|Year : 2019 | Volume
| Issue : 3 | Page : 132-137
Comparative study between patients with subclinical diabetic retinopathy and healthy individuals in the retinal microvascular changes using optical coherence tomography angiography
Abd El-Magid M Tag El-Din
Department of Ophthalmology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
|Date of Submission||08-Feb-2019|
|Date of Acceptance||26-Apr-2019|
|Date of Web Publication||26-Sep-2019|
MD Abd El-Magid M Tag El-Din
Flat 602, Building 13, Omar Zaafan Street, 1st District, Nasr City, Cairo 11765
Source of Support: None, Conflict of Interest: None
Purpose The aim of this study was to compare between patients with subclinical diabetic retinopathy (DR) and healthy individuals in the retinal microvascular changes including vascular density (VD), perfusion density (PD), and foveal avascular zone (FAZ) parameters by using optical coherence tomography angiography (OCTA).
Patient and methods A total of 50 individuals were categorized into two groups: group A (healthy individuals) and group B (diabetic patients). Full ophthalmic examination, best-corrected visual acuity, intraocular pressure measurement, fundus fluorescein angiography, optical coherence tomography, and OCTA were done for all patients.
Results Statistically significant differences were found between the healthy group and the diabetic group in OCTA parameters. VD and PD were significantly decreased in the diabetic patients (P>0.001). FAZ showed significant changes in area value and perimeter; however, the circularity changes were statistically insignificant.
Conclusion OCTA is an effective tool that can provide a noninvasive method in the differentiation between subclinical DR and normal individuals. The FAZ metrics, VD, and PD in patients with subclinical DR showed a significant deviation from the parameters obtained from normal healthy individuals.
Keywords: diabetic retinopathy, foveal avascular zone metrics, optical coherence tomography angiography, perfusion density, vascular density
|How to cite this article:|
Tag El-Din AMM. Comparative study between patients with subclinical diabetic retinopathy and healthy individuals in the retinal microvascular changes using optical coherence tomography angiography. Delta J Ophthalmol 2019;20:132-7
|How to cite this URL:|
Tag El-Din AMM. Comparative study between patients with subclinical diabetic retinopathy and healthy individuals in the retinal microvascular changes using optical coherence tomography angiography. Delta J Ophthalmol [serial online] 2019 [cited 2020 Apr 5];20:132-7. Available from: http://www.djo.eg.net/text.asp?2019/20/3/132/267945
| Introduction|| |
Patients with subclinical diabetic retinopathy (DR) are those who are diagnosed with type II diabetes mellitus (DM) with duration of 4–8 years, with no frank manifestations of DR, neither on clinical examination nor by the common diagnostic tools. DR is the specific microvascular complication of DM and affects one of three patients with DM. DR remains a leading cause of vision loss in working adult population .
Recent studies ,,, supported the concept that the retinal vasculature may provide a summary measure of lifetime exposure to the effects of hyperglycemia. Advances in retinal photographic techniques and in image analysis allowed objective and precise in-vivo measurement of retinal vascular changes. In particular, quantitative assessment of retinopathy signs and measurement of retinal vascular caliber have greatly increased our knowledge of early microcirculation alterations in prediabetes, diabetes, and diabetic macrocirculation and microcirculation complications . Fluorescein angiography and color fundus photography have been used to establish quantitative indices of perfusion in DR . However, these imaging modalities do not resolve retinal capillaries reliably and cannot detect subtle changes .
Optical coherence tomography (OCT) became a part of the standard of care in ophthalmology. It provided cross-sectional and three-dimensional imaging of the anterior segment, retina, and optic nerve head with micrometer scale-depth resolution. Structural OCT enhances the clinician’s ability to detect and monitor fluid exudation associated with vascular diseases . It is however unable to directly detect capillary dropout or pathological vessel growth (neovascularizarion) that constitutes the major vascular changes associated with DR. These features among other vascular abnormalities are assessed clinically by using fluorescein or indocyanine green angiography. To overcome conventional structural OCT’s inability to provide direct blood flow information, several optical coherence tomography angiography (OCTA) methods had been developed . Quantification of retinal perfusion using OCTA has been reported in normal individuals , and retinal vascular diseases . OCTA provided a novel method for noninvasively imaging capillary network and the foveal avascular zone (FAZ) ,. In addition, OCTA can use split-spectrum amplitude-decorrelation angiography algorithm to detect erythrocyte movement . The currently commercially available OCTA machines allowed a four-section division of the retina–choroid complex: superficial capillary plexus, deep capillary plexus, outer retinal layers, and choriocapillaris. A new software update allowed quantification of the vascular density (VD) around the macula. VD was defined as the percentage of the sample area occupied by vessel lumens following binary reconstruction of images. In-vivo quantification of VD and the FAZ area may be useful in detecting and monitoring the progression of retinal vascular changes caused by diabetes and other forms of retinopathy .
This study aimed to evaluate the VD, perfusion density (PD), and FAZ parameter changes in patients with DM showing no manifestations of DR (subclinical DR) by using OCTA.
| Patients and methods|| |
An observational cross-sectional study was performed to evaluate the microvascular changes in diabetic patients, diagnosed with type II DM with duration of 4–8 years, with no frank manifestations of DR neither on clinical examination nor by the common diagnostic tools, ‘fundus fluorescein angiography (FFA) and OCT’ (subclinical DR). This study included 100 eyes of 50 participants; 25 of the patients were diabetic and the other 25 were normal controls. Group A included the healthy individuals, and group B included the diabetic patients.
The study was approved by the Ethics Board of Al-Azhar University. All participants signed a written informed consent before participating in the study.
Inclusion criteria for group A included no history of chronic vascular or metabolic disease, best-corrected visual acuity of at least 1.0 and normal ocular examination, whereas the exclusion criteria included systemic, vascular, or metabolic diseases, history of eye surgery (any type of intraocular surgery or refractive surgery), high normal or high intraocular pressure, and large physiologic cupping.
Inclusion criteria for group B included patients with DM greater than or equal to 5 years and less than or equal to 8 years without DR. Exclusion criteria for group B included the presence of DR or diabetic macular edema; presence of disabling media opacities (e.g. anterior chamber flare, significant cataract, or vitreous opacities); previous intravitreal injection of either antivascular endothelial growth factor or steroids; previous cataract extraction surgery or vitrectomy or pseudophakia; previous focal, grid laser or panretinal photocoagulation; presence of any other vascular or metabolic diseases other than DM; or presence of hereditary or acquired macular dystrophic diseases.
All laboratory investigations were done after 12 h of fasting to evaluate the diabetes profile (glycosylated hemoglobin and fasting blood glucose). Full ophthalmic examination was performed to assess the uncorrected visual acuity as well as best-corrected visual acuity by using Landolt’s C chart. Pupil reaction was assessed, and slit lamp biomicroscopy was performed to assess the corneal clarity and integrity, depth of the anterior chamber, dilatation of the pupil, clarity of the crystalline lens, clarity of the vitreous cavity, anatomical and morphological integrity of the optic disc and posterior pole by noncontact digital wide-field Volk lens (Volk Optical Inc., Mentor, OH, USA) for indirect ophthalmoscopy, and intraocular pressure measurement by Goldmann applanation tonometer (Haag-Streit, Essex, UK).
Colored fundoscopic picture, FFA, OCT, and OCTA were performed to assess the state of the patients’ neurosensory retina and retinal vasculature ([Figure 1] and [Figure 2]). OCT retinal map, and cross lines were obtained by the high-definition OCT (Cirrus by Carl Zeiss Meditec Inc., Dublin, CA, USA). OCTA imaging was performed also by the Cirrus high-definition OCT prototype AngioPlex instrument using the optical microangiography algorithm (Carl Zeiss Meditec Inc.). Both eyes of each participant were scanned with a scan comprising 245 clusters of B-scans repeated 4 times, where each B-scan consisted of 245 A-scans. The effect of eye motion-related artifacts was minimized by the use of tracking. The averaged OCT B-scans were also examined in the usual manner of OCT data to show the retinal tissue. This volume of data was segmented using the CIRRUS inner-limiting membrane and retinal pigment epithelium segmentation algorithms. From these layers, estimates were derived to subdivide the inner retina into 2 distinct physiologic layers: a superficial retinal layer (SRL) and a deeper retinal layer (DRL). The inner retina was estimated as being the tissue between the inner-limiting membrane and an offset from the retinal pigment epithelium of 110 µm. The SRL was defined as the inner 70% of the inner retina, and the DRL was the remaining 30% of the inner retina. The layer estimates were applied to the three-dimensional optical microangiography algorithm motion contrast dataset. A maximum projection method within the layer of interest was used to generate the en-face images. To calculate the PD and vessel density, a thresholding algorithm was applied to the SRL or DRL en-face images to create a binary slab that assigns to each pixel a 1 (perfused) or 0 (background). From this slab, a skeletonized slab was created, representing vessels with a trace of 1 pixel in width . Using an existing algorithm available on the Cirrus device, we used the fovea position as the starting point for an iterative region-growing algorithm that identified the FAZ. The area and perimeter of this zone were calculated, and the circularity index was calculated as 4πA/P, where A is the area and P is the perimeter. The FAZ measures were based only on the SRL because there is only expected to be a single capillary plexus at the border of the FAZ . Each eye underwent three repeated scans with three instruments for a total of nine acquisitions. Eyes were randomly assigned to scanning with a 3×3 or 6×6 mm pattern. Eyes were excluded from subsequent analysis if any acquisition had signal strength of less than 7. To avoid repeatability and reproducibility errors, we obtained each image four times successively. If there was a significant scan quality difference between images, we increased the number of scans.
|Figure 1 Optical coherence tomography angiography automated analysis of the vascular density and foveal avascular zone parameters in a diabetic patient.|
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|Figure 2 Optical coherence tomography angiography automated analysis of the vascular density and foveal avascular zone parameters in a healthy control.|
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| Results|| |
Statistical analysis of the outcomes showed that the mean of the VD in the control group was 20.40±1.56 which showed a statistically significant difference from the diabetic group, which showed a mean VD of 17.65±2.87 (P<0.001, [Table 1]). PD also appeared to be an important biomarker in the diabetic patients as the mean PD in the healthy group was 0.36±0.06, whereas in the diabetic group was 0.33±0.04 (P<0.001), showing a statistically significant difference between the two groups ([Table 1]). FAZ was numerically assessed by measuring the perimeter (P), area (A), and circularity index (C). By comparing these values in both groups, FAZ-A showed a statistically significant difference (P=0.017); the mean value in the control group was 0.26±0.07, whereas in the diabetic group, it was 0.32±0.12. FAZ-P also showed a statistically significant difference (P=0.011), where the mean value in the control group was 2.18± 0.33 and in the diabetic group was 2.46±0.58. It seemed that FAZ-P increases in the diabetic patients. The only value that did not show a statistically significant difference is the FAZ-C (P=0.102), with a mean value of 0.67±0.08 in the control group and 0.63±0.12 in the diabetic group ([Table 1]).
|Table 1 Mean value of vascular density difference, perfusion density difference, and the foveal avascular zone difference between the control group and the diabetic group|
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| Discussion|| |
By reviewing the literature, no similar study was found that perfectly matches this study. The laboratory in-vitro research work suggested that hyperglycemia and DM influence the normal histological status of the retinal tissue and the vessels themselves, by influencing the PD of the tissue. However, this was unidentifiable by the normal diagnostic tools (FFA and OCT) . This study agrees with that of Tam et al.  that established adaptive optics scanning laser ophthalmoscopy (AOSLO) as a method to detect the early unidentifiable diabetic changes such as the capillary changes that can be detected including dropout of individual capillaries, as well as formation and disappearance of microaneurysms. In addition, this study is comparable with the studies by Russmann and Amiji , Frimmel et al. , and Sun et al. .
To visualize the earliest vascular changes in diabetes, this study was done by using the AngioPlex OCTA from Zeiss Meditec, Germany. Each commercially available OCTA device has its own algorithm that analyzes the data. Zeiss AngioPlex uses optical microangiography (OMAG) algorithm. In his review on the commercially available OCTA devices, Burak  claimed that, in a recent study, when algorithms included OMAG, speckle variance, and phase variance, he found that OMAG, as the method utilizing complex OCT signals to contrast retinal blood flow, provided the best visual result for the retinal microvascular networks concerning image contrast and vessel connectivity ,.
Coscas et al.  published normative data for VD in superficial and deep capillary plexus of healthy adults assessed by OCTA. They provided an age-related VD mapping data using OCT angiography in healthy individuals. They used the AngioAnalytics software by OptoVue to quantify VD and FAZ. Part of the outcomes of such study was incomparable with this study, as it was doing an age-related map using different prototype software. However, the FAZ-A mean value is consistent with this study findings. Coscas et al.  postulated that the mean FAZ-A in all age groups is 0.28±1.0 mm2. In this study, statistical analysis showed that the mean FAZ-A for the control group was 0.26±0.7 mm2 which is comparable to the study by Coscas et al.. Another study was conducted by Durbin et al.  and evaluated the ability of measurements of retinal microvasculature by using OCTA to distinguish healthy eyes from eyes with DR. The study was done to differentiate between retinal microvasculature of normal participants and participants with type II diabetes. This study used the same device and software used in this study to examine 50 eyes of 26 participants with diabetes and 50 eyes of 25 normal participants (compared with this study sample, in which 50 eyes of 25 patients were examined in each group). However, the pivotal dissimilarities between this study and this study are the duration of diabetes and the stage of DR in the diabetic group. The mean duration of diabetes in the study by Durbin et al.  was 18.7 years, whereas in this study, it was 6.84±1.20 years. In this study, we excluded any participant showing any frank manifestations of DR, whereas in the study by Durbin et al. , participants with different stages of DR were included. So the results cannot be fairly compared. Durbin et al.  found that the mean PD, for the healthy group, in the SRLs was 0.419, the mean VD was 22.5, and the mean FAZ-A, FAZ-P, and FAZ-C were 0.25, 2.05, and 0.82, respectively. We got relatively close numbers, as the mean PD in the SRL was 0.36±0.06, the mean VD in the SRL was 20.4±1.56, and the mean FAZ-A, FAZ-P, and FAZ-C were 0.26±0.07, 2.18±0.33, and 0.67±0.08, respectively. In the study by Durbin et al. , in the diabetic group, the mean PD in the SRL was 0.409, the mean VD in the SRL was 21.2, and the FAZ-A, FAZ-P, and FAZ-C were 0.26, 2.32, and 0.78, respectively. In this study, we had a PD in the SRL of 0.33±0.04, VD in the SRL of 17.75±2.91, and FAZ-A, FAZ-P, and FAZ-C of 0.31±0.12, 2.46±0.58, and 0.63±0.12, respectively. Despite of dissimilarities in the results, both studies found a statistically significant difference in all variables measured.For repeatability and reproducibility of SRL VD, PD, and FAZ value measurements by using the AngioPlex OCTA device from Carl Zeiss Meditec, Germany, Lei et al.  published a study on that issue concluding that VD and PD of the superficial retinal vasculature can be obtained from OCTA images with high levels of repeatability and reproducibility but can vary with scan pattern and location. They defined reproducibility as the agreement between devices of the same type, whereas repeatability was the agreement in measurements within a device. We found no statistically significant difference between images taken with the same scan quality by the same investigator.
The limitations of this study included the relatively small sample size of both the diabetic group and the control group. There is no normative database available for the time being on ethnic differences in VD, PD, and FAZ values; therefore, we could not select our control volunteers on ethnic basis. We supposed that all had the same values as long as they belonged to the same age group. Fortunately, we did not find an intergroup statistically significant difference in VD, PD, and FAZ values, but these need to be reassessed by further studies with larger sample size and ethnic classification of the groups.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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