Dr.M AZHAR MOHD. YUSUF SHEIKH,Dr.Shukla A K,Dr.Smita Singh,Dr.GIRDHARI GUPTA
Quantitative and Qualitative Comparison of Wide-Field OCT Angiography and Seven Field Montage Fluorescein Angiography in Proliferative Diabetic Retinopathy.
Retinal imaging technology has a greatly evolved over the last 30 years, with the use of digital image capture and greater visualization of the peripheral retina. Since its development nearly 50 years ago, fluorescein angiography remains instrumental in the evaluation of DR, allowing for the visualization of areas of retinal nonperfusion, vascular leakage, microvascular abnormalities, and neovascularization (NV). Traditional angiograms use retinal photographic equipment that is able to visual approximately 30° to 40° of the retina at one time. The DRS1 developed the 7 standard fields (7SFs) protocol in which 7 photographed areas of the retina (3 horizontally across the macula and 4 around the optic nerve) were combined to give nearly 75° of visualization fluorescein angiography using the 7SF protocol, even with today’s modern digital cameras, remains a cumbersome process, requiring a high level of photographic expertise patient cooperation besides risk of dye related minor and major side effects.
A relatively newer technology Optical coherence tomography angiography (OCTA) allows for the evaluation of functional retinal vascular networks without a need for contrast dyes and has shown promising results in allowing non-invasive, functional imaging of retinal and choroidal vasculature. However, the main challenges in OCTA include the limited field of view and eye motion artifacts.[3,4] The wide-field OCTA improves the narrow field of view in traditional OCTA, but some technical difficulties still exist.
In this present study we aim to qualitatively and quantitatively compare widefield montage images of OCT angiography plex elite camera images with 7-field montage Topcon© fluorescein angiography (FA) images in patients with proliferative diabetic retinopathy. We hypothesize that using widefield OCTA in patients with diabetes may provide similar information in a non invasive manner about the severity of DR compared with traditional 7SF, and this information could make a significant contribution to the management of diabetic patients.
Imaging instruments: The commercially available OCTA platform known as the swept-source (SS) OCT PLEX Elite 9000® (Carl Zeiss Meditec, Dublin, CA) uses a swept-source, tunable laser centered at 1060 nm and operating at a scan speed of 100,000 A scans per second with an axial resolution of 6.3 μm. This device utilizes optical micro angiography complex (OMAGc) algorithms to visualize microvasculature and wider OCTA scan protocols (i.e., 9 × 9 mm and 12 × 12 mm OCTA scan protocols). The OCTA can take 12 × 12 mm fields (Fig. 1) and get the wider images by five changes of visual fixation.
In this present study we compared OCTA, PLEX Elite 9000® system with that of traditional 7 field montage to detect NV in patients with DR. We selected the Topcon 7 field montage as the representative FA instrument because it is frequently used as a traditional method as per DRS protocol. This study explored whether the noninvasive wide-angle OCTA could clinically substitute FFA for detecting NV in patients with DR.
Study participants : Participants were patients with proliferative diabetic retinopathy (age ≥ 20 years, type 1 or type 2 diabetes mellitus) who received fluorescein angiography after they underwent a comprehensive ophthalmic examination. They provided written informed consent in accord with procedures approved by the Institutional Review Board of Grewal Eye Institute, Chandigarh and the tenets of the Declaration of Helsinki. This prospective cross-sectional study evaluating imaging instrument performance was carried out at Grewal Eye Institute from August 2017 to March 2018 and its protocol was approved by the Institutional Review Board. The participants underwent FFA using the Topcon camera. FA was performed according to a standard protocol after intravenous injection of 5 ml of 10% sodium fluorescein into one antecubital vein. Images were digitally captured and reviewed after generating 7 field mosaic image using machine software. Subsequently compressed into high-quality Joint Photographic coding Experts Group (JPEG) files. The images were transferred to publicly available image J software. Proliferative DR (PDR) was defined by the presence of NVE and NVD on FFA images. Wide-angle OCTA Three-dimensional OCTA scans of 12 ×12 mm regions were acquired using the swept-source OCTPLEX Elite 9000® instrument (Carl Zeiss Meditec, Dublin, CA). Five OCTA scans were obtained (one at each of five fixation points including center, nasal inferior, nasal superior, temporal inferior, and temporal superior) to obtain a wider field of view . All scans consisted of 500 A-scans per B-scan, repeated twice at each of 500 B scan positions.
We determined the presence of NVE or NVD on the basis of FA in each eye, score of 0 and 1 was given if NVE/NVD was present or absent and total number of NVEs identified were also recorded in each 4 quadrants We also judged the presence of NV on the basis of all five OCTA image generated montage as described by Ishibazawa et al in their previous report with masking distinction of patients. In OCT A montage, the retina slab, one of preset slabs of angiography analysis in the PLEX Elite 9000® system, was examined for the presence of NV. The slab showed the whole retinal vasculature between the inner limiting membrane (ILM) and 70 μm above the retinal pigment epithelium (RPE). The OCTA image of the retina slab vasculature resembled the FA image.
We also evaluated VRI slab for confirmation whenever there is a doubtful NV or it is confused with intraretinal microvascular abnormalities IRMAs. For quantitative analysis all FFA and OCTA images were exported to image J software (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/index.html). Each NV lesion was outlined by the user. The measured number of pixels was then converted into area using a scaling factor applied with consideration of retinal vein size taken as 125um as it exits from the optic disc. Total area of NV was measured on OCTA montage and FFA montage separately. For statistical analysis we calculated the sensitivity and specificity of NV detection. All data were expressed as mean (SD).
70 eyes of 42 patients with diabetic retinopathy were imaged for the study. The patients’ characteristics are described in Table 1. Mean age of patients was 55.9 years (Range: 29-71 years). 32 were males and 10 were females. Average duration of DM was 12.35 years. Average fasting blood sugar was found to be 126.5 mg/dL . 12 number of patients were using insulin and rest were on oral medication.
Detection of NV : NVD was detected in 20 eyes with FFA and 18 eyes with OCTA. NVE was present in 64 eyes on FFA and 60 eyes on OCTA. Total number of NVES identified on FFA were 150 and on OCTA were 153.
We judged the presence of NV on the basis of the retina slabs. Assuming accurate detection of NV areas by FFA, we detected true-positive, false-positive, false-negative, and true-negative NV in 78, 0, 6, and 11 eyes by OCTA of the combination of retina and VRI slabs. The sensitivity and specificity of NV detection was 0.93 and 1, respectively. The positive predictive value was 1 (Table 2).
Quantitative analysis: Mean Average surface area of NVD 0.44 mm2 on OCTA and and 0.72 mm2 on FFA. Mean Average area of all NVEs measured on OCTA was 1.72 mm2 and 2.10 mm2 on FFA respectively.
This study compared the clinical usefulness of wide OCTA images for NV detection with that of FFA images. Previous studies in eyes with diabetic retinopathy have shown that OCTA detects NPA and NV to nearly the same extent as FA [7-9]. But the field of view for conventional OCTA, which is 3 mm× 3 mm or 6 mm× 6 mm, is relatively restricted compared with that for FA. The OCTA, PLEX Elite 9000 system employed in the present study widens the field of view to 12mm× 12mm. The additional OCTA images at four fixation positions of the visual field (nasal inferior, nasal superior, temporal inferior, and temporal superior) made possible approximately 2.4 times enlargement of the single-center OCTA field-of-view. The width of the field of view for the panoramic OCTA image was approximately nine times that of a 6 mm× 6 mm conventional OCTA image.
Despite the limited number of cases in this study, it can be said that NV detected only by FFA, but not by OCTA, is rare. Obviously, field of view in UWFFA is wider comparing with that the complex view of five fixations using the wide-angle OCTA; however, the complex view of the five fixations might be clinically enough useful because most NVs in PDR cases are observed within the mid periphery of the retina where are covered by OCTA images. Recent study by Sawada O et al  has confirmed the usefulness of widefield OCT A images to detect NV in DR and our results also showed a similar pattern, however they did not perform any quantitative analysis of retinal neovascularization. In our study, Mean average size of neovascularization identified on OCT A was less than FFA images and this discrepancy is explainable as on an OCTA image NV is identified by its appearance of abnormal loops or networks whereas we used late frames for FFA to identify NV by amount of leakage associated with it.
In comparison with FA, OCTA offers a number of advantages as an imaging modality. Optical coherence tomographic angiography is noninvasive, can be performed multiple times in succession and can be completed within minutes. Although OCTA cannot directly detect leakage but since Optical coherence tomographic angiography is a new technology, and thus, will require a learning curve for the clinician to interpret and review. Our study used trained ARI network readers already familiar with the technology. Some pathology, such as IRMAS and NV may be slight difficult to differentiate when compared with FA. As with any imaging modality, OCTA does require patient cooperation or the image quality can become degraded from poor fixation, excessive blinking, or patient movement. Other limitations of this study included that the OCTA that was used is not commercially available at present.
We did not look at the coregistered corresponding OCT B-scans, only at independent OCTA images. Because OCTA images are registered with OCT B-scans, evaluation of corresponding OCT B-scans with OCTA images could provide multidimensional information. FA can show the decrease in leakage after treatments such as panretinal photocoagulation (PRP) and anti-VEGF therapy for PDR. Unlike FA, OCTA cannot detect a change in the amount of leakage from NVs. Nevertheless, Ishibazawa et al. was able to show a significant decrease in the vessel area of NV on the optic disc and NV elsewhere following PRP using OCTA , and we also could follow the change in NV extent using wide OCTA after treatment quantitatively.
In conclusion, OCTA was able to noninvasively visualize the retinal vasculature when compared with FA. Optical coherence tomographic angiography may be a useful clinical tool for the ophthalmologist in the evaluation and treatment of patients with DR.
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