Original Paper
Ophthalmologica
Received: February 7, 2015 Accepted after revision: March 13, 2015 Published online: May 13, 2015
Ophthalmologica DOI: 10.1159/000381788
Effects of Retinal Angiography on Optical Coherence Tomography Measurements Young-Joon Jo Hyung-Bin Lim Soo-Hyun Lee Jung-Yeul Kim Department of Ophthalmology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
Abstract Purpose: To evaluate the effects of retinal angiography, using fluorescein and indocyanine green dyes, on optical coherence tomography (OCT) measurements. Methods: In total, 76 eyes from 76 consecutive patients were included. Macular cube 512 × 128 combination scanning and optic disc 200 × 200 scanning using spectral-domain (SD)-OCT were performed twice, before and after retinal angiography, with fluorescein or indocyanine green. Signal strength, regional retinal thickness of the 9 Early Treatment Diabetic Retinopathy Study subfields, total macular volume, and retinal nerve fiber layer thickness obtained before and after angiography were compared. Repeatability was also investigated. Results: Comparing the results of OCT measured before and after retinal angiography, there was no statistically significant difference in any parameter assessed. The interclass correlation values for each measurement were all >0.808 (range 0.808–0.999). Conclusion: Retinal angiography using fluorescein and indocyanine green dyes has no significant effect on OCT measurements. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0030–3755/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/oph
Introduction
Optical coherence tomography (OCT), introduced by Huang et al. [1], is a method for observing the vitreous, retina, and choroid of the eye. The device measures differences in the intensity of the light reflected from each tissue after transmitting light of 800 nm (near-infrared wavelength) and is also used to determine the echo time delay. The more recently introduced spectral-domain OCT (SD-OCT) develops images using Fourier transformation after the spectrum of the light through the interferometer is accepted by the spectrometer. This procedure can obtain more images in a shorter time than timedomain OCT. Consequently, the structure of the macula and optic nerve head can be observed more closely. SDOCT has been used widely for the diagnosis and treatment evaluation of various retinal diseases [2, 3]. Novotny and Alvis [4] first performed fluorescein angiography (FA) using fluorescein. Flower and Hochheimer [5] introduced indocyanine green angiography (ICGA) in 1972. Since then, FA and ICGA have been used widely to understand the pathophysiology of diverse diseases of the retina and choroid as well as to identify disease progression and the effects of treatment. Fluorescein and ICG, both used for retinal angiography, have different absorption and emission wavelengths. Jung-Yeul Kim, MD Department of Ophthalmology Chungnam National University Hospital No. 640 Daesa-dong, Jung-gu, Daejeon, 301-721 (Republic of Korea) E-Mail kimjy @ cnu.ac.kr
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Key Words Spectral-domain optical coherence tomography · Fluorescein angiography · Indocyanine green angiography
S6
S
S3 T6
T3
CM
N3
T
N6
I
I3
Fig. 1. a The 9 subfields corresponding to
I6
1 mm 3 mm
a
Fluorescein is stimulated by blue wavelengths of visible light and emits yellow-green light of 520–530 nm [6]. ICG is stimulated by near-infrared wavelengths and also emits a near-infrared wavelength in the ∼800-nm region [7]. About 80% of injected fluorescein and ∼98% of injected ICG binds to plasma proteins [6, 7]. What is bound remains in blood vessels and what is not bound can leak into the choroid and retina and spreads into the vitreous body and anterior chamber. These residual dyes may interfere with OCT measurements. Many medical institutions now tend to use both retinal angiography and OCT to examine retinal and choroidal diseases at the same time. Accordingly, in the present study, we investigated the potential impact of the remaining dyes after FA and ICGA in the choroid, retina, vitreous, and anterior chamber on OCT results.
Materials and Methods The subjects were patients who visited the Department of Ophthalmology at Chungnam National University Hospital, Daejeon, Republic of Korea, from February to August 2013. This was a prospective observational study. The protocol was approved by the Institutional Review Board of Chungnam National University Hospital. All participants signed informed consent forms, and the study adhered to the tenets of the Declaration of Helsinki. The authors had no commercial or proprietary interest in the material used in this study. Medical history, uncorrected visual acuity, best-corrected visual acuity (BCVA), refractive error using an autorefractor, intraocular pressure (IOP, measured using a non-contact tonometer), slit-lamp
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Ophthalmologica DOI: 10.1159/000381788
6 mm
b
biomicroscopy, and fundus examination were conducted. The IOP of each subject was 350 μm), which can induce a segmentation error in OCT measurements, and those who were using eye drops other than artificial tears. Retinal Angiography Two types of dye, fluorescein and ICG, were used in retinal angiography. The subjects were divided into two subgroups depending on the type of dye used. The FA group was given an intravenous injection of 5 ml fluorescein sodium (fluorescein; Novartis Pharma AG, Basel, Switzerland) before the retinal angiography was conducted, while the ICGA group was injected intravenously with 25 mg ICG (Dianogreen®, 25 mg; Daiichi Sankyo Propharma Co., Osaka, Japan) dissolved in 2 ml distilled water. Optical Coherence Tomography The macular cube 512 × 128 combination scan mode and the optic disc cube 200 × 200 scan mode of the Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, Calif., USA) were used. The macular cube 512 × 128 combination scan mode has 6 × 6 mm areas of macula scanned into 512 × 128 dots to measure the thickness of the outer edges of the optic nerve, fibrous layer, and retinal pigment epithelium. The 6 × 6 mm circle belongs to the Early Treatment of Diabetic Retinopathy Study (ETDRS) subfield [8] and was divided into 3 concentric circles, with diameters of 1, 3, and 6 mm, as the central, inner, and outer circles, respectively; all of these were again split into 4 sides, the superior, inferior, nasal, and temporal sides (fig. 1a). The optic disc cube 200 × 200 scan mode has 6 × 6 mm areas around the optic disc, scanned into 200 × 200 dots. After
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the ETDRS areas. CM = Central macula; S3 = superior inner; N3 = nasal inner; I3 = inferior inner; T3 = temporal inner; S6 = superior outer; N6 = nasal outer; I6 = inferior outer; T6 = temporal outer. b Fourquadrant analysis of the RNFL. S = Superior; N = nasal; I = inferior; T = temporal.
N
Table 1. Baseline characteristics of
FA group
subjects Patients Eyes Mean age ± SD, years Males, % Right laterality, % Mean BCVA ± SD, logMAR Mean refractive error ± SD, SE, D Diagnosis and number of eyes
29 29 56.9 ± 12.7 66.7 50.0 0.06 ± 0.09 –0.6 ± 1.3 Normal DR RVO HTNR ERM
ICGA group
12 (41.4) 8 (27.6) 5 (17.2) 2 (6.9) 2 (6.9)
47 47 58.7 ± 13.4 66.0 52.0 0.12 ± 0.23 –0.6 ± 2.0 Normal AMD CSC RVO
27 (57.4) 15 (31.9) 3 (6.4) 2 (4.3)
Figures in parentheses are percentages. SE, D = Spherical equivalent, diopters; DR = diabetic retinopathy; AMD = age-related macular degeneration; RVO = retinal vein occlusion; CSC = central serous chorioretinopathy; HTNR = hypertensive retinopathy; ERM = epiretinal membrane.
Statistical Analysis Analyses were performed with the SPSS software (version 18.0; SPSS Inc., Chicago, Ill., USA). To assess effects of retinal angiography on OCT measurements, OCT was performed twice, before and after angiography. The paired t test was used to compare the average measured values before and after angiography. To identify any influence of angiography on the repeatability of OCT measurements, we analyzed the averages of the twice-measured values using the interclass correlation (ICC) and a Bland-Altman plot [9]. ICC was calculated by dividing the intersubject variance by the total variance, which is the sum of the intersubject variance and the within-subject variance, to assess the consistency of repeated measurements. The ICC ranges from 0 to 1, with values closer to 1 indicating higher reliability. A result >0.9 indicates very high consistency, and a result >0.7 is considered to be clinically valuable. Statistical significance was set at p < 0.05.
Results
The subject group consisted of 76 eyes in 76 people: 29 eyes were classified into the FA group, and the remaining 47 eyes were classified into the ICGA group. In the FA Effects of Retinal Angiography on OCT Measurements
group, the mean age of patients was 56.9 ± 12.7 years, with 66.7% males. The mean BCVA was 0.06 ± 0.09 logMAR, and the mean refractive error was –0.6 ± 1.3 D. In the FA group, 41% had normal eyes, which was the largest subgroup, followed by those with diabetic retinopathy, retinal vein occlusion, hypertensive retinopathy, and an epiretinal membrane. The average age of the patients in the ICGA group was 58.7 ± 13.4 years, with 66% males. The mean BCVA was 0.12 ± 0.23 logMAR, and the mean refraction error was –0.6 ± 2.0 D. In the ICGA group, 57% had normal eyes, followed by age-related macular degeneration, central serous chorioretinopathy, and retinal vein occlusion (table 1). Influence of Retinal FA No statistically significant differences were found in the thickness of the 9 ETDRS subfields, average macular thickness, signal strength, or macular volume between the measurements performed before and after FA. In fact, none of the measured parameters showed a statistically significant difference (table 2). In addition, all measurements had high ICC values (>0.9) in terms of the thickness of the 9 ETDRS subfields, average macular thickness, macular volume, RNFL thickness, and signal strength (table 3). Indeed, the Bland-Altman plot showed that most values were within the 95% confidence interval, indicating a high level of consistency (fig. 2a, b).
Ophthalmologica DOI: 10.1159/000381788
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being divided into the same 4 sides, the retinal nerve fiber layer (RNFL) thickness was measured (fig. 1b). All patients underwent measurements with the macular cube scan and the optic disc cube scan twice, for a total of 4 cube scans, before retinal angiography. At 20 min after the angiography, both scans were performed twice more, for a total of 4 more cube scans. To reduce the possible occurrence of errors, all OCT measurements were performed by the same experienced operator. OCT measurements before and after angiography were performed in identical conditions, and the examination range was established by autofocusing instead of manual operation.
Table 2. Mean values of macular volume, signal strength, and macular and RNFL thickness measured by OCT in the FA group
Before FA Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
8.5 ± 1.3 10.3 ± 0.6 270.9 ± 35.2 332.1 ± 23.5 324.3 ± 23.3 327.3 ± 15.2 332.2 ± 21.8 290.5 ± 26.2 276.0 ± 24.2 272.5 ± 16.9 303.9 ± 16.1 7.9 ± 1.4 94.8 ± 11.2 123.9 ± 19.1 71.1 ± 12.6 117.7 ± 19.3 66.2 ± 10.5
After FA 8.8 ± 1.3 10.3 ± 0.6 269.8 ± 35.1 331.4 ± 24.2 322.8 ± 23.3 325.5 ± 15.6 331.7 ± 23.3 288.7 ± 25.3 274.6 ± 24.0 271.6 ± 16.7 303.4 ± 18.4 8.0 ± 1.3 95.1 ± 11.2 123.3 ± 19.4 71.6 ± 12.8 117.5 ± 19.7 67.7 ± 11.8
Table 4. Mean values of macular volume, signal strength, and macular and RNFL regional thickness measured by OCT in the ICGA group
p value1 0.057 0.203 0.161 0.472 0.065 0.108 0.532 0.093 0.083 0.638 0.724 0.171 0.776 0.420 0.777 0.965 0.222
Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
Before ICGA After ICGA
p value1
7.6 ± 0.9 9.9 ± 0.8 252.8 ± 49.6 311.7 ± 37.1 305.2 ± 36.3 316.9 ± 43.9 322.9 ± 39.9 272.1 ± 20.9 262.8 ± 21.0 266.3 ± 33.6 292.3 ± 20.2 6.8 ± 0.9 89.6 ± 11.0 112.7 ± 18.0 69.8 ± 15.4 110.6 ± 19.0 65.2 ± 9.8
0.938 0.310 0.905 0.328 0.453 0.549 0.571 0.200 0.428 0.441 0.443 0.298 0.955 0.930 0.925 0.988 0.368
7.6 ± 1.0 9.8 ± 0.8 252.9 ± 51.2 312.8 ± 37.5 303.5 ± 33.9 316.1 ± 46.8 322.7 ± 43.6 271.3 ± 20.5 265.5 ± 30.9 265.1 ± 32.6 291.6 ± 20.9 6.9 ± 1.0 89.7 ± 10.9 112.8 ± 17.1 69.9 ± 14.7 110.6 ± 19.5 64.4 ± 7.9
Data are means ± SDs (μm). 1 Wilcoxon signed-rank test. Data are means ± SDs (μm). 1 Paired t test.
Table 3. ICC of signal strength and macular and RNFL thickness
Table 5. ICC of signal strength and macular and RNFL thickness
in the FA group
in the ICG group 95% CI
0.923 0.994 0.999 0.992 0.998 0.948 0.996 0.997 0.993 0.978 0.978 0.950 0.984 0.986 0.965 0.948 0.932
0.856 – 0.968 0.987 – 0.997 0.999 – 1.000 0.986 – 0.997 0.995 – 0.999 0.895 – 0.976 0.991 – 0.998 0.993 – 0.999 0.988 – 0.997 0.952 – 0.990 0.953 – 0.989 0.896 – 0.976 0.964 – 0.993 0.972 – 0.994 0.930 – 0.984 0.890 – 0.975 0.864 – 0.969
CI = Confidence interval.
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Ophthalmologica DOI: 10.1159/000381788
Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
ICC
95% CI
0.812 0.997 0.998 0.992 0.991 0.925 0.981 0.995 0.978 0.984 0.975 0.808 0.986 0.973 0.983 0.940 0.890
0.694 – 0.921 0.995 – 0.998 0.996 – 0.999 0.989 – 0.997 0.985 – 0.995 0.870 – 0.958 0.967 – 0.989 0.991 – 0.997 0.962 – 0.988 0.975 – 0.990 0.955 – 0.986 0.691 – 0.926 0.975 – 0.992 0.952 – 0.985 0.971 – 0.991 0.894 – 0.966 0.821 – 0.940
CI = Confidence interval.
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Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
ICC
Difference in pre- and post-FA RNFL average thickness (μm)
10 0 –10 –20
275 300 325 350 375 Average of pre- and post-FA macular thickness (μm)
c
40 30 20 10 0 –10 –20 –30 –40
200 300 400 500 600 Average of pre- and post-ICGA macular thickness (μm)
Fig. 2. Bland-Altman plots for macular and RNFL average thick-
ness measured before and after angiography. The solid line indicates the average mean difference, and the dotted lines delineate the 95% confidence limits of agreement. a Bland-Altman plot for measurements of macular average thickness after FA. The mean difference is –0.12. The 95% limits of agreement are –4.53 to 4.29. b Bland-Altman plot for measurements of RNFL average thickness
10 0 –10 –20
b
Difference in pre- and post-ICGA RNFL average thickness (μm)
Difference in pre- and post-ICGA macular average thickness (μm)
a
20
d
60
70 80 90 100 110 120 Average of pre- and post-FA RNFL thickness (μm)
30 20 10 0 –10 –20
40 50 60 70 80 90 Average of pre- and post-ICGA RNFL thickness (μm)
after FA. The mean difference is 1.13. The 95% limits of agreement are –3.22 to 5.48. c Bland-Altman plot for measurements of macular average thickness after ICGA. The mean difference is –0.2. The 95% limits of agreement are –5.04 to 4.64. d Bland-Altman plot for measurements of RNFL average thickness after ICGA. The mean difference is –0.02. The 95% limits of agreement are –4.31 to 4.35.
OCT and retinal angiography are both important tools for diagnosing retinal and choroidal diseases, deciding on treatment plans, and assessing prognoses. An increasing
number of people tend to undergo both tests at the same time. Thus, in this study, we assessed the influence of the dyes used in retinal angiography, such as fluorescein and ICG, on OCT measurements, as well as any effect on the repeatability of the tests. Fluorescein releases yellow-green rays at 520–530 nm after stimulation by absorbing blue rays at a wavelength of 469–490 nm. After intravenous injection, about 80% of the fluorescein combines with plasma proteins, and the remaining 20% circulates in the blood vessels in a free form [6]. Fluorescein that enters the eyeball generally cannot penetrate the retinal vessels due to the tight junctions of vascular endothelial cells. Although it cannot penetrate vessels that are bigger than the choroidal vessel either, it can freely penetrate capillary vessels in other tissues. The diffusion of the outflowing fluorescence is
Effects of Retinal Angiography on OCT Measurements
Ophthalmologica DOI: 10.1159/000381788
Influence of Retinal ICGA No statistically significant difference was found in the thickness of the 9 ETDRS subfields, average macular thickness, RNFL thickness, or signal strength before and after ICGA was performed (table 4). In addition, all test results except the signal strength and RNFL nasal quadrant had ICC values >0.9 (table 5). In the Bland-Altman plot, again, most values were within the 95% confidence interval, indicating a high level of consistency (fig. 2c, d).
Discussion
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Difference in pre- and post-FA macular average thickness (μm)
20
6
Ophthalmologica DOI: 10.1159/000381788
fects of fluorescein and ICG on the repeatability of SDOCT are considered to be negligible. The signal strength can influence the results of OCT. Samarawickrama et al. [20] reported that a group with stronger signal strength showed overestimated values in the macula and the RNFL. Wu et al. [21] reported that the RNFL thickness could be underestimated at low signal strengths. It has been presumed that the fluorescein and ICG that diffuse into the eyeball may then spread into the retina and vitreous and anterior chambers, and that these dyes may have a significant influence on OCT measurements. However, in the present study, we did not find any significant influence of fluorescein or ICG on signal strength or any of the measured values. Xu et al. [22] reported that a near-infrared dye was injected to enhance the contrast of the cross-sections of tissues, which resulted in a clearer image; however, the depth of the image was reduced by approximately 20– 30%. Because ICG can absorb and release near-infrared rays, it was presumed that it may have an influence on the results of OCT. However, we found no significant influence of ICG on the measured values or on the repeatability or reliability of tests. Neither fluorescein nor ICG had any clinically significant impact on OCT. Although ∼20% of the fluorescein may diffuse in a free form into the vitreous cavity and the anterior chamber, its influence on measurement values is presumed to be negligible because its wavelength does not overlap with that of OCT. Although the wavelength of ICG overlaps with that of OCT, it did not have any significant impact on the results, likely because very little dye in a free form was present (almost all of it is bound to plasma proteins). In conclusion, the fluorescein and ICG used in retinal angiography were found to have no clinically significant influence on the various measurements of OCT or the signal strength of the retina or the RNFL. Thus, even if SD-OCT is performed together with retinal angiography using fluorescein or ICG, reliable SD-OCT results can be achieved.
Disclosure Statement The authors have no financial/conflicting interests to disclose. No conflicting relationship exists for any author.
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blocked due to the tight junctions of the retinal pigment epithelium [10]. Regarding ICG, it releases near-infrared rays at a wavelength of 770–880 nm after absorbing them at a wavelength of 790–805 nm [7]. Unlike fluorescein, ∼98% of ICG combines with plasma proteins due to its lipophilic properties, while only ∼2% exists in a free form, circulating mainly in the blood vessels [7]. These dyes can leak into the retina and vitreous and anterior chambers if there is damage to the blood-ocular barriers due to various ocular diseases. When the anterior chamber and anterior vitreous are observed with a slit-lamp microscope after FA, the anterior chamber and vitreous often appear to be green. This study was conducted on the presumption that these diffused dyes might influence the light in OCT and could influence the measured results. Especially in the case of ICG, which has wavelengths similar to those in SD-OCT, even a slight amount of diffused dye may have a significant influence on the OCT results. The blood-ocular barrier usually consists of the bloodretinal barrier and the blood-aqueous barrier. As a result, the aqueous humor may have lower concentrations of electrolytes and proteins than blood plasma [11]. The blood-retinal barrier is made up of retinal pigment epithelium and vascular endothelial cells; the cells are connected by tight junctions [12, 13]. The blood-aqueous barrier consists of nonpigmented ciliary epithelium and the endothelial cells of the iris vessels [14]. If damage occurs to these structures due to, for example, diabetes, proteins and electrolytes may be able to move into the retina and aqueous humor. In a previous study [15], when observing the iris and angle after injecting fluorescein into the blood of healthy people, none of those aged ≤30 years were found to have leaks of fluorescein into the iris or angle. However, the leakage rate tended to increase with age: 80% of subjects aged >60 years were confirmed to have leakage of fluorescein into the iris and angle. The diffusibility and permeability of fluorescein shows statistically significant increases among both healthy people and patients with clinically significant macular edema [14]. Thus, the fluorescein used in retinal angiography may leak into the vitreous body and the anterior chamber; the severity of the leak can vary depending on the disease and the subject’s age. In the present study, Bland-Altman plot and ICC analyses indicated that both the FA and ICGA groups showed a high consistency in the measured values, with high ICC values of >0.8. Many previous studies have reported the reliable repeatability of OCT [16–19]. In the present study, all test results had high ICC values (0.808–0.999), similar to those found in previous studies. Thus, the ef-
References
Effects of Retinal Angiography on OCT Measurements
9 Bland JM, Altman DG: Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;i:307–310. 10 Johnson RN, McDonald HR: Fluorescein angiography: basic principles and interpretation; in Ryan SJ, Hinton DR, Schachat AP, Wilkinson CP (eds): Retina, ed 4. St Louis, CV Mosby, 2006, pp 873–916. 11 Freddo TF: Shifting the paradigm of the blood-aqueous barrier. Exp Eye Res 2001; 73: 581–592. 12 Van Best JA, Kappelhof JP, Laterveer L, Oosterhuis JA: Blood aqueous barrier permeability versus age by fluorophotometry. Curr Eye Res 1987;6:855–863. 13 Moldow B, Sander B, Larsen M, Engler C, Li B, Rosenberg T, Lund-Andersen H: The effect of acetazolamide on passive and active transport of fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by macular oedema. Graefes Arch Clin Exp Ophthalmol 1998;236:881–889. 14 Sander B, Best J, Johansen S, Kessel L, Moldow B: Fluorescein transport through the bloodaqueous and blood-retinal barriers in diabetic macular edema. Curr Eye Res 2003; 27: 247– 252. 15 Satoh K, Takaku Y, Ohtsuki K, Mizuno K: Effects of aging on fluorescein leakage in the iris and angle in normal subjects. Jpn J Ophthalmol 1999;43:166–170. 16 Menke MN, Dabov S, Knecht P, Sturm V: Reproducibility of retinal thickness measurements in healthy subjects using spectralis optical coherence tomography. Am J Ophthalmol 2009;147:467–472.
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17 Wu H, de Boer JF, Chen TC: Reproducibility of retinal nerve fiber layer thickness measurements using spectral domain optical coherence tomography. J Glaucoma 2011; 20: 470– 476. 18 Sharma A, Oakley JD, Schiffman JC, Budenz DL, Anderson DR: Comparison of automated analysis of Cirrus HD OCT spectral-domain optical coherence tomography with stereo photographs of the optic disc. Ophthalmology 2011;118:1348–1357. 19 Comyn O, Heng LZ, Ikeji F, Bibi K, Hykin PG, Bainbridge JW, Patel PJ: Repeatability of Spectralis OCT measurements of macular thickness and volume in diabetic macular edema. Invest Ophthalmol Vis Sci 2012; 53: 7754–7759. 20 Samarawickrama C, Pai A, Huynh SC, Burlutsky G, Wong TY, Mitchell P: Influence of OCT signal strength on macular, optic nerve head, and retinal nerve fiber layer parameters. Invest Ophthalmol Vis Sci 2010; 51: 4471– 4475. 21 Wu Z, Vazeen M, Varma R, Chopra V, Walsh AC, LaBree LD, Sadda SR: Factors associated with variability in retinal nerve fiber layer thickness measurements obtained by optical coherence tomography. Ophthalmology 2007;114:1505–1512. 22 Xu C, Ye J, Marks DL, Boppart SA: Near-infrared dyes as contrast-enhancing agents for spectroscopic optical coherence tomography. Opt Lett 2004;29:1647–1649.
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1 Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, Hee MR, Flotte T, Gregory K, Puliafito CA, et al: Optical coherence tomography. Science 1991; 254: 1178– 1181. 2 Chen TC, Cense B, Pierce MC, Nassif N, Park BH, Yun SH, White BR, Bouma BE, Tearney GJ, de Boer JF: Spectral domain optical coherence tomography: ultra-high speed, ultrahigh resolution ophthalmic imaging. Arch Ophthalmol 2005;123:1715–1720. 3 Wojtkowski M, Srinivasan V, Fujimoto JG, Ko T, Schuman JS, Kowalczyk A, Duker JS: Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 2005; 112:1734–1746. 4 Novotny HR, Alvis DL: A method of photographing fluorescence in circulating blood in the human retina. Circulation 1961;24:82–86. 5 Flower RW, Hochheimer BF: Clinical infrared absorption angiography of the choroid. Am J Ophthalmol 1972;73:458–459. 6 Delori F, Ben-Sira I, Trempe C: Fluorescein angiography with an optimized filter combination. Am J Ophthalmol 1976;82:559–566. 7 Baker KJ: Binding of sulfobromophthalein (BSP) sodium and indocyanine green (ICG) by plasma alpha-1 lipoproteins. Proc Soc Exp Biol Med 1966;122:957–963. 8 Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796–1806.
Ophthalmologica
Received: February 7, 2015 Accepted after revision: March 13, 2015 Published online: May 13, 2015
Ophthalmologica DOI: 10.1159/000381788
Effects of Retinal Angiography on Optical Coherence Tomography Measurements Young-Joon Jo Hyung-Bin Lim Soo-Hyun Lee Jung-Yeul Kim Department of Ophthalmology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
Abstract Purpose: To evaluate the effects of retinal angiography, using fluorescein and indocyanine green dyes, on optical coherence tomography (OCT) measurements. Methods: In total, 76 eyes from 76 consecutive patients were included. Macular cube 512 × 128 combination scanning and optic disc 200 × 200 scanning using spectral-domain (SD)-OCT were performed twice, before and after retinal angiography, with fluorescein or indocyanine green. Signal strength, regional retinal thickness of the 9 Early Treatment Diabetic Retinopathy Study subfields, total macular volume, and retinal nerve fiber layer thickness obtained before and after angiography were compared. Repeatability was also investigated. Results: Comparing the results of OCT measured before and after retinal angiography, there was no statistically significant difference in any parameter assessed. The interclass correlation values for each measurement were all >0.808 (range 0.808–0.999). Conclusion: Retinal angiography using fluorescein and indocyanine green dyes has no significant effect on OCT measurements. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0030–3755/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/oph
Introduction
Optical coherence tomography (OCT), introduced by Huang et al. [1], is a method for observing the vitreous, retina, and choroid of the eye. The device measures differences in the intensity of the light reflected from each tissue after transmitting light of 800 nm (near-infrared wavelength) and is also used to determine the echo time delay. The more recently introduced spectral-domain OCT (SD-OCT) develops images using Fourier transformation after the spectrum of the light through the interferometer is accepted by the spectrometer. This procedure can obtain more images in a shorter time than timedomain OCT. Consequently, the structure of the macula and optic nerve head can be observed more closely. SDOCT has been used widely for the diagnosis and treatment evaluation of various retinal diseases [2, 3]. Novotny and Alvis [4] first performed fluorescein angiography (FA) using fluorescein. Flower and Hochheimer [5] introduced indocyanine green angiography (ICGA) in 1972. Since then, FA and ICGA have been used widely to understand the pathophysiology of diverse diseases of the retina and choroid as well as to identify disease progression and the effects of treatment. Fluorescein and ICG, both used for retinal angiography, have different absorption and emission wavelengths. Jung-Yeul Kim, MD Department of Ophthalmology Chungnam National University Hospital No. 640 Daesa-dong, Jung-gu, Daejeon, 301-721 (Republic of Korea) E-Mail kimjy @ cnu.ac.kr
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Key Words Spectral-domain optical coherence tomography · Fluorescein angiography · Indocyanine green angiography
S6
S
S3 T6
T3
CM
N3
T
N6
I
I3
Fig. 1. a The 9 subfields corresponding to
I6
1 mm 3 mm
a
Fluorescein is stimulated by blue wavelengths of visible light and emits yellow-green light of 520–530 nm [6]. ICG is stimulated by near-infrared wavelengths and also emits a near-infrared wavelength in the ∼800-nm region [7]. About 80% of injected fluorescein and ∼98% of injected ICG binds to plasma proteins [6, 7]. What is bound remains in blood vessels and what is not bound can leak into the choroid and retina and spreads into the vitreous body and anterior chamber. These residual dyes may interfere with OCT measurements. Many medical institutions now tend to use both retinal angiography and OCT to examine retinal and choroidal diseases at the same time. Accordingly, in the present study, we investigated the potential impact of the remaining dyes after FA and ICGA in the choroid, retina, vitreous, and anterior chamber on OCT results.
Materials and Methods The subjects were patients who visited the Department of Ophthalmology at Chungnam National University Hospital, Daejeon, Republic of Korea, from February to August 2013. This was a prospective observational study. The protocol was approved by the Institutional Review Board of Chungnam National University Hospital. All participants signed informed consent forms, and the study adhered to the tenets of the Declaration of Helsinki. The authors had no commercial or proprietary interest in the material used in this study. Medical history, uncorrected visual acuity, best-corrected visual acuity (BCVA), refractive error using an autorefractor, intraocular pressure (IOP, measured using a non-contact tonometer), slit-lamp
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Ophthalmologica DOI: 10.1159/000381788
6 mm
b
biomicroscopy, and fundus examination were conducted. The IOP of each subject was 350 μm), which can induce a segmentation error in OCT measurements, and those who were using eye drops other than artificial tears. Retinal Angiography Two types of dye, fluorescein and ICG, were used in retinal angiography. The subjects were divided into two subgroups depending on the type of dye used. The FA group was given an intravenous injection of 5 ml fluorescein sodium (fluorescein; Novartis Pharma AG, Basel, Switzerland) before the retinal angiography was conducted, while the ICGA group was injected intravenously with 25 mg ICG (Dianogreen®, 25 mg; Daiichi Sankyo Propharma Co., Osaka, Japan) dissolved in 2 ml distilled water. Optical Coherence Tomography The macular cube 512 × 128 combination scan mode and the optic disc cube 200 × 200 scan mode of the Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, Calif., USA) were used. The macular cube 512 × 128 combination scan mode has 6 × 6 mm areas of macula scanned into 512 × 128 dots to measure the thickness of the outer edges of the optic nerve, fibrous layer, and retinal pigment epithelium. The 6 × 6 mm circle belongs to the Early Treatment of Diabetic Retinopathy Study (ETDRS) subfield [8] and was divided into 3 concentric circles, with diameters of 1, 3, and 6 mm, as the central, inner, and outer circles, respectively; all of these were again split into 4 sides, the superior, inferior, nasal, and temporal sides (fig. 1a). The optic disc cube 200 × 200 scan mode has 6 × 6 mm areas around the optic disc, scanned into 200 × 200 dots. After
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the ETDRS areas. CM = Central macula; S3 = superior inner; N3 = nasal inner; I3 = inferior inner; T3 = temporal inner; S6 = superior outer; N6 = nasal outer; I6 = inferior outer; T6 = temporal outer. b Fourquadrant analysis of the RNFL. S = Superior; N = nasal; I = inferior; T = temporal.
N
Table 1. Baseline characteristics of
FA group
subjects Patients Eyes Mean age ± SD, years Males, % Right laterality, % Mean BCVA ± SD, logMAR Mean refractive error ± SD, SE, D Diagnosis and number of eyes
29 29 56.9 ± 12.7 66.7 50.0 0.06 ± 0.09 –0.6 ± 1.3 Normal DR RVO HTNR ERM
ICGA group
12 (41.4) 8 (27.6) 5 (17.2) 2 (6.9) 2 (6.9)
47 47 58.7 ± 13.4 66.0 52.0 0.12 ± 0.23 –0.6 ± 2.0 Normal AMD CSC RVO
27 (57.4) 15 (31.9) 3 (6.4) 2 (4.3)
Figures in parentheses are percentages. SE, D = Spherical equivalent, diopters; DR = diabetic retinopathy; AMD = age-related macular degeneration; RVO = retinal vein occlusion; CSC = central serous chorioretinopathy; HTNR = hypertensive retinopathy; ERM = epiretinal membrane.
Statistical Analysis Analyses were performed with the SPSS software (version 18.0; SPSS Inc., Chicago, Ill., USA). To assess effects of retinal angiography on OCT measurements, OCT was performed twice, before and after angiography. The paired t test was used to compare the average measured values before and after angiography. To identify any influence of angiography on the repeatability of OCT measurements, we analyzed the averages of the twice-measured values using the interclass correlation (ICC) and a Bland-Altman plot [9]. ICC was calculated by dividing the intersubject variance by the total variance, which is the sum of the intersubject variance and the within-subject variance, to assess the consistency of repeated measurements. The ICC ranges from 0 to 1, with values closer to 1 indicating higher reliability. A result >0.9 indicates very high consistency, and a result >0.7 is considered to be clinically valuable. Statistical significance was set at p < 0.05.
Results
The subject group consisted of 76 eyes in 76 people: 29 eyes were classified into the FA group, and the remaining 47 eyes were classified into the ICGA group. In the FA Effects of Retinal Angiography on OCT Measurements
group, the mean age of patients was 56.9 ± 12.7 years, with 66.7% males. The mean BCVA was 0.06 ± 0.09 logMAR, and the mean refractive error was –0.6 ± 1.3 D. In the FA group, 41% had normal eyes, which was the largest subgroup, followed by those with diabetic retinopathy, retinal vein occlusion, hypertensive retinopathy, and an epiretinal membrane. The average age of the patients in the ICGA group was 58.7 ± 13.4 years, with 66% males. The mean BCVA was 0.12 ± 0.23 logMAR, and the mean refraction error was –0.6 ± 2.0 D. In the ICGA group, 57% had normal eyes, followed by age-related macular degeneration, central serous chorioretinopathy, and retinal vein occlusion (table 1). Influence of Retinal FA No statistically significant differences were found in the thickness of the 9 ETDRS subfields, average macular thickness, signal strength, or macular volume between the measurements performed before and after FA. In fact, none of the measured parameters showed a statistically significant difference (table 2). In addition, all measurements had high ICC values (>0.9) in terms of the thickness of the 9 ETDRS subfields, average macular thickness, macular volume, RNFL thickness, and signal strength (table 3). Indeed, the Bland-Altman plot showed that most values were within the 95% confidence interval, indicating a high level of consistency (fig. 2a, b).
Ophthalmologica DOI: 10.1159/000381788
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being divided into the same 4 sides, the retinal nerve fiber layer (RNFL) thickness was measured (fig. 1b). All patients underwent measurements with the macular cube scan and the optic disc cube scan twice, for a total of 4 cube scans, before retinal angiography. At 20 min after the angiography, both scans were performed twice more, for a total of 4 more cube scans. To reduce the possible occurrence of errors, all OCT measurements were performed by the same experienced operator. OCT measurements before and after angiography were performed in identical conditions, and the examination range was established by autofocusing instead of manual operation.
Table 2. Mean values of macular volume, signal strength, and macular and RNFL thickness measured by OCT in the FA group
Before FA Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
8.5 ± 1.3 10.3 ± 0.6 270.9 ± 35.2 332.1 ± 23.5 324.3 ± 23.3 327.3 ± 15.2 332.2 ± 21.8 290.5 ± 26.2 276.0 ± 24.2 272.5 ± 16.9 303.9 ± 16.1 7.9 ± 1.4 94.8 ± 11.2 123.9 ± 19.1 71.1 ± 12.6 117.7 ± 19.3 66.2 ± 10.5
After FA 8.8 ± 1.3 10.3 ± 0.6 269.8 ± 35.1 331.4 ± 24.2 322.8 ± 23.3 325.5 ± 15.6 331.7 ± 23.3 288.7 ± 25.3 274.6 ± 24.0 271.6 ± 16.7 303.4 ± 18.4 8.0 ± 1.3 95.1 ± 11.2 123.3 ± 19.4 71.6 ± 12.8 117.5 ± 19.7 67.7 ± 11.8
Table 4. Mean values of macular volume, signal strength, and macular and RNFL regional thickness measured by OCT in the ICGA group
p value1 0.057 0.203 0.161 0.472 0.065 0.108 0.532 0.093 0.083 0.638 0.724 0.171 0.776 0.420 0.777 0.965 0.222
Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
Before ICGA After ICGA
p value1
7.6 ± 0.9 9.9 ± 0.8 252.8 ± 49.6 311.7 ± 37.1 305.2 ± 36.3 316.9 ± 43.9 322.9 ± 39.9 272.1 ± 20.9 262.8 ± 21.0 266.3 ± 33.6 292.3 ± 20.2 6.8 ± 0.9 89.6 ± 11.0 112.7 ± 18.0 69.8 ± 15.4 110.6 ± 19.0 65.2 ± 9.8
0.938 0.310 0.905 0.328 0.453 0.549 0.571 0.200 0.428 0.441 0.443 0.298 0.955 0.930 0.925 0.988 0.368
7.6 ± 1.0 9.8 ± 0.8 252.9 ± 51.2 312.8 ± 37.5 303.5 ± 33.9 316.1 ± 46.8 322.7 ± 43.6 271.3 ± 20.5 265.5 ± 30.9 265.1 ± 32.6 291.6 ± 20.9 6.9 ± 1.0 89.7 ± 10.9 112.8 ± 17.1 69.9 ± 14.7 110.6 ± 19.5 64.4 ± 7.9
Data are means ± SDs (μm). 1 Wilcoxon signed-rank test. Data are means ± SDs (μm). 1 Paired t test.
Table 3. ICC of signal strength and macular and RNFL thickness
Table 5. ICC of signal strength and macular and RNFL thickness
in the FA group
in the ICG group 95% CI
0.923 0.994 0.999 0.992 0.998 0.948 0.996 0.997 0.993 0.978 0.978 0.950 0.984 0.986 0.965 0.948 0.932
0.856 – 0.968 0.987 – 0.997 0.999 – 1.000 0.986 – 0.997 0.995 – 0.999 0.895 – 0.976 0.991 – 0.998 0.993 – 0.999 0.988 – 0.997 0.952 – 0.990 0.953 – 0.989 0.896 – 0.976 0.964 – 0.993 0.972 – 0.994 0.930 – 0.984 0.890 – 0.975 0.864 – 0.969
CI = Confidence interval.
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Ophthalmologica DOI: 10.1159/000381788
Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
ICC
95% CI
0.812 0.997 0.998 0.992 0.991 0.925 0.981 0.995 0.978 0.984 0.975 0.808 0.986 0.973 0.983 0.940 0.890
0.694 – 0.921 0.995 – 0.998 0.996 – 0.999 0.989 – 0.997 0.985 – 0.995 0.870 – 0.958 0.967 – 0.989 0.991 – 0.997 0.962 – 0.988 0.975 – 0.990 0.955 – 0.986 0.691 – 0.926 0.975 – 0.992 0.952 – 0.985 0.971 – 0.991 0.894 – 0.966 0.821 – 0.940
CI = Confidence interval.
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Signal strength (macular cube) Macular volume Central macula Superior 3 Temporal 3 Inferior 3 Nasal 3 Superior 6 Temporal 6 Inferior 6 Nasal 6 Signal strength (RNFL) RNFL average thickness Superior (RNFL) Temporal (RNFL) Inferior (RNFL) Nasal (RNFL)
ICC
Difference in pre- and post-FA RNFL average thickness (μm)
10 0 –10 –20
275 300 325 350 375 Average of pre- and post-FA macular thickness (μm)
c
40 30 20 10 0 –10 –20 –30 –40
200 300 400 500 600 Average of pre- and post-ICGA macular thickness (μm)
Fig. 2. Bland-Altman plots for macular and RNFL average thick-
ness measured before and after angiography. The solid line indicates the average mean difference, and the dotted lines delineate the 95% confidence limits of agreement. a Bland-Altman plot for measurements of macular average thickness after FA. The mean difference is –0.12. The 95% limits of agreement are –4.53 to 4.29. b Bland-Altman plot for measurements of RNFL average thickness
10 0 –10 –20
b
Difference in pre- and post-ICGA RNFL average thickness (μm)
Difference in pre- and post-ICGA macular average thickness (μm)
a
20
d
60
70 80 90 100 110 120 Average of pre- and post-FA RNFL thickness (μm)
30 20 10 0 –10 –20
40 50 60 70 80 90 Average of pre- and post-ICGA RNFL thickness (μm)
after FA. The mean difference is 1.13. The 95% limits of agreement are –3.22 to 5.48. c Bland-Altman plot for measurements of macular average thickness after ICGA. The mean difference is –0.2. The 95% limits of agreement are –5.04 to 4.64. d Bland-Altman plot for measurements of RNFL average thickness after ICGA. The mean difference is –0.02. The 95% limits of agreement are –4.31 to 4.35.
OCT and retinal angiography are both important tools for diagnosing retinal and choroidal diseases, deciding on treatment plans, and assessing prognoses. An increasing
number of people tend to undergo both tests at the same time. Thus, in this study, we assessed the influence of the dyes used in retinal angiography, such as fluorescein and ICG, on OCT measurements, as well as any effect on the repeatability of the tests. Fluorescein releases yellow-green rays at 520–530 nm after stimulation by absorbing blue rays at a wavelength of 469–490 nm. After intravenous injection, about 80% of the fluorescein combines with plasma proteins, and the remaining 20% circulates in the blood vessels in a free form [6]. Fluorescein that enters the eyeball generally cannot penetrate the retinal vessels due to the tight junctions of vascular endothelial cells. Although it cannot penetrate vessels that are bigger than the choroidal vessel either, it can freely penetrate capillary vessels in other tissues. The diffusion of the outflowing fluorescence is
Effects of Retinal Angiography on OCT Measurements
Ophthalmologica DOI: 10.1159/000381788
Influence of Retinal ICGA No statistically significant difference was found in the thickness of the 9 ETDRS subfields, average macular thickness, RNFL thickness, or signal strength before and after ICGA was performed (table 4). In addition, all test results except the signal strength and RNFL nasal quadrant had ICC values >0.9 (table 5). In the Bland-Altman plot, again, most values were within the 95% confidence interval, indicating a high level of consistency (fig. 2c, d).
Discussion
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Difference in pre- and post-FA macular average thickness (μm)
20
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Ophthalmologica DOI: 10.1159/000381788
fects of fluorescein and ICG on the repeatability of SDOCT are considered to be negligible. The signal strength can influence the results of OCT. Samarawickrama et al. [20] reported that a group with stronger signal strength showed overestimated values in the macula and the RNFL. Wu et al. [21] reported that the RNFL thickness could be underestimated at low signal strengths. It has been presumed that the fluorescein and ICG that diffuse into the eyeball may then spread into the retina and vitreous and anterior chambers, and that these dyes may have a significant influence on OCT measurements. However, in the present study, we did not find any significant influence of fluorescein or ICG on signal strength or any of the measured values. Xu et al. [22] reported that a near-infrared dye was injected to enhance the contrast of the cross-sections of tissues, which resulted in a clearer image; however, the depth of the image was reduced by approximately 20– 30%. Because ICG can absorb and release near-infrared rays, it was presumed that it may have an influence on the results of OCT. However, we found no significant influence of ICG on the measured values or on the repeatability or reliability of tests. Neither fluorescein nor ICG had any clinically significant impact on OCT. Although ∼20% of the fluorescein may diffuse in a free form into the vitreous cavity and the anterior chamber, its influence on measurement values is presumed to be negligible because its wavelength does not overlap with that of OCT. Although the wavelength of ICG overlaps with that of OCT, it did not have any significant impact on the results, likely because very little dye in a free form was present (almost all of it is bound to plasma proteins). In conclusion, the fluorescein and ICG used in retinal angiography were found to have no clinically significant influence on the various measurements of OCT or the signal strength of the retina or the RNFL. Thus, even if SD-OCT is performed together with retinal angiography using fluorescein or ICG, reliable SD-OCT results can be achieved.
Disclosure Statement The authors have no financial/conflicting interests to disclose. No conflicting relationship exists for any author.
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blocked due to the tight junctions of the retinal pigment epithelium [10]. Regarding ICG, it releases near-infrared rays at a wavelength of 770–880 nm after absorbing them at a wavelength of 790–805 nm [7]. Unlike fluorescein, ∼98% of ICG combines with plasma proteins due to its lipophilic properties, while only ∼2% exists in a free form, circulating mainly in the blood vessels [7]. These dyes can leak into the retina and vitreous and anterior chambers if there is damage to the blood-ocular barriers due to various ocular diseases. When the anterior chamber and anterior vitreous are observed with a slit-lamp microscope after FA, the anterior chamber and vitreous often appear to be green. This study was conducted on the presumption that these diffused dyes might influence the light in OCT and could influence the measured results. Especially in the case of ICG, which has wavelengths similar to those in SD-OCT, even a slight amount of diffused dye may have a significant influence on the OCT results. The blood-ocular barrier usually consists of the bloodretinal barrier and the blood-aqueous barrier. As a result, the aqueous humor may have lower concentrations of electrolytes and proteins than blood plasma [11]. The blood-retinal barrier is made up of retinal pigment epithelium and vascular endothelial cells; the cells are connected by tight junctions [12, 13]. The blood-aqueous barrier consists of nonpigmented ciliary epithelium and the endothelial cells of the iris vessels [14]. If damage occurs to these structures due to, for example, diabetes, proteins and electrolytes may be able to move into the retina and aqueous humor. In a previous study [15], when observing the iris and angle after injecting fluorescein into the blood of healthy people, none of those aged ≤30 years were found to have leaks of fluorescein into the iris or angle. However, the leakage rate tended to increase with age: 80% of subjects aged >60 years were confirmed to have leakage of fluorescein into the iris and angle. The diffusibility and permeability of fluorescein shows statistically significant increases among both healthy people and patients with clinically significant macular edema [14]. Thus, the fluorescein used in retinal angiography may leak into the vitreous body and the anterior chamber; the severity of the leak can vary depending on the disease and the subject’s age. In the present study, Bland-Altman plot and ICC analyses indicated that both the FA and ICGA groups showed a high consistency in the measured values, with high ICC values of >0.8. Many previous studies have reported the reliable repeatability of OCT [16–19]. In the present study, all test results had high ICC values (0.808–0.999), similar to those found in previous studies. Thus, the ef-
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Effects of Retinal Angiography on OCT Measurements
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