 7 subjects breathing 100% oxygen (n ¼ 101 vessels) were used. Vessel ac.at. calibers from OCT phase images were measured vertically along the optical axis by three Submitted: October 22, 2015 independent graders. The data from RVA fundus images were corrected for magnification to Accepted: December 17, 2015 obtain absolute values. Citation: Fondi K, Aschinger GC, Bata RESULTS. The average vessel diameter as obtained from OCT images during normoxia was AM, et al. Measurement of retinal lower than from RVA images (83.8 6 28.2 lm versus 86.6 6 28.0 lm, P < 0.001). The same vascular caliber from optical coher- phenomenon was observed during 100% oxygen breathing (OCT: 81.0 6 22.4 lm, RVA: 85.5 ence tomography phase images. In- 6 26.0 lm; P ¼ 0.001). Although the agreement between the two methods was generally vest Ophthalmol Vis Sci. high, the difference in individual vessels could be as high as 40%. These differences were 2016;57:OCT121–OCT129. neither dependent on absolute vessel size nor preferably found in specific subjects. DOI:10.1167/iovs.15-18476 Interobserver differences between OCT evaluators were much lower than differences between the techniques.

CONCLUSIONS. Extracting vessel calibers from OCT phase images may be an attractive approach to overcome some of the problems associated with fundus imaging. The source of differences in vessel caliber between the two methods remains to be investigated. In addition, it remains unclear whether OCT-based vessel caliber measurement is superior to fundus camera–based imaging in risk stratiﬁcation for systemic or ocular disease. (ClinicalTrials.gov numbers, NCT00914407, NCT02531399.) Keywords: retinal vessel diameter, humans, retinal perfusion

etinal vascular calibers are usually measured from fundus A potential approach to overcome these problems is to use R photographs using digital imaging.1 Most approaches optical coherence tomography (OCT). This technique offers the nowadays follow the formula developed by Hubbard and advantage of easier recording, provides three-dimensional coworkers1 to calculate the central retinal arteriolar equivalent information, and is, at least in depth, independent of magnifi- (CRAE) and the central retinal venular equivalent (CRVE). The cation problems. The measurement of vascular caliber data from dimensionless quotient arteriovenous ratio (AVR) is used in OCT images is, however, not straightforward. In OCT, larger most studies because it is independent of the magnification of retinal vessels cause a characteristic shadowing effect that is the image, which depends on both the optics of the fundus caused by the scattering of light at red blood cells (RBCs). camera and the optical properties of the eye.1 Extraction of data can be done either vertically along the axis of Because abnormalities in retinal vascular calibers are the illuminating beam or horizontally in the retinal plane. In this associated with a wide variety of cardiovascular, ocular, kidney, context, it needs to be considered that the resolution of typical and brain diseases, accurate measurement of retinal vascular commercially available OCT systems is in the order of 5 lm calibers is desired.2 However, some limitations of the currently verticallyand15to20lm horizontally.4 In larger vessels, a available technology prevent the translation of such measure- characteristic shadowing effect caused by the scattering of light ment into clinical praxis: the absolute measurement of vessel at RBCs can impair accurate vessel delineation. It follows that caliber is not possible, measurements are usually done from several different approaches were published to extract caliber one fundus image only and recorded at an undefined time point data from retinal vessels based on OCT.5–8 during the cardiac cycle, pupil dilatation is required, and the In the present study, we set out to measure retinal vascular three-dimensional geometry of the vessel is not taken into caliber from the phase values of the complex OCT signal. More account.2,3 than a decade ago, it was shown that extraction of the phase

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from Fourier-domain OCT (FD-OCT) images can be used to contrast blood vessels.9,10 Nowadays these techniques are widely used in OCT angiography and also form the basis for quantitative blood ﬂow measurement.11 This approach was used in the present study to measure vessel diameters and then compare them to the measurements of vessel calibers from fundus images in healthy subjects.

METHODS Subjects The data in the present report were obtained from one yet unpublished study and two studies that were published previously.12,13 The studies were undertaken to measure total retinal blood ﬂow and total retinal oxygen extraction in healthy subjects. The study protocols were approved by the Ethics Committee of the Medical University of Vienna and followed the guidelines set forth in the Declaration of Helsinki. All subjects passed a screening examination before the study day that included a physical examination, blood sampling to assess hematologic status and chemistry, a 12-lead electrocardiogram, the measurement of visual acuity, slit lamp biomicroscopy, funduscopy, and the measurement of IOP. Exclusion criteria were ametropia ‡3 diopters, anisometropia ‡3 diopters, other ocular abnormalities, and any clinically relevant illness as judged by the investigators, as well as a blood donation or intake of any medication in the 3 weeks before the study. The participants had to abstain from beverages containing alcohol or caffeine in the 12 hours before the study visit.

Protocol The measurements were conducted under dilated pupil conditions using a custom-built dual-beam bidirectional Doppler FD-OCT to measure phase shifts and a Retinal Vessel Analyzer (RVA; Imedos Systems UG, Jena, Germany) to quantify vessel calibers.12,13 Subjects were measured while breathing ambient air (n¼ 13) or 100% oxygen (n ¼ 7, gases for human use; Messer, Vienna, Austria), which was delivered via a partially expanded reservoir bag at atmospheric pressure. The phase of inhaling 100% oxygen lasted 30 minutes and measurements began 15 minutes after the start of the inhalation.

Extraction of Retinal Calibers From OCT Phase Images The measurements were performed with a dual-beam Doppler FD-OCT system as described in detail previously.12,14,15 Briefly, two orthogonally polarized probe beams under a known angle Da are used to illuminate the fundus. The system records the FIGURE 1. Sample measurement in a healthy subject. Fundus image (A) spectra of the two channels as a function of frequency using and OCT phase image (B) are acquired at the same position. Data from two identical spectrometers. When the beams fall onto blood fundus images are obtained within the retinal plane, data from phase vessels, the back-reflected light in each channel is Doppler- OCT images are obtained from the depth profile, because OCT provides better resolution in depth than transversally. shifted because of the movement of the RBCs. We have shown that with such a setup it is possible to measure absolute blood flow in particular retinal vessels14 as well as total retinal blood phase image from the channel that showed better phase flow.12 The refractive index of blood (1.37) at the used light contrast between moving RBCs and static tissue. The outer source’s wavelength was included in the calculations.14 In the border of the phase-shifted areas was determined manually by current study, we extracted retinal calibers from these three independent observers (KF, AMB, LL). The retinal vessel measurements (Fig. 1). A total of 60 frames were recorded diameter as obtained from the OCT phase images was defined for each vessel during a measurement period of 5 seconds. as the mean of those seven measurements. Hence, our observation time was longer than one cardiac cycle. Frames 0, 10, 20, 30, 40, 50, and 59 of each recording Extraction of Retinal Calibers From Fundus Images were evaluated, resulting in a total of seven diameter readings for each vessel. In each of these images, the areas with phase The OCT setup is integrated into a commercially available RVA shifts caused by the moving RBCs were evaluated, using the (Imedos Systems UG), and the details of this coupling were

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FIGURE 2. Bland-Altman plots comparing retinal vessel diameters as obtained with OCT and RVA. Data are presented during both breathing room air and 100% oxygen. Retinal arteries (red) and retinal veins (blue) are presented separately. On the x-axis, the mean value of RVA and OCT data are presented; on the y-axis, the difference between values as obtained with RVA and OCT is shown.

recently reported.12 Imaging with the RVA is done via a fundus OCT data by linear correlation analysis. Data during ambient camera (FF450plus; Carl Zeiss Meditec AG, Jena, Germany) and room air breathing and 100% oxygen breathing were calculated a charge-coupled device camera allowing for the measurement separately. A P value less than 0.05 was considered statistically of retinal vessel diameters. The principle of measurement of significant. All statistical analysis was done with SPSS Version vessel diameters with this technique is essentially a measure- 22 (IBM SPSS Statistics, Armonk, NY, USA). ment of the width of the RBC column inside the vessels.3,16 In the present study, we used a prototype analyzing software provided by Imedos, which allows for calculation of absolute RESULTS values in micrometers based on the individual axial eye length, the axial refraction for each subject, and the optical A total of 214 retinal vessels were evaluated under breathing characteristics of the fundus camera system. This software room air. The average vessel diameter in OCT images was 83.8 was already used in our previous studies.12,13 6 28.2 lm; the average vessel diameter in RVA images was 86.6 6 28.0 lm. The difference of 2.8 6 10.7 lm was statistically significant (P < 0.001). During 100% oxygen breathing, a total Statistical Analysis of 101 vessels were evaluated. Again, the retinal vessel From our data, CRAE, CRVE, as well as AVR were calculated. diameters were smaller when evaluated using OCT (81.0 6 This was done by using the formula developed by Hubbard and 22.4 lm) as compared with RVA (85.5 6 26.0 lm; t-test P ¼ coworkers,1 in the revised version of Knudtson et al.17 As 0.001). Bland-Altman plots for comparing OCT and RVA data explained above, the retinal vessel diameters from the OCT are presented in Figure 2. The data are presented separately for measurements were calculated as the means obtained by the arteries and veins. As evidenced also from t-test analysis, data three evaluators. Retinal vessel diameter data were then were slightly higher when measured with RVA, although the compared between the two methods that we used. Several difference is small. In some cases, however, considerable types of analysis were performed. Paired t-tests were used to differences were found between RVA and OCT data. These calculate significant differences between the two techniques. deviations were as high as 40% and seen equally in arteries and In addition, we prepared Bland-Altman plots and plotted the veins. This is also shown in the graphs summarizing the frequency of relative differences. Linear correlation analysis frequencies of relative differences between the two measuring was done for each subject individually. Furthermore, we methods (Fig. 3). During normoxia, 61.9% of the retinal analyzed the differences among the three evaluators of the arteries and 66.3% of the retinal veins were larger when

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FIGURE 3. Relative difference in retinal vessel diameters as obtained with OCT and RVA. Data are presented during both breathing room air and 100% oxygen. Retinal arteries (red) and retinal veins (blue) are presented separately.

measured with RVA than OCT. During hyperoxia, 62.3% and DISCUSSION 66.7% of retinal arteries and retinal veins, respectively, were larger when measured with the RVA than with OCT, In the present study, we explore the opportunity to measure respectively. retinal vascular calibers from OCT phase images. This may be In Figures 4 and 5, the individual correlations for retinal an attractive approach because the contrast between blood arteries and retinal veins are presented during normoxia and vessels and the surrounding tissue is higher in phase than in hyperoxia, respectively. Correlations were generally high, and amplitude images. Our data indicate good agreement between the regression line was close to 45 degrees. For retinal veins retinal vessel caliber measurements by OCT and caliber during normoxia, the deviations from regression line slopes of measurements on fundus images. Data as obtained with OCT 1 were small. Only one case (subject 8) showed a slope of were, however, slightly lower than those obtained with the regression line of 0.46 during breathing room air. This subject’s RVA. In addition, deviations in some individual vessels were correlation in the retinal arteries was, however, good. relatively high. The lower average data as obtained with phase-sensitive Figure 6 presents the relative differences between OCT and OCT may be caused by the phase noise of the OCT system. RVA data for each investigator separately. The data indicate that Whereas in fundus imaging the vessel caliber is defined by the the RVA values were always higher than OCT values column of the RBCs,3 in phase-sensitive OCT, the caliber independently of the evaluator. The differences between the information is extracted from the velocity data. Very low evaluators were considerably smaller than the differences velocities close to the vessel wall may therefore be missed with between the methods. the OCT technology because of the phase noise of the system. Figure 7 shows the linear regression analysis for the data In our measurements, we minimize this problem by using obtained by the three investigators. During normoxia, the oversampling,15,18 but still the diameter may be underestimat- correlation was high (correlation coefficients between 0.95 ed accordingly. Alternatively, it also may be that vessel and 0.96) with the slope of regression lines close to 1 (between diameters as obtained from fundus images in the present study 0.99 and 1.01). During hyperoxia, the slope of regression lines are too large. This could, for instance, result from imperfect was also close to 1 (between 0.94 and 0.98) but the correlation focusing of the retinal plane during RVA measurements, was weaker (correlation coefficients between 0.73 and 0.85). although care was taken to obtain optimal image quality. Figure 8 compares CRAE, CRVE, and AVR between the two Moreover, one has to consider that the shape of the vessel is methods. Under normoxia, mean CRAE (154.5 6 11.9) and not necessarily circular and that RVA and OCT, as used in the CRVE (227.6 6 17.5) with a mean AVR of 0.68 6 0.04 present study, measure horizontal and vertical diameters, calculated from the OCT data were again smaller than the RVA respectively. If such a phenomenon exists, it should, however, data (CRAE 158.4 6 13.4, CRVE 231.2 6 25.4, AVR 0.69 6 be more pronounced in veins than in arteries because of the 0.06). But these differences did not reach statistical signifi- lower transmural pressure. cance (CRAE P ¼ 0.15, CRVE P ¼ 0.46, AVR P ¼ 0.46). Similarly, In the absence of a true gold standard technology for under hyperoxia, these equivalents were also smaller in the measuring absolute vessel diameters, it is difficult to answer OCT data (CRAE 142.0 6 11.2, CRVE 195.4 6 10.9, AVR 0.73 which of the examined techniques shows better validity. As 6 0.06) than in the data from the RVA (CRAE 149.7 6 11.0, shown in Figures 2 and 3, the values obtained by the two CRVE 211.6 6 28.5, AVR 0.72 6 0.09). Also under hyperoxia, techniques can in some vessels differ considerably. The these differences did not reach a level of statistical significance reasons for these differences are not clear. The Bland-Altman (CRAE P ¼ 0.10, CRVE P ¼ 0.08, AVR P ¼ 0.80). plots presented in Figure 2 indicate that this is not more

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FIGURE 4. Correlation of retinal vessel diameters as obtained with OCT and RVA in individual subjects. Data are presented during breathing room air. Retinal arteries (red) and retinal veins (blue) are presented in the same graph.

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FIGURE 5. Correlation of retinal vessel diameters as obtained with OCT and RVA in individual subjects. Data are presented during 100% oxygen breathing. Retinal arteries (red) and retinal veins (blue) are presented in the same graph.

frequently found in vessels of smaller calibers. This would between evaluators was much higher than between OCT be the case if phase noise would be responsible, because and RVA (see also Fig. 6). there is a linear correlation between velocity and diameter Interestingly, the data presented in Figure 7 indicate that in retinal vessels.19,20 The data presented in Figures 4 and 5 there was better agreement between observers during indicate that the differences between the methods are not normoxia than during hyperoxia. It is well established that primarily found in selected subjects, but rather are observed during 100% oxygen breathing, retinal vessels show pro- in individual vessels of some subjects. This also indicates nounced vasoconstriction associated with a pronounced that magniﬁcation problems with the RVA are not the reduction in retinal blood ﬂow and retinal oxygen extrac- primarysourceofthesedifferences.Finally,Figure7 tion.13,21–25 Assuch,ourdatamightindicatethatthe indicates that the main difference between the RVA and interobserver variability is less pronounced in larger than in OCT is not due to grader differences, because agreement smaller vessels. To which degree an automated measurement

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FIGURE 6. Relative difference in retinal vessel diameters as obtained with OCT and RVA presented for each evaluator separately. Data are presented during both breathing room air and 100% oxygen.

FIGURE 7. Correlation of retinal vessel diameters as obtained from different evaluators using OCT data. Data are presented during room air and 100% oxygen breathing.

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FIGURE 8. Bland-Altman plots comparing CRAE, CRVE, and AVR as obtained with OCT and RVA. Data are presented during both breathing room air and 100% oxygen. On the x-axis the mean value of RVA and OCT data are presented; on the y-axis, the difference between values as obtained with RVA and OCT is shown.

of vessel diameters from phase images would reduce the whether the measurement of absolute vessel caliber offers difference between RVA and OCT data remains to be advantages in this respect. investigated. In conclusion, the measurement of vessel calibers from In the present study, we used images as obtained with a OCT data may be an attractive approach for future studies. bidirectional Doppler OCT system to extract vessel caliber Further studies are required to better understand the relation data. This system was originally developed for measuring total between data as obtained from fundus imaging and those 12 retinal blood flow and for extracting three-dimensional extracted from OCT. Extracting phase data from OCT images 26 velocity profiles. For the present application, this has the may, however, overcome some of the limitations of classical advantage that two images were available, of which the one fundus imaging and may therefore be an interesting approach with the better contrast could be chosen for evaluation. for risk stratification in systemic and ocular disease. Furthermore, with this OCT system, images were recorded over a certain period of time, providing representative mean vessel caliber values, whereas fundus images are taken with the Acknowledgments RVA at a single undefined time point during the cardiac Supported by the Austrian Science Foundation (FWF; Projects 3,12 cycle. Other investigators used faster Doppler OCT systems P26157, KLI250, KLI 283, and KLI340). for measuring retinal blood flow either using B-scans or enface images.27–31 How the diameter data as obtained with such Disclosure: K. Fondi, None; G.C. Aschinger, None; A.M. Bata, technologies compares with fundus camera–based imaging None; P.A. Wozniak, None; L. Liao, None; G. Seidel, None; V. remains to be investigated. Doblhoff-Dier, None; D. Schmidl, None; G. Garhofer¨ , None; A wide variety of large-scale studies have looked into the R.M. Werkmeister, None; L. Schmetterer, None association between retinal vascular calibers and disease. Among others, clear associations with altered retinal vascular References diameters were shown for incident stroke,32,33 systemic hypertension,34 diabetic retinopathy,35 and glaucoma.36 In 1. Hubbard LD, Brothers RJ, King WN, et al. Methods for these studies, CRAE, CRVE, or AVR were used for risk evaluation of retinal microvascular abnormalities associated assessment. Figure 8 indicates that CRAE, CRVE, and AVR with hypertension/sclerosis in the atherosclerosis risk in may significantly differ if taken from either OCT or RVA. How communities study 1. Ophthalmology. 1999;106:2269–2280. OCT and fundus imaging data compare in risk assessment is 2. Ikram MK, Ong YT, Cheung CY, Wong TY. Retinal vascular therefore unknown. In addition, it remains to be established caliber measurements: clinical significance, current knowl-

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