- Email: [email protected]
Reproducibility of Optical Coherence Tomography Measurements in Children
Reproducibility of Optical Coherence Tomography Measurements in Children IRENE ALTEMIR, VICTORIA PUEYO, NOEMI ELÍA, VICENTE POLO, JOSE M. LARROSA, AND DANIEL OROS ● PURPOSE:
To determine the interobserver and intraobserver reproducibility of a Fourier-domain optical coherence tomography device (Cirrus HD OCT; Carl Zeiss Meditec, Dublin, California, USA) in normal pediatric eyes. ● DESIGN: Prospective cross-sectional study. ● METHODS: One hundred healthy children were recruited prospectively and consecutively. Only 1 randomly chosen eye per subject was included in the study. The eye underwent 3 scans centered on the optic disc and another 3 scans centered on the macula that were acquired by a single operator. A fourth examination was performed by a second operator. Interobserver and intraobserver reproducibility were described by intraclass correlation coefficients (ICCs) and coefficients of variation (COVs). ● RESULTS: The mean age was 9.15 years (range, 6.22 to 11.31 years; standard deviation, 1.05 years). Mean retinal nerve fiber layer thickness was 99.53 m (standard deviation, 10.10 m), and mean macular thickness was 282.91 m (standard deviation, 11.83 m). All the parameters evaluated were highly reproducible. Intraobserver COVs of the retinal nerve fiber layer measurements ranged from 2.24% to 5.52%, and the COV of macular thickness was 0.97%. The intraclass correlation coefficient was greater than 0.8 for all the parameters. The interobserver COV ranged from 2.23% to 5.18%, and the COV of macular thickness was 0.82%. In all the evaluated parameters, the intraclass correlation coefficient was more than 0.75. Repeatability was slightly better in children older than 10 years than in children younger than 9 years. ● CONCLUSIONS: Retinal nerve fiber layer and macular measurements obtained by Fourier-domain optical coherence tomography showed good repeatability for healthy eyes in the pediatric population. Cirrus HD OCT examinations of the retina are reliable in children. (Am J Ophthalmol 2013;155:171–176. © 2013 by Elsevier Inc. All rights reserved.) Accepted for publication June 18, 2012. From the Department of Ophthalmology, Hospital Universitario Miguel Servet, Zaragoza, Spain (I.A., V.Pu., V.Po., J.M.L.); the Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain (V.Pu., V.Po., J.M.L., D.O.); Department of Applied Physics, University of Zaragoza, Zaragoza, Spain (N.E.); and the Department of Obstetrics, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain (D.O.). Inquiries to Victoria Pueyo, Department of Ophthalmology, Hospital Universitario Miguel Servet, C. Isabel la Católica 1-3, 50009 Zaragoza, Spain; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2012.06.012
©
2013 BY
I
N RECENT YEARS, SEVERAL DEVICES THAT ALLOW AN
objective and quantitative evaluation of retinal structures have become useful in clinical practice because of the need for objective tests that complement funduscopy or photographs, especially in children, in whom they may prove difficult to perform. One of instrument that is becoming increasingly popular in pediatric ophthalmology is optical coherence tomography (OCT). OCT is a noninvasive, noncontact method that uses low-coherence interferometry to perform high-resolution cross-sectional imaging of tissue morphologic features, providing an optical biopsy.1 The latest OCT devices, Fourier-domain (FD) OCTs, offer increased resolution compared with time-domain instruments. Current commercially available OCT instruments provide improved axial image resolution, between 5 and 7 m, compared with earlier generations of OCT that ranged between 8 and 10 m.1–3 A number of publications have proved the feasibility and validity of this technique in different clinical applications in children for diseases such as glaucoma, retinopathy of prematurity, and neurofibromatosis type 1.4 – 6 All the OCT devices have an integrated normative database, which includes only individuals 18 years of age and older. To evaluate changes in retinal measurements accurately, it is first necessary to determine the range in the normal population and to quantify the accuracy, reproducibility, and repeatability of measurements made by the system.7 The objectivity and reproducibility of Cirrus OCT have been proven by several authors in adults, but never in children.8 –15 The purpose of the present study was to examine the interobserver and intraobserver reproducibility of repeated measurements of the retinal nerve fiber layer (RNFL), optic disc, and macular measurements with an FD OCT in healthy children.
METHODS THIS STUDY WAS UNDERTAKEN IN AN ELEMENTARY
school from December 2010 through March 2011 as part of the Environmental Fetal Factors in the Development of the Optic Nerve and the ReTina study (EFFORT). From the 598 eligible children, 358 were included in the study, giving an acceptance rate of 60%. One hundred healthy children were recruited prospectively and consecutively
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TABLE 1. Optical Coherence Tomography Measurements in Children Obtained by 2 Examiners
Average RNFL, m Superior RNFL, m Temporal RNFL, m Inferior RNFL, m Nasal RNFL, m Rim area, mm2 Disc area, mm2 Cup-to-disc area ratio Macular thickness, m Macular volume, mm3
Measurement 1
Measurement 2
Measurement 3
P Valuea
Measurement 4
P Valueb
99.53 ⫾ 10.10 125.57 ⫾ 18.05 68.78 ⫾ 10.68 133.14 ⫾ 17.34 70.99 ⫾ 12.02 1.59 ⫾ 0.33 2.06 ⫾ 0.38 0.43 ⫾ 0.17 282.91 ⫾ 11.83 10.18 ⫾ 0.43
98.68 ⫾ 10.80 123.66 ⫾ 18.10 68.94 ⫾ 11.10 131.40 ⫾ 20.14 70.74 ⫾ 13.01 1.59 ⫾ 0.31 2.05 ⫾ 0.37 0.42 ⫾ 0.17 282.76 ⫾ 12.04 10.18 ⫾ 0.44
99.13 ⫾ 9.98 125.11 ⫾ 17.20 68.61 ⫾ 9.21 130.82 ⫾ 21.12 72.19 ⫾ 12.69 1.62 ⫾ 0.32 2.09 ⫾ 0.36 0.43 ⫾ 0.16 282.56 ⫾ 12.59 10.17 ⫾ 0.46
.34 .64 .34 .39 .68 .77 .82 .94 .67 .52
98.59 ⫾ 10.04 124.36 ⫾ 16.98 68.41 ⫾ 10.10 131.56 ⫾ 16.47 70.28 ⫾ 13.40 1.57 ⫾ 0.32 2.02 ⫾ 0.38 0.42 ⫾ 0.17 282.29 ⫾ 10.16 10.16 ⫾ 0.44
.03 .30 .56 .08 .39 .48 .18 .21 .14 .15
RNFL ⫽ retinal nerve fiber layer. Measurements 1, 2, and 3 correspond to examinations performed by the first examiner, and measurement 4 corresponds to the examination performed by the second examiner. Data are reported as mean ⫾ standard deviation unless otherwise noted. a Significance of the comparison among measurements 1, 2, and 3. b Significance of the comparison between measurements 1 and 4.
from among the 358 for the reproducibility and repeatability study.16 All subjects underwent a comprehensive ophthalmologic evaluation that included monocular visual acuity (HOTV chart read at 300 cm), stereopsis assessment (TNO test at 40 cm), ocular motility evaluation, and retinal and optic nerve assessments by means of OCT (Humphrey Zeiss Instruments, Dublin, California, USA). All children with abnormal results (visual acuity worse than 20/25, strabismus, or history of ocular diseases) were examined under cycloplegic mydriasis and the refractive error was measured. The RNFL and optic disc measurements were obtained using the optic disc cube 200 ⫻ 200 protocol. Under this protocol, a 3-dimensional cube of data is generated over a 6-mm2 grid of 200 horizontal scan lines, each composed of 200 A-scans. A Cirrus software algorithm automatically detects the center of the optic disc from this volume scan and positions a 3.46-mm diameter calculation circle over this point. From the 256 A-scans along this circle, the borders of the RNFL are delineated and thickness is calculated at each point along the circle. The macular images were obtained using the macula cube 200 ⫻ 200 protocol. This protocol generates 200 ⫻ 200 volume cube images with 200 linear scans performed by A scans and analyzes a cube 6 mm in diameter around the macula. Retinal thickness was calculated using the built-in macular analysis software on the Cirrus device, which is determined automatically by taking the difference between the inner limiting membrane and retinal pigment epithelium boundaries. The examinations were performed without pupil dilation.17 Only scans with 7 strength/signal or more were accepted. Images with artifacts or missing parts were excluded and repeated. Internal fixation was used to suppress ocular movements, because it results in the 172
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TABLE 2. Intraobserver Reproducibility of Optical Coherence Tomography Measurements in Children: Intraobserver Coefficients of Variation and Intraclass Correlation Coefficients of the Measurements
Average RNFL Superior RNFL Temporal RNFL Inferior RNFL Nasal RNFL Rim area Disc area Cup-to-disc area ratio Macular thickness Macular volume
COV (%)
ICC
2.24 4.54 3.93 5.01 5.52 10.64 7.75 11.25 0.97 1.00
0.957 0.928 0.877 0.888 0.908 0.858 0.885 0.972 0.942 0.940
COV ⫽ coefficient of variation; ICC ⫽ intraclass correlation coefficient; RNFL ⫽ retinal nerve fiber layer.
highest reproducibility.8 Three scans were performed by a single operator (I.A.), and a fourth scan was performed by a second operator (N.E.). Between scans, subject position and focus were disrupted randomly, and alignment parameters had to be newly adjusted at the start of each image acquisition. The parameters collected were mean RNFL thickness (360 degrees), RNFL thickness in 4 quadrants (inferior, superior, nasal, temporal), ring area, disc area, cup-to-disc area ratio, macular thickness, and macular volume. To be enrolled in the project, written informed consent was given by the parents or guardians of the child. The only exclusion criterion was the absence of a signed informed consent. Because we wanted to examine a sample representative of the normal pediatric population, no other exclusion criteria were considered. Statistical analyses OF
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FIGURE 1. Bland-Altman plots showing the level of intraobserver concordance between the optical coherence tomography measurements of the retinal nerve fiber layer (RNFL) and macula in children.
were carried out with the Statistical Package for the Social Sciences version 15.0 (SPSS, Inc, Chicago, Illinois, USA). Interobserver and intraobserver reproducibility were described by intraclass correlation coefficients (ICCs) and coefficients of variation (COVs). For the intraobserver study, we compared the results from the first 3 examinations performed by the same examiner (I.A.). For the interobserver study, the first and the fourth examinations were compared because they were performed by 2 different examiners (I.A., N.E.). COVs were calculated as the standard deviation divided by the average of the measurement value, expressed as a percentage. A COV of less than 10% was considered reproducible and a COV of less than 6% was considered highly reproducible. The ICCs were considered to provide slight reliability (values between 0 and 0.2), fair reliability (values between 0.21 to 0.4), moderate reliability (values between 0.41 and 0.6), substantial reliability (values between 0.61 to 0.8), or almost perfect reliability (values of more than 0.81). COVs obtained in different groups of children were compared according to their age. Children were divided into categories younger than 9 years (34 children), from 9 to 10 years (36 children), and older than 10 years (30 children). COVs were compared by analysis of variance with the Bonferroni post hoc test. P values less than .05 (P ⬍ .05) were considered statistically significant. For multiple comparisons, we used the Bonferroni post hoc correction.
TABLE 3. Interobserver Reproducibility of Optical Coherence Tomography Measurements in Children: Interobserver Coefficients of Variation and Intraclass Correlation Coefficients of the Measurements
Average RNFL Superior RNFL Temporal RNFL Inferior RNFL Nasal RNFL Rim area Disc area Cup-to-disc area Macular thickness Macular volume
2.23 4.00 3.41 3.46 5.18 8.68 7.25 9.21 0.82 0.85
0.955 0.881 0.901 0.928 0.886 0.773 0.825 0.957 0.949 0.945
6.22 to 11.31 years, with a mean age of 9.15 years. Mean best-corrected visual acuity (logarithm of the minimal angle of resolution) was ⫺0.01 (20/20 Snellen equivalent), with a range from 0.3 to ⫺0.2. The refractive errors ranged from ⫺3.00 to ⫹4.50 of spherical equivalent. Stereoacuity was full (60 seconds of arc or better) in 94 children and was reduced (worse than 60 seconds of arc) in 6 children. Twenty-nine of 100 children (29%) demonstrated ocular motility anomalies (21 exophoria (21%), 6 endophoria (6%), 2 esotropia (2%)). No patient from the study had to be excluded because of bad OCT image quality. Table 1 shows the results obtained in the global and sectorial analysis of the RNFL and macula, measured by
ONE HUNDRED CHILDREN WERE INCLUDED IN THE STUDY
(52 boys and 48 girls). The age of the patients ranged from REPRODUCIBILITY
ICC
COV ⫽ coefficient of variation; ICC ⫽ intraclass correlation coefficient; RNFL ⫽ retinal nerve fiber layer.
RESULTS
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FIGURE 2. Bland-Altman plots showing the level of interobserver concordance between the optical coherence tomography measurements of the retinal nerve fiber layer (RNFL) and macula in children.
OCT by observer 1 in the first, second, and third scans and by observer 2 in the fourth scan. None of the differences between measurements may be considered as statistically significant after Bonferroni correction for multiple comparisons. As expected, quadrant distribution followed a double-hump pattern, being higher for the inferior quadrant, followed by superior, nasal, and temporal quadrants. Mean differences between the measurements obtained by the 2 operators were less than 3 m in all parameters evaluated. ● INTRAOBSERVER
and macular thickness reproducibility between the 2 observers. Although most of the measurements showed higher COVs in younger children compared with older children, differences were not statistically significant for any parameter (mean RNFL thickness COV, 2.91% in the group of children younger than 9 years and 1.82% in the group of children 9 years of age or older; P ⫽ .133).
DISCUSSION
One hundred children were included in the intraobserver study. All RNFL and macular measurements were highly reproducible. COVs and ICCs of the measurements are presented in Table 2. Optic nerve parameters showed lower reproducibility. The parameter exhibiting the highest intraobserver reproducibility was the average RNFL with a COV of 2.24%. ICCs showed an almost perfect reliability in all the parameters evaluated (ICCs ⬎ 0.81), and the ICC was 0.957 for the average RNFL. Figure 1 shows Bland-Altman plots of the average RNFL thickness and macular thickness reproducibility between the intraobserver measurements. REPRODUCIBILITY:
OCT IS PART OF DAILY CLINICAL PRACTICE. RELIABILITY
and repeatability of diagnostic tools need to be ascertained, especially in children, whose cooperation is limited. Cirrus OCT represents the latest commercially available generation of OCT, with higher axial resolution compared with conventional time-domain OCT. To our knowledge, this is the first report of the study of the reproducibility of the RNFL and macular measurements using high-density FD OCT in healthy children. Direct comparison of RNFL values between the different OCT devices may be difficult because of different technical specifications, imaging protocols, and different thickness measurement algorithms. Cirrus OCT measurements result in larger retinal thickness.18 Our study shows that reproducibility of Cirrus OCT in the pediatric population is excellent, both for RNFL and macular measurements. RNFL and macular measurements provided by Cirrus OCT in children differ from those provided by previous OCT devices. The measurements we obtained in children are comparable with those reported in adults. We found an average RNFL thickness of 98.59 to 99.53 m and a macular
● INTEROBSERVER REPRODUCIBILITY: One hundred children were included in the interobserver study. COVs and ICCs of the measurements are presented in Table 3. All the RNFL and macular measurements were highly reproducible. Optic nerve parameters showed lower reproducibility. The highest interobserver reproducibility was observed for the average RNFL, with a COV of 2.23%. ICCs showed almost perfect reliability in all parameters evaluated, and the ICC was 0.955 for mean RNFL. Figure 2 shows Bland-Altman plots of average RNFL thickness
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thickness of 282.29 to 283.03 m, which is in agreement with previous results obtained in adults.12,19,20 Differences among commercially available devices in the acquisition and analyses of the images can be observed in the optic nerve and retinal measurements.21–24 FD OCT has demonstrated advantages over time-domain OCT in the retinal evaluation of healthy eyes,25 but reproducibility of the new Cirrus OCT devices in healthy children has not yet been reported. Our study suggests that Cirrus OCT shows good intraobserver and interobserver reproducibility when measuring macular and RNFL thickness in the normal pediatric population. Most of the parameters showed a COV of less than 5%, which is highly reproducible and clinically adequate. Our values of intraobserver and interobserver reproducibility are in good agreement with several other studies previously performed in adults. Menke and associates assessed the reproducibility of the RNFL measurements provided by FD OCT in 38 normal subjects.13 Intrasession reproducibility was good, with a mean ICC of 0.90 and mean COV of 4.2% and 4% for operator 1 and 2, respectively. Interobserver reproducibility also was good, with only 0.9 m of the mean difference between measurements of operator 1 and 2. García-Martín and associates tested the reproducibility of RNFL and macular measurements from 72 healthy subjects with the Cirrus spectral-domain OCT device.12 The mean COV for intraobserver reproducibility was 1.2% for macular thickness and 4.4% for average RNFL thickness. The ICCs ranged from 0.823 to 0.992. Interobserver reproducibility differences between both operators were less than 3 m. As in these studies, we found the worst reproducibility in the nasal quadrant, with an intraobserver COV of
5.73% and an interobserver COV of 5.17%. The average RNFL thickness showed the highest reproducibility, with a COV of 2.78% and 2.17% for intraobserver and interobserver reproducibility, respectively. The only parameters with COVs of more than 5% are the optic nerve head parameters (disc area, rim area, and cup-to-disc area ratio). This may be because of increased susceptibility of these measurements to an imprecise centering. Previous versions of OCT showed good reproducibility in children. Eriksson and associates reported a COV lower than 2% and an ICC higher than 0.9 in all macular areas in children.24 Wang and associates reported a COV of less than 5%, less than 8%, and less than 13%, respectively, for macular thickness, RNFL thickness, and optic disc parameters.26 These results are comparable with ours obtained with the latest commercially available version of OCT and with those obtained in adults.9,15 Limitations of the present study are mainly related to possible confounding factors influencing the examination. Axial length was not taken into account. We assume that our measurements were obtained in children without high refractive errors or ocular disease, and it could be related to higher reproducibility. Another limitation may be that all the examinations were performed the same day and with the same device. However, previous authors have shown that measurements are not significantly affected by these factors.14 OCT has been shown to be a useful tool to examine the retina in children. However, for a diagnostic instrument to be considered clinically adequate, it must be highly reproducible. Our study reports that FD OCT measurements of the macula, RNFL, and optic nerve are reliable and highly reproducible in children 6 to 12 years of age.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF interest and none were reported. This study was supported by the Jesus de Gangoiti Barrena Foundation (Bilbao, España). Involved in Design and conduct of study (I.A., V.Pu., N.E., D.O.); Collection, management, and interpretation of data (I.A., V.Pu., N.E., D.O., V.Po., J.L.); and Preparation and review of manuscript (I.A., V.Pu., N.E., D.O., V.Po., J.L.). This was a prospective study. This study adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee (Comité Ético de Investigación Clínica de Aragón). Informed consent for research was obtained from each enrolled child and was signed by each child’s parents or guardians.
5. Baker PS, Tasman W. Optical coherence tomography imaging of the fovea in retinopathy of prematurity. Ophthalmic Surgery Lasers Imaging 2010;41(2):201–206. 6. Chang L, El-Dairi MA, Frempong TA, et al. Optical coherence tomography in the evaluation of neurofibromatosis type-1 subjects with optic pathway gliomas. J AAPOS 2010; 14(6):511–517. 7. Budenz DL, Anderson DR, Varma R, et al. Determinants of normal retinal nerve fiber layer thickness measured by Stratus OCT. Ophthalmology 2007;114(6):1046 –1052. 8. Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography. Ophthalmology 1996;103(11): 1889 –1898. 9. Pueyo V, Polo V, Larrosa JM, Mayoral F, Ferreras A, Honrubia FM. Reproducibility of optic nerve head and
REFERENCES 1. Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Prog Retin Eye Res 2008;27(1):45– 88. 2. Choma M, Sarunic M, Yang C, Izatt J. Sensitivity advantage of swept Fourier domain optical coherence tomography. Opt Express 2003;11(18):2183–2189. 3. Wojtkowski M, Srinivasan V, Fujimoto JG, et al. Threedimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 2005; 112(10):1734 –1746. 4. Nadeau S, Gire J, Coste R, Cornand E, Denis E. Papillary retinal nerve fiber layer thickness measurement using optical coherence tomography in children with ocular hypertension and juvenile glaucoma. J Fr Ophtalmol 2010;33(4):249 –257.
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18. Kakinoki M, Sawada O, Sawada T, Kawamura H, Ohji M. Comparison of macular thickness between Cirrus HD-OCT and Stratus OCT. Ophthalmic Surg Lasers Imaging 2009;40(2): 135–140. 19. Savini G, Carbonelli M, Barboni P. Retinal nerve fiber layer thickness measurement by Fourier-domain optical coherence tomography: a comparison between cirrus-HD OCT and RTVue in healthy eyes. J Glaucoma 2010;19(6):369 –372. 20. Grover S, Murthy RK, Brar VS, Chalam KV. Comparison of retinal thickness in normal eyes using Stratus and Spectralis optical coherence tomography. Invest Ophthalmol Vis Sci 2010;51(5):2644 –2647. 21. Leung CK, Cheung CY, Weinreb RN, et al. Comparison of macular thickness measurements between time domain and spectral domain optical between time domain and spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2008;49(11):4893– 4897. 22. El-Dairi MA, Asrani SG, Enyedi LB, Freedman SF. Optical coherence tomography in the eyes of normal children. Arch Ophthalmol 2009;127(1):50 –58. 23. Huynh SC, Wang XY, Rochtchina E, Mitchell P. Distribution of macular thickness by optical coherence tomography: findings from a population-based study of 6-year-old children. Invest Ophthalmol Vis Sci 2006;47(6):2351–2357. 24. Eriksson U, Holmström G, Alm A, Larsson E. A populationbased study of macular thickness in full-term children assessed with Stratus OCT: normative data and repeatability. Acta Ophthalmol 2009;87(7):741–745. 25. Forte R, Cennamo GL, Finelli ML, de Crecchio G. Comparison of time domain Stratus OCT and spectral domain SLO/OCT for assessment of macular thickness and volume. Eye (Lond) 2009;23(11):2071–2078. 26. Wang XY, Huynh SC, Burlutsky G, Ip J, Stapleton F, Mitchell P. Reproducibility of and effect of magnification on optical coherence tomography measurements in children. Am J Ophthalmol 2007;143(3):484 – 488.
retinal nerve fiber layer thickness measurements using optical coherence tomography. Arch Soc Esp Oftalmol 2006;81(4): 205–211. Paunescu LA, Schuman JS, Price LL, et al. Reproducibility of nerve fiber thickness, macular thickness, and optic nerve head measurements using StratusOCT. Invest Ophthalmol Vis Sci 2004;45(6):1716 –1724. Muscat S, Parks S, Kemp E, Keating D. Repeatability and reproducibility of macular thickness measurements with the Humphrey OCT system. Invest Ophthalmol Vis Sci 2002; 43(2):490 – 495. García-Martín E, Pinilla I, Idoipe M, Fuertes I, Pueyo V. Intra and interoperator reproducibility of retinal nerve fibre and macular thickness measurements using Cirrus Fourierdomain OCT. Acta Ophthalmol 2011;89(1):e23– e29. Menke MN, Knecht P, Sturm V, Dabov S, Funk J. Reproducibility of nerve fiber layer thickness measurements using 3D Fourier-domain OCT. Invest Ophthalmol Vis Sci 2008; 49(12):5386 –5391. Cremasco F, Massa G, Gonçalves Vidotti V, Pedroso de Carvalho Lupinacci Á, Costa VP. Intrasession, intersession, and interexaminer variabilities of retinal nerve fiber layer measurements with spectral-domain OCT. Eur J Ophthalmol 2011;(3):264 –270. Budenz DL, Chang RT, Huang X, Knighton RW, Tielsch JM. Reproducibility of retinal nerve fiber thickness measurements using the Stratus OCT in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 2005;46(7):2440 –2443. McAlinden C, Khadka J, Pesudovs K. Statistical methods for conducting agreement (comparison of clinical tests) and precision (repeatability or reproducibility) studies in optometry and ophthalmology. Ophthalmic Physiol Opt 2011;31(4): 330 –338. Massa GC, Vidotti VG, Cremasco F, Lupinacci AP, Costa VP. Influence of pupil dilation on retinal nerve fibre layer measurements with spectral domain OCT. Eye 2010;24(9): 1498 –1502.
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Biosketch Irene Altemir, DOO, Bch, MsC, is an optometrist especialist in pediatric population. She completed her Master’s degree in 2011 at the Pennsylvania College of Optometry, Salus University in Philadelphia. She has a dedicated pediatric neuro-ophthalmology practice and clinical research program at the Miguel Servet University Hospital in Zaragoza, Spain. Ms Altemir is currently working on her PhD on neurological damage in children.
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To determine the interobserver and intraobserver reproducibility of a Fourier-domain optical coherence tomography device (Cirrus HD OCT; Carl Zeiss Meditec, Dublin, California, USA) in normal pediatric eyes. ● DESIGN: Prospective cross-sectional study. ● METHODS: One hundred healthy children were recruited prospectively and consecutively. Only 1 randomly chosen eye per subject was included in the study. The eye underwent 3 scans centered on the optic disc and another 3 scans centered on the macula that were acquired by a single operator. A fourth examination was performed by a second operator. Interobserver and intraobserver reproducibility were described by intraclass correlation coefficients (ICCs) and coefficients of variation (COVs). ● RESULTS: The mean age was 9.15 years (range, 6.22 to 11.31 years; standard deviation, 1.05 years). Mean retinal nerve fiber layer thickness was 99.53 m (standard deviation, 10.10 m), and mean macular thickness was 282.91 m (standard deviation, 11.83 m). All the parameters evaluated were highly reproducible. Intraobserver COVs of the retinal nerve fiber layer measurements ranged from 2.24% to 5.52%, and the COV of macular thickness was 0.97%. The intraclass correlation coefficient was greater than 0.8 for all the parameters. The interobserver COV ranged from 2.23% to 5.18%, and the COV of macular thickness was 0.82%. In all the evaluated parameters, the intraclass correlation coefficient was more than 0.75. Repeatability was slightly better in children older than 10 years than in children younger than 9 years. ● CONCLUSIONS: Retinal nerve fiber layer and macular measurements obtained by Fourier-domain optical coherence tomography showed good repeatability for healthy eyes in the pediatric population. Cirrus HD OCT examinations of the retina are reliable in children. (Am J Ophthalmol 2013;155:171–176. © 2013 by Elsevier Inc. All rights reserved.) Accepted for publication June 18, 2012. From the Department of Ophthalmology, Hospital Universitario Miguel Servet, Zaragoza, Spain (I.A., V.Pu., V.Po., J.M.L.); the Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain (V.Pu., V.Po., J.M.L., D.O.); Department of Applied Physics, University of Zaragoza, Zaragoza, Spain (N.E.); and the Department of Obstetrics, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain (D.O.). Inquiries to Victoria Pueyo, Department of Ophthalmology, Hospital Universitario Miguel Servet, C. Isabel la Católica 1-3, 50009 Zaragoza, Spain; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2012.06.012
©
2013 BY
I
N RECENT YEARS, SEVERAL DEVICES THAT ALLOW AN
objective and quantitative evaluation of retinal structures have become useful in clinical practice because of the need for objective tests that complement funduscopy or photographs, especially in children, in whom they may prove difficult to perform. One of instrument that is becoming increasingly popular in pediatric ophthalmology is optical coherence tomography (OCT). OCT is a noninvasive, noncontact method that uses low-coherence interferometry to perform high-resolution cross-sectional imaging of tissue morphologic features, providing an optical biopsy.1 The latest OCT devices, Fourier-domain (FD) OCTs, offer increased resolution compared with time-domain instruments. Current commercially available OCT instruments provide improved axial image resolution, between 5 and 7 m, compared with earlier generations of OCT that ranged between 8 and 10 m.1–3 A number of publications have proved the feasibility and validity of this technique in different clinical applications in children for diseases such as glaucoma, retinopathy of prematurity, and neurofibromatosis type 1.4 – 6 All the OCT devices have an integrated normative database, which includes only individuals 18 years of age and older. To evaluate changes in retinal measurements accurately, it is first necessary to determine the range in the normal population and to quantify the accuracy, reproducibility, and repeatability of measurements made by the system.7 The objectivity and reproducibility of Cirrus OCT have been proven by several authors in adults, but never in children.8 –15 The purpose of the present study was to examine the interobserver and intraobserver reproducibility of repeated measurements of the retinal nerve fiber layer (RNFL), optic disc, and macular measurements with an FD OCT in healthy children.
METHODS THIS STUDY WAS UNDERTAKEN IN AN ELEMENTARY
school from December 2010 through March 2011 as part of the Environmental Fetal Factors in the Development of the Optic Nerve and the ReTina study (EFFORT). From the 598 eligible children, 358 were included in the study, giving an acceptance rate of 60%. One hundred healthy children were recruited prospectively and consecutively
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TABLE 1. Optical Coherence Tomography Measurements in Children Obtained by 2 Examiners
Average RNFL, m Superior RNFL, m Temporal RNFL, m Inferior RNFL, m Nasal RNFL, m Rim area, mm2 Disc area, mm2 Cup-to-disc area ratio Macular thickness, m Macular volume, mm3
Measurement 1
Measurement 2
Measurement 3
P Valuea
Measurement 4
P Valueb
99.53 ⫾ 10.10 125.57 ⫾ 18.05 68.78 ⫾ 10.68 133.14 ⫾ 17.34 70.99 ⫾ 12.02 1.59 ⫾ 0.33 2.06 ⫾ 0.38 0.43 ⫾ 0.17 282.91 ⫾ 11.83 10.18 ⫾ 0.43
98.68 ⫾ 10.80 123.66 ⫾ 18.10 68.94 ⫾ 11.10 131.40 ⫾ 20.14 70.74 ⫾ 13.01 1.59 ⫾ 0.31 2.05 ⫾ 0.37 0.42 ⫾ 0.17 282.76 ⫾ 12.04 10.18 ⫾ 0.44
99.13 ⫾ 9.98 125.11 ⫾ 17.20 68.61 ⫾ 9.21 130.82 ⫾ 21.12 72.19 ⫾ 12.69 1.62 ⫾ 0.32 2.09 ⫾ 0.36 0.43 ⫾ 0.16 282.56 ⫾ 12.59 10.17 ⫾ 0.46
.34 .64 .34 .39 .68 .77 .82 .94 .67 .52
98.59 ⫾ 10.04 124.36 ⫾ 16.98 68.41 ⫾ 10.10 131.56 ⫾ 16.47 70.28 ⫾ 13.40 1.57 ⫾ 0.32 2.02 ⫾ 0.38 0.42 ⫾ 0.17 282.29 ⫾ 10.16 10.16 ⫾ 0.44
.03 .30 .56 .08 .39 .48 .18 .21 .14 .15
RNFL ⫽ retinal nerve fiber layer. Measurements 1, 2, and 3 correspond to examinations performed by the first examiner, and measurement 4 corresponds to the examination performed by the second examiner. Data are reported as mean ⫾ standard deviation unless otherwise noted. a Significance of the comparison among measurements 1, 2, and 3. b Significance of the comparison between measurements 1 and 4.
from among the 358 for the reproducibility and repeatability study.16 All subjects underwent a comprehensive ophthalmologic evaluation that included monocular visual acuity (HOTV chart read at 300 cm), stereopsis assessment (TNO test at 40 cm), ocular motility evaluation, and retinal and optic nerve assessments by means of OCT (Humphrey Zeiss Instruments, Dublin, California, USA). All children with abnormal results (visual acuity worse than 20/25, strabismus, or history of ocular diseases) were examined under cycloplegic mydriasis and the refractive error was measured. The RNFL and optic disc measurements were obtained using the optic disc cube 200 ⫻ 200 protocol. Under this protocol, a 3-dimensional cube of data is generated over a 6-mm2 grid of 200 horizontal scan lines, each composed of 200 A-scans. A Cirrus software algorithm automatically detects the center of the optic disc from this volume scan and positions a 3.46-mm diameter calculation circle over this point. From the 256 A-scans along this circle, the borders of the RNFL are delineated and thickness is calculated at each point along the circle. The macular images were obtained using the macula cube 200 ⫻ 200 protocol. This protocol generates 200 ⫻ 200 volume cube images with 200 linear scans performed by A scans and analyzes a cube 6 mm in diameter around the macula. Retinal thickness was calculated using the built-in macular analysis software on the Cirrus device, which is determined automatically by taking the difference between the inner limiting membrane and retinal pigment epithelium boundaries. The examinations were performed without pupil dilation.17 Only scans with 7 strength/signal or more were accepted. Images with artifacts or missing parts were excluded and repeated. Internal fixation was used to suppress ocular movements, because it results in the 172
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TABLE 2. Intraobserver Reproducibility of Optical Coherence Tomography Measurements in Children: Intraobserver Coefficients of Variation and Intraclass Correlation Coefficients of the Measurements
Average RNFL Superior RNFL Temporal RNFL Inferior RNFL Nasal RNFL Rim area Disc area Cup-to-disc area ratio Macular thickness Macular volume
COV (%)
ICC
2.24 4.54 3.93 5.01 5.52 10.64 7.75 11.25 0.97 1.00
0.957 0.928 0.877 0.888 0.908 0.858 0.885 0.972 0.942 0.940
COV ⫽ coefficient of variation; ICC ⫽ intraclass correlation coefficient; RNFL ⫽ retinal nerve fiber layer.
highest reproducibility.8 Three scans were performed by a single operator (I.A.), and a fourth scan was performed by a second operator (N.E.). Between scans, subject position and focus were disrupted randomly, and alignment parameters had to be newly adjusted at the start of each image acquisition. The parameters collected were mean RNFL thickness (360 degrees), RNFL thickness in 4 quadrants (inferior, superior, nasal, temporal), ring area, disc area, cup-to-disc area ratio, macular thickness, and macular volume. To be enrolled in the project, written informed consent was given by the parents or guardians of the child. The only exclusion criterion was the absence of a signed informed consent. Because we wanted to examine a sample representative of the normal pediatric population, no other exclusion criteria were considered. Statistical analyses OF
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FIGURE 1. Bland-Altman plots showing the level of intraobserver concordance between the optical coherence tomography measurements of the retinal nerve fiber layer (RNFL) and macula in children.
were carried out with the Statistical Package for the Social Sciences version 15.0 (SPSS, Inc, Chicago, Illinois, USA). Interobserver and intraobserver reproducibility were described by intraclass correlation coefficients (ICCs) and coefficients of variation (COVs). For the intraobserver study, we compared the results from the first 3 examinations performed by the same examiner (I.A.). For the interobserver study, the first and the fourth examinations were compared because they were performed by 2 different examiners (I.A., N.E.). COVs were calculated as the standard deviation divided by the average of the measurement value, expressed as a percentage. A COV of less than 10% was considered reproducible and a COV of less than 6% was considered highly reproducible. The ICCs were considered to provide slight reliability (values between 0 and 0.2), fair reliability (values between 0.21 to 0.4), moderate reliability (values between 0.41 and 0.6), substantial reliability (values between 0.61 to 0.8), or almost perfect reliability (values of more than 0.81). COVs obtained in different groups of children were compared according to their age. Children were divided into categories younger than 9 years (34 children), from 9 to 10 years (36 children), and older than 10 years (30 children). COVs were compared by analysis of variance with the Bonferroni post hoc test. P values less than .05 (P ⬍ .05) were considered statistically significant. For multiple comparisons, we used the Bonferroni post hoc correction.
TABLE 3. Interobserver Reproducibility of Optical Coherence Tomography Measurements in Children: Interobserver Coefficients of Variation and Intraclass Correlation Coefficients of the Measurements
Average RNFL Superior RNFL Temporal RNFL Inferior RNFL Nasal RNFL Rim area Disc area Cup-to-disc area Macular thickness Macular volume
2.23 4.00 3.41 3.46 5.18 8.68 7.25 9.21 0.82 0.85
0.955 0.881 0.901 0.928 0.886 0.773 0.825 0.957 0.949 0.945
6.22 to 11.31 years, with a mean age of 9.15 years. Mean best-corrected visual acuity (logarithm of the minimal angle of resolution) was ⫺0.01 (20/20 Snellen equivalent), with a range from 0.3 to ⫺0.2. The refractive errors ranged from ⫺3.00 to ⫹4.50 of spherical equivalent. Stereoacuity was full (60 seconds of arc or better) in 94 children and was reduced (worse than 60 seconds of arc) in 6 children. Twenty-nine of 100 children (29%) demonstrated ocular motility anomalies (21 exophoria (21%), 6 endophoria (6%), 2 esotropia (2%)). No patient from the study had to be excluded because of bad OCT image quality. Table 1 shows the results obtained in the global and sectorial analysis of the RNFL and macula, measured by
ONE HUNDRED CHILDREN WERE INCLUDED IN THE STUDY
(52 boys and 48 girls). The age of the patients ranged from REPRODUCIBILITY
ICC
COV ⫽ coefficient of variation; ICC ⫽ intraclass correlation coefficient; RNFL ⫽ retinal nerve fiber layer.
RESULTS
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FIGURE 2. Bland-Altman plots showing the level of interobserver concordance between the optical coherence tomography measurements of the retinal nerve fiber layer (RNFL) and macula in children.
OCT by observer 1 in the first, second, and third scans and by observer 2 in the fourth scan. None of the differences between measurements may be considered as statistically significant after Bonferroni correction for multiple comparisons. As expected, quadrant distribution followed a double-hump pattern, being higher for the inferior quadrant, followed by superior, nasal, and temporal quadrants. Mean differences between the measurements obtained by the 2 operators were less than 3 m in all parameters evaluated. ● INTRAOBSERVER
and macular thickness reproducibility between the 2 observers. Although most of the measurements showed higher COVs in younger children compared with older children, differences were not statistically significant for any parameter (mean RNFL thickness COV, 2.91% in the group of children younger than 9 years and 1.82% in the group of children 9 years of age or older; P ⫽ .133).
DISCUSSION
One hundred children were included in the intraobserver study. All RNFL and macular measurements were highly reproducible. COVs and ICCs of the measurements are presented in Table 2. Optic nerve parameters showed lower reproducibility. The parameter exhibiting the highest intraobserver reproducibility was the average RNFL with a COV of 2.24%. ICCs showed an almost perfect reliability in all the parameters evaluated (ICCs ⬎ 0.81), and the ICC was 0.957 for the average RNFL. Figure 1 shows Bland-Altman plots of the average RNFL thickness and macular thickness reproducibility between the intraobserver measurements. REPRODUCIBILITY:
OCT IS PART OF DAILY CLINICAL PRACTICE. RELIABILITY
and repeatability of diagnostic tools need to be ascertained, especially in children, whose cooperation is limited. Cirrus OCT represents the latest commercially available generation of OCT, with higher axial resolution compared with conventional time-domain OCT. To our knowledge, this is the first report of the study of the reproducibility of the RNFL and macular measurements using high-density FD OCT in healthy children. Direct comparison of RNFL values between the different OCT devices may be difficult because of different technical specifications, imaging protocols, and different thickness measurement algorithms. Cirrus OCT measurements result in larger retinal thickness.18 Our study shows that reproducibility of Cirrus OCT in the pediatric population is excellent, both for RNFL and macular measurements. RNFL and macular measurements provided by Cirrus OCT in children differ from those provided by previous OCT devices. The measurements we obtained in children are comparable with those reported in adults. We found an average RNFL thickness of 98.59 to 99.53 m and a macular
● INTEROBSERVER REPRODUCIBILITY: One hundred children were included in the interobserver study. COVs and ICCs of the measurements are presented in Table 3. All the RNFL and macular measurements were highly reproducible. Optic nerve parameters showed lower reproducibility. The highest interobserver reproducibility was observed for the average RNFL, with a COV of 2.23%. ICCs showed almost perfect reliability in all parameters evaluated, and the ICC was 0.955 for mean RNFL. Figure 2 shows Bland-Altman plots of average RNFL thickness
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thickness of 282.29 to 283.03 m, which is in agreement with previous results obtained in adults.12,19,20 Differences among commercially available devices in the acquisition and analyses of the images can be observed in the optic nerve and retinal measurements.21–24 FD OCT has demonstrated advantages over time-domain OCT in the retinal evaluation of healthy eyes,25 but reproducibility of the new Cirrus OCT devices in healthy children has not yet been reported. Our study suggests that Cirrus OCT shows good intraobserver and interobserver reproducibility when measuring macular and RNFL thickness in the normal pediatric population. Most of the parameters showed a COV of less than 5%, which is highly reproducible and clinically adequate. Our values of intraobserver and interobserver reproducibility are in good agreement with several other studies previously performed in adults. Menke and associates assessed the reproducibility of the RNFL measurements provided by FD OCT in 38 normal subjects.13 Intrasession reproducibility was good, with a mean ICC of 0.90 and mean COV of 4.2% and 4% for operator 1 and 2, respectively. Interobserver reproducibility also was good, with only 0.9 m of the mean difference between measurements of operator 1 and 2. García-Martín and associates tested the reproducibility of RNFL and macular measurements from 72 healthy subjects with the Cirrus spectral-domain OCT device.12 The mean COV for intraobserver reproducibility was 1.2% for macular thickness and 4.4% for average RNFL thickness. The ICCs ranged from 0.823 to 0.992. Interobserver reproducibility differences between both operators were less than 3 m. As in these studies, we found the worst reproducibility in the nasal quadrant, with an intraobserver COV of
5.73% and an interobserver COV of 5.17%. The average RNFL thickness showed the highest reproducibility, with a COV of 2.78% and 2.17% for intraobserver and interobserver reproducibility, respectively. The only parameters with COVs of more than 5% are the optic nerve head parameters (disc area, rim area, and cup-to-disc area ratio). This may be because of increased susceptibility of these measurements to an imprecise centering. Previous versions of OCT showed good reproducibility in children. Eriksson and associates reported a COV lower than 2% and an ICC higher than 0.9 in all macular areas in children.24 Wang and associates reported a COV of less than 5%, less than 8%, and less than 13%, respectively, for macular thickness, RNFL thickness, and optic disc parameters.26 These results are comparable with ours obtained with the latest commercially available version of OCT and with those obtained in adults.9,15 Limitations of the present study are mainly related to possible confounding factors influencing the examination. Axial length was not taken into account. We assume that our measurements were obtained in children without high refractive errors or ocular disease, and it could be related to higher reproducibility. Another limitation may be that all the examinations were performed the same day and with the same device. However, previous authors have shown that measurements are not significantly affected by these factors.14 OCT has been shown to be a useful tool to examine the retina in children. However, for a diagnostic instrument to be considered clinically adequate, it must be highly reproducible. Our study reports that FD OCT measurements of the macula, RNFL, and optic nerve are reliable and highly reproducible in children 6 to 12 years of age.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF interest and none were reported. This study was supported by the Jesus de Gangoiti Barrena Foundation (Bilbao, España). Involved in Design and conduct of study (I.A., V.Pu., N.E., D.O.); Collection, management, and interpretation of data (I.A., V.Pu., N.E., D.O., V.Po., J.L.); and Preparation and review of manuscript (I.A., V.Pu., N.E., D.O., V.Po., J.L.). This was a prospective study. This study adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee (Comité Ético de Investigación Clínica de Aragón). Informed consent for research was obtained from each enrolled child and was signed by each child’s parents or guardians.
5. Baker PS, Tasman W. Optical coherence tomography imaging of the fovea in retinopathy of prematurity. Ophthalmic Surgery Lasers Imaging 2010;41(2):201–206. 6. Chang L, El-Dairi MA, Frempong TA, et al. Optical coherence tomography in the evaluation of neurofibromatosis type-1 subjects with optic pathway gliomas. J AAPOS 2010; 14(6):511–517. 7. Budenz DL, Anderson DR, Varma R, et al. Determinants of normal retinal nerve fiber layer thickness measured by Stratus OCT. Ophthalmology 2007;114(6):1046 –1052. 8. Schuman JS, Pedut-Kloizman T, Hertzmark E, et al. Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography. Ophthalmology 1996;103(11): 1889 –1898. 9. Pueyo V, Polo V, Larrosa JM, Mayoral F, Ferreras A, Honrubia FM. Reproducibility of optic nerve head and
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Biosketch Irene Altemir, DOO, Bch, MsC, is an optometrist especialist in pediatric population. She completed her Master’s degree in 2011 at the Pennsylvania College of Optometry, Salus University in Philadelphia. She has a dedicated pediatric neuro-ophthalmology practice and clinical research program at the Miguel Servet University Hospital in Zaragoza, Spain. Ms Altemir is currently working on her PhD on neurological damage in children.
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