Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Widefield Swept-Source Optical Coherence Tomography Angiography of Proliferative Diabetic Retinopathy

Elie H. Motulsky, MD, PhD; Guanghui Liu, MD, PhD; Yingying Shi, MD; Fang Zheng, MD; Harry W. Flynn, MD; Giovanni Gregori, PhD; Philip J. Rosenfeld, MD, PhD

Abstract

BACKGROUND AND OBJECTIVE:

To demonstrate the utility of widefield swept-source optical coherence tomography angiography (SS-OCTA) for the diagnosis and management of proliferative diabetic retinopathy (PDR).

PATIENTS AND METHODS:

Consecutive patients with vision-threatening diabetic retinopathy were imaged with widefield SS-OCTA using the 12 mm × 12 mm scan pattern.

RESULTS:

Twenty-four eyes of 12 patients underwent SS-OCTA imaging. In all 24 eyes, the en face total retinal flow images detected areas of decreased retinal perfusion, and the en face vitreoretinal interface (VRI) slabs detected foci of retinal neovascularization (NV). NV was treated and followed using the VRI images.

CONCLUSIONS:

Widefield SS-OCTA is a useful, noninvasive technology for the detection and monitoring of NV in PDR. Features of interest, such as areas of decreased retinal perfusion, increased retinal thickness, and NV, can be identified from different en face slabs extracted from a single 12 mm × 12 mm scan.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:474–484.]

Abstract

BACKGROUND AND OBJECTIVE:

To demonstrate the utility of widefield swept-source optical coherence tomography angiography (SS-OCTA) for the diagnosis and management of proliferative diabetic retinopathy (PDR).

PATIENTS AND METHODS:

Consecutive patients with vision-threatening diabetic retinopathy were imaged with widefield SS-OCTA using the 12 mm × 12 mm scan pattern.

RESULTS:

Twenty-four eyes of 12 patients underwent SS-OCTA imaging. In all 24 eyes, the en face total retinal flow images detected areas of decreased retinal perfusion, and the en face vitreoretinal interface (VRI) slabs detected foci of retinal neovascularization (NV). NV was treated and followed using the VRI images.

CONCLUSIONS:

Widefield SS-OCTA is a useful, noninvasive technology for the detection and monitoring of NV in PDR. Features of interest, such as areas of decreased retinal perfusion, increased retinal thickness, and NV, can be identified from different en face slabs extracted from a single 12 mm × 12 mm scan.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:474–484.]

Introduction

Diabetic retinopathy (DR) is a major cause of preventable blindness among working-age adults around the world.1 About a third of diabetic patients have vision-threatening DR, which is defined as severe, nonproliferative DR or proliferative DR (PDR) or the presence of diabetic macular edema (DME).2 PDR is characterized by the growth of retinal neovascularization (NV).3 Retinal NV of the optic disc (NVD) or elsewhere (NVE) can dramatically impact vision by causing vitreous hemorrhages or tractional retinal detachments.4 Both NVDs and NVEs appear on fundus biomicroscopy as irregular vascular networks either along the retinal surface or protruding into the vitreous cavity.

Although the clinical examination remains an important component for the staging of DR, fluorescein angiography (FA) is the gold standard for the diagnosis and monitoring of PDR.5 Some might advocate that FA is expensive, time-consuming, requires a trained photographer, involves uncomfortable bright lights, and requires the intravenous injection of a fluorescent dye that can be associated with nausea and vomiting, along with the much rarer complications of anaphylaxis and even death.6 Due to all these disadvantages, FA is not usually repeated at all clinical visits. Moreover, FA is not a suitable screening tool for the growing diabetic population worldwide, which likely results in an under-reporting of PDR.7

Optical coherence tomography (OCT) is a noninvasive imaging technology that can acquire cross-sectional images of the retina and is used routinely for the diagnosis and management of DME.8 OCT angiography (OCTA) provides en face images with blood flow information, which can serve as an alternative to FA in diabetic patients.9–11 The low cost per study, ease of use, safety, and shorter imaging time associated with OCTA permit the acquisition of angiographic images with unprecedented frequency, potentially providing new information on disease progression. Furthermore, OCTA can visualize the retinal capillary networks much better than FA and can be used to obtain a variety of quantitative measurements, including vessel density, areas of decreased perfusion, and NV size.11–14

Commercial spectral-domain OCTA (SD-OCTA) instruments have a wavelength of 840 nm and a scanning rate of about 70,000 A-scans per second. The macular retinal microcirculation in patients with DR has been studied using SD-OCTA to identify microaneurysms, retinal ischemia, intraretinal microvascular abnormalities, and NV. Nevertheless, the field of view (FOV) is usually limited to about 20°.15–18 Swept-source OCTA (SS-OCTA), which uses a longer wavelength of 1,060 nm and has a faster scanning rate (at least 100,000 A-scans per seconds), can acquire wider field B-scans and en face angiographic retinal images.19 SS-OCTA can be performed using both 12 mm × 12 mm and 15 mm × 9 mm raster scans, and fully automated algorithms can be used to montage these scans to produce en face images, covering a FOV of about 80°.11, 20 This widefield capability is of particular interest in retinal vascular diseases such as DR.21

Historically, the diagnosis of PDR has relied on the dilated fundus exam, which can be combined with FA. Once diagnosed, the clinical management of PDR has been influenced by two major randomized clinical trials. The effectiveness of panretinal photocoagulation (PRP) for PDR was first reported by the Diabetic Retinopathy Study and later confirmed by the Early Treatment Diabetic Retinopathy Study.22–24 Although PRP reduced rates of severe vision loss, it causes permanent peripheral visual field loss, decreased night vision, and can worsen DME.25,26 More recently, intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors have been used to treat PDR, and the Diabetic Retinopathy Clinical Research Network Protocol S demonstrated that ranibizumab (Lucentis; Genentech, South San Francisco, CA) was noninferior to PRP for the treatment of PDR.27 In addition to ranibizumab, both bevacizumab (Avastin, Genentech Roche, South San Francisco, CA) and aflibercept (Eylea; Regeneron, Tarrytown, NY) have been shown to be effective for the treatment of PDR.28,29

Regardless of the treatment chosen to manage PDR, the clinician needs to be able to reliably document and follow macular edema and NV. OCTA has clear theoretical advantages over FA for monitoring PDR, and wider-field imaging with SS-OCTA has definite advantages over the limited FOV provided by SD-OCTA imaging. In the current study, we demonstrate the utility of using wider field SS-OCTA imaging with a 12 mm × 12 mm scan pattern for the diagnosis and monitoring of PDR in patients with vision-threatening DR.

Patients and Methods

Patients with severe, nonproliferative DR and PDR were recruited at the Bascom Palmer Eye Institute between March 2016 and May 2018 for this prospective SS-OCT study. The institutional review board of the University of Miami Miller School of Medicine approved the study and an informed consent was obtained from all patients. The study was performed in accordance with the tenets of the Declaration of Helsinki and compliant with the Health Insurance Portability and Accountability (HIPPA) Act of 1996.

All patients underwent a detailed clinical examination including best-corrected visual acuity (BCVA), refraction, slit-lamp, ophthalmoscopy, intraocular pressure, color fundus photography, SD-OCT imaging, and SS-OCTA imaging.

SS-OCTA imaging was performed using a PLEX Elite 9000 (Carl Zeiss Meditec, Dublin, CA), with a central wavelength of 1,060 nm, a scan rate of 100,000 A-scans per second, and the FastTrac motion-correction system. A cube scan pattern covering a 12 mm × 12 mm FOV (approximately 40°) was used. This scan consisted of 512 A-scans per each horizontal B-scan and 512 separate B-scan positions. The B-scans were repeated twice at each position. When the NV was not fully contained in a single scan centered at the fovea, extra 12 mm × 12 mm scans were acquired to create montaged images.

In order to best visualize retinal perfusion and/or NV, different OCT slabs were used to generate en face flow images. The total retinal flow image, which was used to assess the retinal perfusion, corresponded to a slab between the internal limiting membrane (ILM) and the retinal pigment epithelium (RPE). To evaluate retinal NV, we used an en face vitreoretinal interface (VRI) slab in which the upper boundary was parallel to the ILM contour, between 250 μm and 500 μm above the ILM toward the vitreous cavity, and the lower boundary was set 30 μm below the ILM. This VRI slab visualized retinal NV by identifying both structural signal and blood flow between the ILM and the vitreous cavity. Retinal thickness maps (RTMs) were generated to assess for the presence of DME.

Patients received intravitreal injections of anti-VEGF drugs and/or a PRP treatment at the physician's discretion.

Results

A total of 24 eyes of 12 diabetic patients (seven men and five women) with vision-threatening DR were enrolled, imaged, analyzed, and followed using SS-OCTA imaging. At baseline, the average age of the patients was 48.5 years ± 12.8 years. Three patients had a type 1 diabetes and nine had type 2 diabetes. Twenty-one eyes were phakic and three eyes were pseudophakic. Eight eyes were treatment-naïve, 13 eyes were previously treated with PRP, and 14 eyes were treated with anti-VEGF therapy. BCVA ranged from 20/20 to 3/200.

The ability to detect areas of decreased retinal perfusion and NV through the use of the flow images from the total retinal and vitreoretinal interface (VRI) slabs are demonstrated in Figure 1. At baseline, areas of decreased retinal perfusion were found in all 24 eyes. Among all the 24 eyes, NVE were identified in 22 eyes and NVD was identified in 12 eyes by using the 12 mm × 12 mm SS-OCTA image centered on the fovea (Figure 1A). Macular perfusion deficits could be easily visualized from the single central scan (Figure 1A), whereas the full extent of NVD, NVE, and the retinal perfusion deficits outside of the vascular arcades required a larger FOV (Figures 1A, 1B, 2C, and 2D).

Swept-source optical coherence tomography angiography 12 mm × 12 mm scan of the left eye from a 57-year-old woman with proliferative diabetic retinopathy. (A) En face total retinal flow image showing retinal ischemia adjacent to the temporal arcade vessels. (B) En face vitreoretinal (VRI) slab image shows three areas of retinal neovascularization elsewhere (NVE) identified by the yellow, blue, and white arrowheads. (C) B-scan with segmentation lines for the en face VRI slab image. (D) B-scan with color-coded flow and an arrow depicting NVE. Red represents flow within the retina, and green represents flow beneath the retina. (E, F) B-scans with flow corresponding to the blue and white dashed lines in B. Blue and white arrowheads, respectively, point to two foci of NVE, identified as focal elevations above the internal limiting membrane and associated with red flow.

Figure 1.

Swept-source optical coherence tomography angiography 12 mm × 12 mm scan of the left eye from a 57-year-old woman with proliferative diabetic retinopathy. (A) En face total retinal flow image showing retinal ischemia adjacent to the temporal arcade vessels. (B) En face vitreoretinal (VRI) slab image shows three areas of retinal neovascularization elsewhere (NVE) identified by the yellow, blue, and white arrowheads. (C) B-scan with segmentation lines for the en face VRI slab image. (D) B-scan with color-coded flow and an arrow depicting NVE. Red represents flow within the retina, and green represents flow beneath the retina. (E, F) B-scans with flow corresponding to the blue and white dashed lines in B. Blue and white arrowheads, respectively, point to two foci of NVE, identified as focal elevations above the internal limiting membrane and associated with red flow.

Right eye of a 37-year-old type 1 diabetic man with proliferative diabetic retinopathy. (A) Widefield color fundus photography. (B) Fluorescein angiography at 1 minute showing neovascularization of the optic disc (NVD; yellow arrowhead) and neovascularization elsewhere (NVE; white arrowheads). (C–F) Swept-source optical coherence tomography angiography montaged images of 12 mm × 12 mm scans. (C) En face image of a total retinal slab that demonstrates peripheral retinal ischemia. (D) En face vitreoretinal interface (VRI) slab image that demonstrates the presence of NVE (white arrowheads) and NVD (yellow arrowheads). (E, F) Corresponding montaged B-scans with and without flow through the fovea that demonstrate the presence of a fibrovascular membrane arising from the optic disc (yellow arrowhead). (E) A yellow dashed segmentation line depicts the VRI slab, and the red color in F depicts flow within the retina and NVE.

Figure 2.

Right eye of a 37-year-old type 1 diabetic man with proliferative diabetic retinopathy. (A) Widefield color fundus photography. (B) Fluorescein angiography at 1 minute showing neovascularization of the optic disc (NVD; yellow arrowhead) and neovascularization elsewhere (NVE; white arrowheads). (C–F) Swept-source optical coherence tomography angiography montaged images of 12 mm × 12 mm scans. (C) En face image of a total retinal slab that demonstrates peripheral retinal ischemia. (D) En face vitreoretinal interface (VRI) slab image that demonstrates the presence of NVE (white arrowheads) and NVD (yellow arrowheads). (E, F) Corresponding montaged B-scans with and without flow through the fovea that demonstrate the presence of a fibrovascular membrane arising from the optic disc (yellow arrowhead). (E) A yellow dashed segmentation line depicts the VRI slab, and the red color in F depicts flow within the retina and NVE.

In eight eyes, it was possible to follow neovascular areas in the macular region using a single scan centered on the fovea, whereas in the remaining 16 eyes, additional SS-OCTA 12 mm × 12 mm scans were needed to visualize the full extent of the NVs. These additional scans were montaged together to obtain B-scans and en face slab images over a larger FOV (Figure 2). These montages were useful for monitoring both the NVD and NVE (Figures 2C–2F).

At baseline, a 37-year-old man with type 1 diabetes and treatment-naïve PDR in the right eye was evaluated using a color fundus image (Figure 2A), FA (Figure 2B), total retinal flow montaged image (Figure 2C), and the en face VRI montaged slab (Figure 2D) demonstrating NVD (yellow arrowheads) with NVE (white arrowheads). Effects of treatment over time could be assessed using a single centered 12 mm × 12 mm scan (Figure 3). At baseline (Figures 3A–3D), the patient exhibited NVD and NVE and received combined therapy consisting of anti-VEGF injections and PRP laser. Twenty days after the initial treatment, SS-OCTA imaging did not detect the NVD (Figures 3E–3L), and by 6 months after the initial treatment, the structural B-scan showed a detachment of the posterior vitreous (Figures 3I–3L). In addition, a decrease in the DME was evident on both the RTMs and the B-scans (white arrowheads), with no flow detectable in the area identified previously as NVD (Figures 3I–3L).

Follow-up from Figure 2 using a multisegmentation imaging strategy on a single 12 mm × 12 mm swept-source optical coherence tomography angiography scan of proliferative diabetic retinopathy with neovascularization elsewhere (NVE) and neovascularization of the optic disc (NVD). Follow-up of the treatment-naive right eye from a 37-year-old type 1 diabetic man, the same patient as in Figure 2. First column: Retinal thickness maps (RTMs). Second column: En face vitreoretinal (VRI) slab images. Third column: Foveal B-scans with and without flow, and with and without the yellow segmentation lines depicting the VRI slab. Red flow represents the retinal flow, whereas green represents flow beneath the retina. (A–D) Baseline visit that shows diabetic macular edema (DME) on the RTM and on B-scans (white arrowhead) and NVD (yellow arrowhead). (E–H) Twenty days after initial treatment, which included an intravitreal anti-vascular endothelial growth factor injection and panretinal photocoagulation. The DME is diminished (white arrowhead). The NVD (yellow arrowhead) is still present on the B-scan, but no flow is detected in panel H. (I–L) Six months after the baseline visit, the DME has resolved and no flow is detected in panels J and L, although the prepapillary tissue is still present (yellow arrow).

Figure 3.

Follow-up from Figure 2 using a multisegmentation imaging strategy on a single 12 mm × 12 mm swept-source optical coherence tomography angiography scan of proliferative diabetic retinopathy with neovascularization elsewhere (NVE) and neovascularization of the optic disc (NVD). Follow-up of the treatment-naive right eye from a 37-year-old type 1 diabetic man, the same patient as in Figure 2. First column: Retinal thickness maps (RTMs). Second column: En face vitreoretinal (VRI) slab images. Third column: Foveal B-scans with and without flow, and with and without the yellow segmentation lines depicting the VRI slab. Red flow represents the retinal flow, whereas green represents flow beneath the retina. (A–D) Baseline visit that shows diabetic macular edema (DME) on the RTM and on B-scans (white arrowhead) and NVD (yellow arrowhead). (E–H) Twenty days after initial treatment, which included an intravitreal anti-vascular endothelial growth factor injection and panretinal photocoagulation. The DME is diminished (white arrowhead). The NVD (yellow arrowhead) is still present on the B-scan, but no flow is detected in panel H. (I–L) Six months after the baseline visit, the DME has resolved and no flow is detected in panels J and L, although the prepapillary tissue is still present (yellow arrow).

Figure 4 shows the left eye of a 29-year-old type 1 diabetic woman with PDR followed during the course of 2 years. She had been treated with PRP 14 months before the baseline SS-OCTA scan was acquired. Both NVD (blue arrowheads) and NVE (yellow and white arrowheads) were found to be growing along the surface of the retina. Figures 4A through 4D show DME on the RTM, as well as NVD (blue arrowhead) and NVE (yellow and white arrowheads) on the VRI flow slabs. Anti-VEGF therapy was administered at this time. Figures 4E through 4H show images acquired 1 year after baseline. An increase in the NVD and NVE was detected despite an anti-VEGF injection 3 weeks prior to this visit. Another anti-VEGF injection was given at this visit and after 15 days, the DME was diminished with decreased flow observed within both the NVD and NVE (Figures 4I–4L). The patient continued to be monitored and after 1 additional year, the recurrence of the DME, NVD, and NVE was observed (Figures 4M–4P).

Two-year follow-up using a multisegmentation imaging strategy on a single 12 mm × 12 mm swept-source optical coherence tomography angiography (SS-OCTA) scan of proliferative diabetic retinopathy (PDR). Left eye of a 29-year-old type 1 diabetic woman with neovascularization elsewhere (NVE) and neovascularization of the optic disc (NVD) previously treated with a panretinal photocoagulation laser 14 months before the SS-OCTA baseline visit. First column: Retinal thickness maps (RTMs). Second column: En face vitreoretinal (VRI) slab images. Third column: B-scans with flow corresponding to the yellow or white dashed lines found in the images of the second column. Red flow represents the retinal flow, whereas green represents flow beneath the retina. (A–D) Baseline visit shows diabetic macular edema (DME) on the RTM, NVE on both en face VRI slab image and B-scans (yellow and white arrowheads), and NVD (blue arrowhead). The patient received an anti-vascular endothelial growth factor (VEGF) injection. (E–H) Eleven months after baseline, despite an anti-VEGF injection 3 weeks before this visit, DME was still present on the RTM, and the en face VRI slab image shows an enlarged area flow associated with NVE (yellow and white arrow) and persistent NVD (blue arrow). Two weeks later, an anti-VEGF injection is given. (I–L) Two weeks after the injection, the RTM shows a decrease in the DME, whereas the en face VRI slab image shows decreased flow within both the NVD (blue arrowhead) and NVE (yellow and white arrowhead). (M–P) Patient was monitored and after 1 year, recurrence of the DME, NVD, and NVE were detected.

Figure 4.

Two-year follow-up using a multisegmentation imaging strategy on a single 12 mm × 12 mm swept-source optical coherence tomography angiography (SS-OCTA) scan of proliferative diabetic retinopathy (PDR). Left eye of a 29-year-old type 1 diabetic woman with neovascularization elsewhere (NVE) and neovascularization of the optic disc (NVD) previously treated with a panretinal photocoagulation laser 14 months before the SS-OCTA baseline visit. First column: Retinal thickness maps (RTMs). Second column: En face vitreoretinal (VRI) slab images. Third column: B-scans with flow corresponding to the yellow or white dashed lines found in the images of the second column. Red flow represents the retinal flow, whereas green represents flow beneath the retina. (A–D) Baseline visit shows diabetic macular edema (DME) on the RTM, NVE on both en face VRI slab image and B-scans (yellow and white arrowheads), and NVD (blue arrowhead). The patient received an anti-vascular endothelial growth factor (VEGF) injection. (E–H) Eleven months after baseline, despite an anti-VEGF injection 3 weeks before this visit, DME was still present on the RTM, and the en face VRI slab image shows an enlarged area flow associated with NVE (yellow and white arrow) and persistent NVD (blue arrow). Two weeks later, an anti-VEGF injection is given. (I–L) Two weeks after the injection, the RTM shows a decrease in the DME, whereas the en face VRI slab image shows decreased flow within both the NVD (blue arrowhead) and NVE (yellow and white arrowhead). (M–P) Patient was monitored and after 1 year, recurrence of the DME, NVD, and NVE were detected.

Figure 5 shows 19 months of follow-up for a 57-year-old type 2 diabetic man with inferonasal NVE (yellow arrowheads) in left eye. The patient was treatment-naïve and was treated exclusively with anti-VEGF injections using a monthly injection regimen. At baseline, obvious inferonasal NVE and DME were observed (Figures 5C and 5D). The patient was treated with anti-VEGF therapy. One month later, after a single anti-VEGF injection, decreased flow within the NVE was observed (Figures 5E and 5F). A further decrease in flow within the NVE was observed at 2 months (Figures 5G and 5H). At 3 months, minimal neovascular flow was detected and the DME was now resolved (Figures 5I and 5J). After 2 more months and five anti-VEGF injections, flow within the NVE and DME was greatly diminished (Figures 5K and 5L). After a total of 16 anti-VEGF injections and 19 months after baseline, blood flow within the NVE became undetectable (Figures 5M and 5N).

Follow-up of treatment-naïve left eye of a 57-year-old type 2 diabetic man with inferonasal retinal neovascularization elsewhere (NVE). (A–D) Baseline visit. (A) Widefield fundus picture shows NVE adjacent to inferior arcade. The yellow square represents one 12 mm × 12 mm swept-source optical coherence tomography angiography (SS-OCTA) scan. (B) En face total retinal flow montage showing inferior retinal ischemia associated with NVE (yellow arrowhead). (C–N) Follow-up of NVE (yellow arrowheads) using a single 12 mm × 12 mm inferonasal SS-OCTA scan. Left column represents the retinal thickness map (RTM), whereas the adjacent right column is the en face vitreoretinal interface (VRI) slab image. (C, D) baseline visit, RTM shows diabetic macular edema (DME), and en face VRI slab image shows inferior NVE. The patient was treated exclusively with anti-vascular endothelial growth factor (VEGF) injections using a monthly regimen. (E, F) One month after a single anti-VEGF injection, decreased flow within the NVE is observed. (G, H) A month later, after an anti-VEGF injection, further decrease in flow within the NVE was observed. (I, J) A month later, after three anti-VEGF injections, minimal neovascular flow is observed on the en face VRI slab image, and the DME has resolved on the RTM. (K, L) Two months later, after five anti-VEGF injections, flow within the NVE and DME were less in the en face VRI slab image and the RTM. (M, N) Nineteen months after baseline and after 16 anti-VEGF injections, flow within the NVE was undetectable on the en face VRI slab image, but persistent DME was present on the RTM.

Figure 5.

Follow-up of treatment-naïve left eye of a 57-year-old type 2 diabetic man with inferonasal retinal neovascularization elsewhere (NVE). (A–D) Baseline visit. (A) Widefield fundus picture shows NVE adjacent to inferior arcade. The yellow square represents one 12 mm × 12 mm swept-source optical coherence tomography angiography (SS-OCTA) scan. (B) En face total retinal flow montage showing inferior retinal ischemia associated with NVE (yellow arrowhead). (C–N) Follow-up of NVE (yellow arrowheads) using a single 12 mm × 12 mm inferonasal SS-OCTA scan. Left column represents the retinal thickness map (RTM), whereas the adjacent right column is the en face vitreoretinal interface (VRI) slab image. (C, D) baseline visit, RTM shows diabetic macular edema (DME), and en face VRI slab image shows inferior NVE. The patient was treated exclusively with anti-vascular endothelial growth factor (VEGF) injections using a monthly regimen. (E, F) One month after a single anti-VEGF injection, decreased flow within the NVE is observed. (G, H) A month later, after an anti-VEGF injection, further decrease in flow within the NVE was observed. (I, J) A month later, after three anti-VEGF injections, minimal neovascular flow is observed on the en face VRI slab image, and the DME has resolved on the RTM. (K, L) Two months later, after five anti-VEGF injections, flow within the NVE and DME were less in the en face VRI slab image and the RTM. (M, N) Nineteen months after baseline and after 16 anti-VEGF injections, flow within the NVE was undetectable on the en face VRI slab image, but persistent DME was present on the RTM.

Figure 6 shows the eye of a 58-year-old type 2 diabetic woman that was classified as severe, nonproliferative DR at baseline and subsequently developed NVD during the course of follow-up. NVD was detected by using a 12 mm × 12 mm SS-OCTA scan centered on the fovea. At the baseline visit, no evidence of DME was detected on the RTM or B-scans, and no NV was detected on the en face VRI slab image or B-scans (Figures 6A–6D). However, 10 months later, the RTM showed extrafoveal DME, and the en face VRI slab image detected NVD, which was confirmed by the corresponding B-scan (Figures 6E–6H). Since the patient was asymptomatic, the mild, extrafoveal DME was observed. Three months later, the RTM showed an increase in the DME (Figure 6I) and the en face VRI slab image showed that the NVD was enlarging (Figure 6J–L). Anti-VEGF therapy was administered. One year later, after eight anti-VEGF injections, the NVD was no longer detectable (Figures 6M–6P).

Follow-up using a multisegmentation imaging strategy on a single 12 mm × 12 mm swept-source optical coherence tomography angiography (SS-OCTA) scan of a left eye with severe nonproliferative diabetic retinopathy (DR) that turned into a proliferative DR. Left eye of a 58-year-old type 2 diabetic woman classified as severe nonproliferative DR at baseline that subsequently developed neovascularization of the optic disc (NVD; yellow arrowhead) during the course of follow-up detected by SS-OCTA. First column: Retinal thickness maps (RTMs). Second column: En face vitreoretinal (VRI) slab images. Third column: Foveal B-scans with and without yellow segmentation lines depicting the VRI slab and with or without flow. Red flow represents the retinal flow, whereas green represents flow beneath the retina. (A–D) Baseline visit that shows a minimal parafoveal diabetic macular edema (DME). No NVD was detected at this visit. (E–H) Ten months later, the RTM showed extrafoveal DME, and the en face VRI slab image detected NVD and confirmed by the corresponding B-scan with flow. (I–L) Three months later, the RTM showed an increase in the DME and the en face VRI slab image showed an enlargement of the NVD. Anti-vascular endothelial growth factor therapy was given. (M–P) Nine months later and after eight injections, the RTM shows diminished DME and no detectable flow corresponding to NVD.

Figure 6.

Follow-up using a multisegmentation imaging strategy on a single 12 mm × 12 mm swept-source optical coherence tomography angiography (SS-OCTA) scan of a left eye with severe nonproliferative diabetic retinopathy (DR) that turned into a proliferative DR. Left eye of a 58-year-old type 2 diabetic woman classified as severe nonproliferative DR at baseline that subsequently developed neovascularization of the optic disc (NVD; yellow arrowhead) during the course of follow-up detected by SS-OCTA. First column: Retinal thickness maps (RTMs). Second column: En face vitreoretinal (VRI) slab images. Third column: Foveal B-scans with and without yellow segmentation lines depicting the VRI slab and with or without flow. Red flow represents the retinal flow, whereas green represents flow beneath the retina. (A–D) Baseline visit that shows a minimal parafoveal diabetic macular edema (DME). No NVD was detected at this visit. (E–H) Ten months later, the RTM showed extrafoveal DME, and the en face VRI slab image detected NVD and confirmed by the corresponding B-scan with flow. (I–L) Three months later, the RTM showed an increase in the DME and the en face VRI slab image showed an enlargement of the NVD. Anti-vascular endothelial growth factor therapy was given. (M–P) Nine months later and after eight injections, the RTM shows diminished DME and no detectable flow corresponding to NVD.

Figure 7 shows the treatment-naïve right eye of a 41-year-old type 2 diabetic man with PDR. Both NVD and the NVE were detected. At baseline, the color fundus image (Figure 7A), FA (Figure 7B), total retinal flow image (Figure 7C), and the en face VRI slab (Figure 7D) showed NVD (yellow arrowheads) with NVE (white arrowheads). The patient received two sessions of PRP laser treatments and 3 weeks later, the en face VRI slab showed unambiguous enlargement of both the NVD and NVE (yellow and white arrowheads, respectively, in Figure 7E). Additional PRP laser was given, plus a single intravitreal anti-VEGF injection 2 weeks later, resulting in the decrease of both the NVD and NVE (Figure 7G). The patient received two more sessions of PRP. Eleven weeks after the last anti-VEGF injection and following a total of four PRP sessions, the NVD and NVE appeared stable on the en face VRI slab image (Figure 7H). Overall, five sessions of PRP and two anti-VEGF injections were administered to the patient followed by a period of observation. Five months after the last treatment, the en face VRI slab image showed an increase in both the NVD and NVE (Figure 7I).

Treatment-naïve proliferative diabetic retinopathy in the right eye of a 41-year-old type 2 diabetic man presenting with neovascularization elsewhere (NVE) and neovascularization of the optic disc (NVD). (A–D) Baseline visit. (E–I) Follow-ups. (A) Color fundus image showing NVD and retinal hemorrhages in the posterior pole. (B) Fluorescein angiography shows leakage from NVD and minimal leakage from two foci of NVE. (C–I) Swept-source optical coherence tomography angiography (SS-OCTA) montaged image of two 12 mm ×12 mm scans. (C) En face total retinal flow image demonstrates the peripheral and temporal areas of macular ischemic area. NVD is seen as flow associated with the optic disc. (D–I) En face vitreoretinal interface (VRI) slab images. (D) En face VRI slab detects NVD (yellow arrowhead) and two foci of NVE (white arrowheads) along the superior arcade. (E) A month after two sessions of panretinal photocoagulation (PRP), the VRI slab image shows unambiguous enlargement of both the NVD and NVE. Additional PRP was given, and a single intravitreal anti-vascular endothelial growth factor (VEGF) injection was given 2 weeks later. (F) Two weeks after the anti-VEGF injection, the VRI slab image shows a decrease in both NVE and NVD. Another anti-VEGF injection is given. (G) A month later, the VRI slab image detected even less flow in both the NVD and NVE. Two additional PRP sessions were given. (H) Two months later, the VRI slab image remains stable. In total, five sessions of PRP and two anti-VEGF injections were given to the patient followed by a period of observation. (I) Five months after the last treatment, the en face VRI flow image shows an increase in both the NVD and NVE.

Figure 7.

Treatment-naïve proliferative diabetic retinopathy in the right eye of a 41-year-old type 2 diabetic man presenting with neovascularization elsewhere (NVE) and neovascularization of the optic disc (NVD). (A–D) Baseline visit. (E–I) Follow-ups. (A) Color fundus image showing NVD and retinal hemorrhages in the posterior pole. (B) Fluorescein angiography shows leakage from NVD and minimal leakage from two foci of NVE. (C–I) Swept-source optical coherence tomography angiography (SS-OCTA) montaged image of two 12 mm ×12 mm scans. (C) En face total retinal flow image demonstrates the peripheral and temporal areas of macular ischemic area. NVD is seen as flow associated with the optic disc. (D–I) En face vitreoretinal interface (VRI) slab images. (D) En face VRI slab detects NVD (yellow arrowhead) and two foci of NVE (white arrowheads) along the superior arcade. (E) A month after two sessions of panretinal photocoagulation (PRP), the VRI slab image shows unambiguous enlargement of both the NVD and NVE. Additional PRP was given, and a single intravitreal anti-vascular endothelial growth factor (VEGF) injection was given 2 weeks later. (F) Two weeks after the anti-VEGF injection, the VRI slab image shows a decrease in both NVE and NVD. Another anti-VEGF injection is given. (G) A month later, the VRI slab image detected even less flow in both the NVD and NVE. Two additional PRP sessions were given. (H) Two months later, the VRI slab image remains stable. In total, five sessions of PRP and two anti-VEGF injections were given to the patient followed by a period of observation. (I) Five months after the last treatment, the en face VRI flow image shows an increase in both the NVD and NVE.

Discussion

Widefield SS-OCTA imaging was able to detect NVD and NVE in eyes with PDR using either a 12 mm × 12 mm scan centered on the fovea or several 12 mm × 12 mm images assembled into a montage. In addition, these imaging strategies were useful for following disease progression and response to treatment for up to 2 years. Although not yet tested in a comparative prospective clinical trial, our observations strongly support using SS-OCTA as the single preferred imaging strategy for the detection and monitoring of NV (Figures 37). The decrease in flow within the NV appeared to be an objective strategy for determining whether the treatment was effective (Figures 37). These findings support previous reports that anti-VEGF therapy reduces blood flow within NV, whereas the fibrovascular NV may not completely regress.9 However, when the anti-VEGF effect fades away, an increase in detectable flow within or around the NVD and NVE can be observed (Figures 4 and 7). This increase in flow could result from increased perfusion of existing neovascular channels, the extension of previous NV, or the development of new neovascular foci.

SS-OCTA imaging can capture both structure and flow information over a large FOV. Different segmentation strategies from a single cube raster scan are able to show different retinal features. For instance, DME can be detected using the RTM, decreased macular perfusion detected using the en face total retinal slab, and NVD and NVE detected using the en face VRI slab. Occasionally, NVE can be detected using the en face total retinal slab, which extends from the ILM to the RPE, but that only occurs when the NVE is immediately adjacent to the ILM. When the NVE is elevated off the ILM, then the VRI slab identifies the entire NVE. Therefore, SS-OCTA imaging is a useful strategy for the diagnosis, treatment, and follow-up of NV.

SS-OCTA 12 mm × 12 mm scans centered on fovea were able to identify areas of NVD and NVE within the 40° FOV. For monitoring NVE outside the arcades and nasal to the optic nerve, several flow images were acquired and automatically assembled into a montage using the software available on the instrument (Version 1.7). Since FA was not performed on all patients, we cannot confirm that all foci of NVD or NVE were detected. However, it seems likely that SS-OCTA detected all NVD and all the foci of NVE within the FOV, but this remains to be determined by a formal comparative study with FA. As anti-VEGF therapy for the treatment of PDR becomes more commonplace, it is reasonable to assume that widefield SS-OCTA imaging will become more useful in the OCTA-guided management of PDR.27,30,31

Currently, SS-OCTA images can be automatically montaged to achieve a FOV up to 80°. Future software and hardware updates will permit an even wider FOV. These features will further increase the attractiveness and usefulness of SS-OCTA as a clinical tool for the diagnosis and monitoring of DR. At the present time, major drawbacks that prevent widespread adoption of this SS-OCTA platform are the cost of the instrument, the lack of reimbursement in the U.S., and a concern that the technology is evolving so rapidly that the investment may become outdated in the near future.

Limitations of this study include the lack of FA on all patients, no masked grading of the SS-OCTA images, no uniform treatment strategy by the clinicians, the small number of patients, and a potential patient selection bias, since non-severe proliferative DR or PDR patients needed to be referred for SS-OCTA imaging. Possible sites of NV might exist outside the imaging FOV, but whether these distant sites are clinically relevant remain to be determined. We propose that even if peripheral NV was present, the sites of NV within the imaging FOV could serve as sentinel lesions for the diagnosis, treatment, and retreatment of PDR. Therefore, foci of NV detected by SS-OCTA within the 40° or 80° FOV may reflect the VEGF levels within the eye and may serve as imaging biomarkers for monitoring DR. Whether the detection of one or all the NV foci is important needs to be studied. Moreover, whether montaged SS-OCTA images of the posterior pole are as good as widefield FA images for the detection and monitoring of NV and more importantly, whether it makes a difference in the visual acuity outcomes of diabetic patients remains to be determined. A prospective study will be needed to determine the benefit of OCTA-guided treatment compared to widefield FA-guided treatment. In summary, this report demonstrates the apparent benefits of SS-OCTA widefield imaging for the detection of retinal perfusion deficits, NVD, and NVE.

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Authors

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami (EHM, GL, YS, FZ, HWFJ, GG, PJR); and the Department of Ophthalmology, Affiliated People's Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, P.R. China (GL).

Supported by grants from Carl Zeiss Meditec (Dublin, CA), the Salah Foundation, the National Eye Institute Center Core Grant (P30EY014801), and a Research to Prevent Blindness Unrestricted Grant to the Department of Ophthalmology, University of Miami Miller School of Medicine.

Dr. Liu was supported by the Scholarship of Fujian Province for Studying Abroad in 2015. Drs. Gregori and Rosenfeld received research support from Carl Zeiss Meditec. Dr. Gregori and the University of Miami co-own a patent that is licensed to Carl Zeiss Meditec. Dr. Rosenfeld has also received additional research support from Genentech and Tyrogenex. He is a consultant for Achillion Pharmaceuticals, Acucela, Boehringer-Ingelheim, Carl Zeiss Meditec, Chengdu Kanghong Biotech, Ocunexus Therapeutics, Genentech, Healios K.K, Hemera Biosciences, F. Hoffmann-La Roche Ltd., Isarna Pharmaceuticals, Lin Bioscience, MacRegen, NGM Biopharmaceuticals, Ocunexus, Ocudyne, Tyrogenex, and Unity Biotechnology, and has equity interest in Apellis, Digisight, and Ocudyne. Dr. Flynn is a DRCR Network Data and Safety Monitoring Committee member; opinions expressed are his own and are not representative of DRCR-Net. The remaining authors report no relevant financial disclosures.

Address correspondence to Philip J. Rosenfeld, MD, PhD, Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL, 33136; email: prosenfeld@miami.edu.

Received: July 12, 2018
Accepted: January 17, 2019

10.3928/23258160-20190806-01

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