Optical coherence tomography angiography (OCTA) is a new, non-invasive technology that allows visualization of microvasculature of the eye in specific layers without the need for a contrast agent.1,2 By detecting motion contrast of blood flow between consecutive OCT images, an image is produced in which structural and blood flow information is shown in tandem.1,3,4 Although OCTA, other than fluorescein angiography or indocyanine green angiography, is not capable of detecting dye leakage,1 it allows for the acquisition of images with a much higher contrast and resolution1,4 while gaining volumetric angiographic information. Today OCTA, therefore, is frequently used for study of change in retina and choroid.
As one of the most highly vascularized tissues of the human body, the choroid holds several functions. Apart from supplying the outer retinal layers with nutrition and oxygen, the choroid is thought to play an important role in the adjustment of the retinal position as well as in the secretion of growth factors leading to vascularization and scleral growth.3,5 Further it is assumed to regulate the temperature of the retina.5 Due to its multiple functions within the eye the choroid is involved in the pathogenesis of several ophthalmic diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR)3 or myopic choroidal neovascularization (CNV).6 This makes the choroid a highly interesting tissue to monitor.
Previous studies have detected a decrease in choroidal perfusion in subjects with high myopia.7–11 This decrease in blood flow is subject of great interest as it is discussed to be a trigger for macular complications such as cataract formation, posterior staphyloma, retinal detachment, chorioretinal atrophy, or myopic choroidal neovascularization.12–15
The aim of our study was to examine whether the decrease in choroidal perfusion within myopic subjects already takes place in low myopia. In the present study, we therefore assessed the choriocapillary (CC) blood flow in subjects with low myopia by using the OCTA technique. We correlated choroidal blood flow values with spherical equivalent refraction (SER), bulbus axial length (AL), and choroidal thickness (CT) as parameters of myopia and compared mean CC flow values between the low myopic and the emmetropic control group.
Patients and Methods
Subjects and Study Design
A total of 82 healthy volunteers enrolled in this cross-sectional clinical study from January 2017 to May 2017. To eliminate the effect of presbyopia, the age range was set between 20 years and 40 years. Subjects with SER ranging from −1.00 diopters (D) to −6.00 D were designated as the myopic group, with AL being 20 mm or greater and less than 26.5 mm.16 Subjects with SER ranging from + 0.75 D to −0.75 D were designated as the emmetropic control group. Exclusion criteria were any previous history of vitreoretinal disease, systemic diseases with potential ocular affection, as well as any history of ocular or retinal surgery.
The study was approved by the ethics committee of the Technical University of Munich and was performed in accordance with the Declaration of Helsinki. All subjects gave written informed consent.
OCTA Image Acquisition
The OCTA images were obtained in healthy individuals without pupillary dilatation using the AngioVue software of the Avanti RTVue XR spectral-domain OCT device (OptoVue, Fremont, CA). Split-spectrum amplitude decorrelation (SSADA) was used to reduce the signal-to-noise ratio of the obtained blood flow information.1,17 We obtained 3 mm × 3 mm frame scans with a rate of 70,000 A-scans per second, containing 304 × 304 A-scans with two consecutive B-scans with a bandwidth of 50 nm and a centered light source of 840 nm. For motion correction and reduction of motion artifacts, each scan was obtained through two orthogonal OCTA images.12 Automatic segmentation by the AngioVue software led to en face projection images showing the superficial retinal capillary plexus (SCP), deep retinal capillary plexus (DCP), and outer retina, as well as the CC. The SCP was segmented with an inner boundary 3 μm below the internal limiting membrane and an outer boundary 16 μm below the inner plexiform layer (IPL). The DCP was segmented with an inner boundary 16 μm below the IPL and an outer boundary 69 μm below the IPL. The outer retina was segmented with an inner boundary 69 μm below the IPL and an outer boundary 31 μm below the RPE-Bruch-membrane complex. The CC was segmented with an inner boundary 31 μm below retinal pigment epithelium (RPE)-Bruch's membrane complex and an outer boundary 60 μm below RPE-Bruch's membrane complex.
All images were checked for sufficient image quality and segmentation. Any image showing motion artifacts, projection artifacts, or segmentation errors greater than three lines was excluded.
A single-line enhanced high-definition (HD) scan was performed for measurement of central choroidal thickness (CT).
OCTA Image Analysis
The raw en face OCTA 3 mm × 3 mm images and their corresponding cross-sectional B-scan images were used to determine the center of the foveal avascular zone (Figure 1). The intersection of the red and the green line in the en face OCTA showing the SCP was set at a manually adjusted point, which was considered to be in the middle of the fovea. While switching into the CC layer within the same OCTA image, the intersection remained in the same place. Using the flow tool in OptoVue, blood flow in the CC was measured within a circle with an area of 3.14 mm2, which was manually positioned with its center at the previously shown intersection of the red and green lines, corresponding to the central fovea. The choriocapillary flow area (mm2), being defined as the selected area (mm2) minus the non-flow-area (mm2), was then automatically calculated by the AngioVue software.
Quantification of choriocapillary blood flow using en face optical coherence tomography angiography (OCTA) and corresponding cross-sectional B-scan. Upper left: En face OCTA image of the superficial retinal capillary plexus. The intersection of the red and green line has been placed in the center of the foveal avascular zone. Lower left: Corresponding cross-sectional B-scan. Upper middle: En face OCTA image in the same subject after switching into the choriocapillaris (CC) layer. The green and red lines still intersect in the center of the fovea. Areas of flow signal appear white whereas areas with absent flow signal appear dark. Lower middle: Corresponding cross-sectional B-scan with a segmentation level marking the CC. Upper right: En face OCTA image of the CC in the same subject. The yellow colored area corresponds to a circle with a radius of 1 mm and thus an area of 3.14 mm2, in which blood flow is measured. Its center has been placed on the previously shown intersection of the red and green lines (central fovea). Lower right, corresponding cross-sectional B-scan.
To ensure correct measurements all CC flow area measurements were obtained by two independent investigators. We then used a Bland-Altman blot to account for the inter-rater reliability. The bias was −0.0001 ± 0.00255 mm2 with limits of agreement ranging from −0.00476 to 0.00496 mm2. There was no proportional bias. Having accorded beforehand on a good match of values if the differences lay within the range of ± 0.005 mm2, the calculated limits were acceptable for a good inter-rater reliability.
For CT measurement, the enhanced HD OCTs were analyzed by using the built-in caliper tool. CT was defined as the perpendicular distance between the Bruch's membrane and the choroidal scleral junction and was obtained at the foveal center (Figure 2).12
A horizontal enhanced high-definition optical coherence tomography image showing choroidal thickness (CT) measurement using the caliper tool of the AngioVue software. CT, indicated by the orange line, was measured at the foveal center in a perpendicular distance between the Bruch's membrane and the choroidal scleral junction.
Axial Bulbus Length and Spherical Equivalent Refraction Measurement
Each subject underwent AL measurement by optical biometry (IOL Master; Carl Zeiss Meditec, Jena, Germany) and auto-refraction measurement (AR-1 Autorefractometer; Nidek, Gamagori, Japan). The refraction data were converted to SER by adding half of the cylinder power to the sphere power.
To account for correlated measurements within a subject, we calculated a generalized estimating equation with an interchangeable correlation matrix. Values are given as the mean with standard deviation if not stated otherwise and were calculated with SPSS software (version 23.0; SPSS, Chicago, IL). A P value of less than .05 was considered to be significant.
One hundred fifty-seven eyes of 82 healthy subjects (53 female, 29 male) were included in our study after consideration of our set exclusion criteria as described in the methods section. The myopic group consisted of 78 eyes of 45 subjects (33 female, 12 male). The mean age was 29.31 years ± 4.95 years. The spherical equivalent refraction (SER) was −2.56 D ± 1.39 D. The subfoveal CT was 305.23 μm ± 74.69 μm, and the AL was 24.26 mm ± 0.95 mm. The emmetropic control group consisted of 79 eyes of 44 subjects (26 female, 18 male). The mean age was 28.58 years ± 5.13 years. The SER was −0.19 D ± 0.43 D. The CT was 326.21 μm ± 64.95 μm, and the AL was 23.48 mm ± 0.75 mm.
CT as a dependent variable was correlated with SER and AL as parameters of myopia using linear regression analysis. As expected, CT showed a statistically significant negative correlation with SER (P = .017) (Figure 3). There could also be seen a negative correlation with AL (P = .180) (Figure 3).
Correlation between choroidal thickness (CT) as the dependent variable versus spherical equivalent refraction (SER) and axial bulbus length (AL). Left, scatter plot showing SER (X axis) versus CT (Y axis), P = .017. Right, scatter plot showing AL (X axis) versus CT (Y axis), P = .180.
Subfoveal choriocapillary blood flow as the dependent variable was correlated with multiple quantitative parameters using linear regression analysis. There was no significant correlation with CT (P = .820), SER (P = .798), or AL (P = .269) (Figure 4).
Correlation between choriocapillary blood flow area as the dependent variable versus choroidal thickness (CT), spherical equivalent refraction (SER), and axial bulbus length (AL). Left, scatter plot of CT (X axis) versus choriocapillary flow area (Y axis), P = .820. Middle, scatter plot of SER (X axis) versus choriocapillary flow area (Y axis), P = .798. Right, scatter plot of AL (X axis) versus choriocapillary flow area (Y axis), P = .269.
The mean subfoveal choriocapillary blood flow area was compared between the myopic group and the emmetropic control group. The mean subfoveal choriocapillary blood flow area was 1.970 ± 0.035 mm2 in the myopic group and 1.980 ± 0.034 mm2 in the emmetropic control group. The estimated mean flow area difference between the groups was −0.006 mm2 with a 95% confidence interval ranging from −0.018 mm2 to 0.005 mm2 with a corresponding P value of 0.266 (Figure 5).
Boxplots showing the choriocapillary blood flow area in the myopic group and the emmetropic control group. The blood flow area in the emmetropic group was 1.980 ± 0.034 mm2. The blood flow area in the myopic group was 1.970 ± 0.035 mm2. The mean difference lay at −0.006 mm2 with a 95 % confidence interval ranging from −0.018 mm2 to 0.005 mm2 with a corresponding P value of .266.
This study was able to identify a statistically significant thinning of the CT with increasing myopia in terms of SER. This finding conforms to previously published works concerning high myopia,12,18–20 which have repeatedly shown a negative correlation between CT and SER. A reason being discussed for the thinning of the choroid in myopia is the longer AL of the eye that results in ocular stretching and thinning of the choroid.21
Unlike previous studies, our study examined the change in choriocapillaris blood flow in low myopia (−1 D to −6 D). Our findings suggest a non-changing blood flow on OCTA within the range of low myopia compared to emmetropic subjects. This might indicate that the CC layer has a compensatory mechanism for CT thinning within the range of low myopia, especially taking into account that we were unable to detect an increased area of non-flow. Previous studies concerning high myopia have given rise to the assumption that choroidal perfusion decreases within high myopic subjects. A recent study by Al-Sheikh et al.12 was able to show blood flow alterations in highly myopic subjects in terms of an increase of total and average CC flow void area. As the first study to examine blood flow quantitatively in highly myopic eyes, these findings correlated with results from previous histological studies led in chicks with visual degradation induced myopia. As such Hirata and Negi22 were able to measure a decrease in density and capillary diameter in the CC of myopic patients, as well as an increase in distance between adjacent intercapillary meshes by using scanning electron microscopy. The animal model led by Shih et al.10 moreover was able to show a decrease in choroidal blood flow using doppler velocimetry. Similar findings were obtained in a study led by Akyol et al.,7 in which a decrease in choroidal blood flow was measured in degenerative myopia using color Doppler ultrasonography. A recent study led by Sayanagi et al.23 concerning myopic maculopathy further showed that myopic CC degradation differs depending on the category of myopic maculopathy. Accordingly, it can be distinguished between a complete loss of CC in areas of patchy atrophy and a decreased density of the CC in areas with diffuse atrophy.
One of the most serious complications of pathologic myopia is the myopic choroidal neovascularization (mCNV). Given its sudden onset and progressive deterioration in central vision, it has a poor prognosis if left untreated.24 Histopathological studies indicate that replacement of the choroidal vasculature by fibrous tissue is common in pathologic myopia.25 It is especially this atrophy, as well as the formation of lacquer cracks resulting from thinning and stretching of the eye, that poses the greatest risk for the formation of mCNV.23,26 Knowing OCTA appearance of the CC layer will probably help detect mCNV alterations from an early stage on in future. The examination of the choroid therefore plays an important role to detect early pathologic myopia associated alterations as well as to describe atrophy.
Our study design has several strengths. By using an age-matched group, we attempted to eliminate the effects of presbyopia. We excluded any subject with previous history of ocular or systemic diseases that might have an effect on the microvasculature or its imaging to minimize the probability of artifacts.
It should nevertheless be taken into account that our study also has several limitations. The exclusion of highly myopic subjects surely reduces the visibility of the impact high myopia has on the CC. In addition, we are aware that the distribution of myopia in terms of SER is not quite equal in our study, but that there is a higher representation of low myopic eyes. Possible changes in CC blood flow occurring in low myopia might therefore stay concealed. Further, the OCTA technique itself brings along limitations that include motion and projection artefacts, which reduce the validity of the measured flow values. Even though we evaluated each image for artifacts, we therefore cannot rule out method inherent inaccuracy of the image acquisition. In addition, the OCTA technique lacks the ability to measure the velocity of the blood flow but rather flow itself. Therefore, flow void areas either show areas of complete absence of flow or areas in which flow is smaller than the set threshold.
In conclusion, the results of our study might indicate that there is a compensatory mechanism in low myopic eyes that prevents CC alterations seen in high myopia. As complications, such as mCNV, come along with pathologic myopia, the choroid might have a great relevance when it comes to the detection of myopia-associated alterations.
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