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Proliferative Diabetic Retinopathy

Emily D. Cole, BS; Nadia K. Waheed, MD, MPH; and Jay S. Duker, MD

Diabetic retinopathy (DR) is a leading cause of blindness in working-aged adults in the developed world.^1–3 In particular, proliferative diabetic retinopathy (PDR) is a vision-threatening condition with high ocular morbidity.⁴ PDR is characterized by the development of new retinal vessels that grow through the internal limiting membrane (ILM) into the vitreous cavity as well as on the optic disc. Retinal ischemia stimulates the production of vascular endothelial growth factors (VEGFs), which is considered to be the primary stimulus for neovascularization.^5–7 These new vessels have walls composed of endothelium that are fragile and susceptible to vitreous and preretinal hemorrhage, which can cause severe vision loss. Traction exerted on the posterior hyaloid by the neovascularization can also cause retinal detachment.⁶

FLUORESCEIN ANGIOGRAPHY OF PROLIFERATIVE DIABETIC RETINOPATHY

While clinical examination is the standard of care for grading the severity of DR, fluorescein angiography (FA) is routinely performed alongside clinical examination to identify features, such as leaking microaneurysms, ischemic areas, and retinal neovascularization. FA is the current gold standard for visualizing retinal vasculature in vivo.^8–10 It can be used to identify features of PDR such as microaneurysms, ischemic retina, intraretinal microvascular abnormalities (IRMA), neovascularization elsewhere (NVE), and neovascularization of the disc (NVD). FA is an invasive study, however, that requires intravenous administration of dye that may cause nausea and vomiting, and rarely, anaphylaxis.^11–13 The overall time needed to complete an FA study is ~10 minutes compared to ~3 seconds per image acquisition on optical coherence tomography angiography (OCTA).

FA is able to visualize areas of neovascularization in PDR. It identifies areas of capillary leakage, such as in microaneurysms and neovascularization secondary to PDR. Another major advantage of FA over OCTA is the ability to view a wide-field image of the retinal vasculature, and identify peripheral areas of neovascularization, ischemia, and microaneurysms.^14,15 It is able to provide a higher resolution and depth-resolved image of the retinal vasculature compared to FA. Precise evaluation of the vasculature at different capillary levels is not feasible using FA because of the scattering of fluorescent light obscuring the view, particularly in the deep retinal capillary plexus.¹⁶ OCTA, however, can provide a high-resolution, depth-resolved image of the vascular layers and better visualize the microvascular features of DR that can be obscured by fluorescein leakage. Currently, both FA and OCTA have distinct advantages and disadvantages in visualizing features of PDR, and these 2 imaging modalities should be used in conjunction with each other.

IRMA are defined by the Early Treatment Diabetic Retinopathy Study as “tortuous intraretinal vascular segments in fields 4-7.”17 The severity of IRMA has been shown to be a risk factor for progression to PDR. However, it is unclear whether IRMA are direct precursors to NVE. On color fundus photographs, IRMA can be distinguished from NVE by their location deeper in the retina, a more burgundy color, occurrence adjacent to cotton-wool spots, and the presence of venous looping. When abnormal blood vessels breach the ILM and grow into the posterior hyaloid, they are called NVE. FA will show leakage in NVE, but not in IRMA.^5,18

On OCTA, retinal neovascularization can be visualized in the en face plane by segmenting the OCTA above the level of the ILM, whereas IRMA can be visualized mainly in the superficial plexus. The neovascularization appears as fan-shaped vessels extending into the vitreous.¹⁹ NVE and NVD appear as spiral, looped, and irregular microvasculature extending into the vitreous. They can be confirmed by evaluating the corresponding OCT-B scan for the presence of hyper-reflective tissue anterior to the ILM. While fine details of neovascularization are obscured by leakage on the FA, they can be clearly visualized in fine detail on OCTA. By manually scrolling through the volumetric en face OCTA at the vitreoretinal interface, it is possible to visualize the full extent of the neovascularization. OCTA can also be used to visualize the reduction in size and changes to structure of the neovascular membranes that occur after anti-VEGF therapy.²⁰ Active NVD can be easily visualized with OCTA, since there is active flow in the vessels extending into the vitreous (Figure 22-1). Inactive NVD is more difficult to visualize, however, since the sclerotic vessels may not have flow, and therefore cannot be visualized on OCTA. In this case, the vessels may not appear on OCTA, but instead cause shadowing and signal blockage in the OCTA (Figure 22-2).

A limitation of OCTA in visualizing NVD and NVE is the limited field of view and the trade-off in resolution with larger fields of view. Though multiple images can be montaged together, this is a time-consuming process. The OCTA en face acquisition areas currently range from 3 × 3 mm to 8 × 8 mm on commercially available devices; however, the resolution is decreased in larger scans because the same or comparable number of B-scans is used across a larger area. The 3 × 3 mm OCT angiograms can visualize greater microvascular detail than the FA or indocyanine green angiography images.^21,22 Peripherally located neovascularization may be harder to visualize with currently commercially available OCTA scan patterns centered at the macula. However, it is possible to image a peripheral location with OCTA, as demonstrated with several examples of various morphologies shown in Figure 22-3. Jansson et al²³ demonstrated that most NVE are located inferonasal to the optic disc and along the superior arcades, which suggests that a larger field of view is needed to expand OCTA visualization of NVE and NVD.

Doppler OCT is a related imaging modality that has been used to evaluate NVD. Doppler OCT depends on the phase shift of moving erythrocytes to generate an image. Miura et al²⁴ were able to use the Doppler shift of blood flow to confirm the presence of early NVD, as well as vessels in various stages of development. In the future, applications of Doppler OCTA can be used to assess retinal blood flow in patients with NVD.

OCTA can visualize microvascular features of DR, such as microaneurysms, intraretinal microvascular abnormalities, clustered capillaries, capillary tortuosity, abnormal capillary loops, reduced capillary density, and areas of flow impairment.25 These features are observed with increasing frequency and severity in PDR compared to nonproliferative diabetic retinopathy (NPDR). It is also possible to visualize vascular remodeling near the foveal avascular zone (FAZ) and FAZ enlargement.^20,26 Multimodal imaging of a patient with these microvascular features of PDR is shown in Figure 22-4.

Microaneurysms are present in PDR and are characterized as saccular outpouchings originating predominantly from the retinal venous capillaries. They are located mainly in the macula and in the inner nuclear layer, and can be visualized in both the superficial and deep plexuses on segmented OCTA.²⁷ OCTA enables the resolution of retinal layers to be resolved and identification of areas of nonperfusion. There is variability in microaneurysm count when directly comparing FA and OCTA images.²⁶ FA may offer an advantage when locating leaking microaneurysms, since OCTA is not able to visualize leakage. Visualization of microaneurysms with OCTA is further complicated by low flow in microaneurysms, which may fall below the slowest detectable flow of the device. It is possible to increase the interscan time, which will increase the sensitivity of OCTA in detecting microaneurysms with possibly a concurrent increase in noise artifact. For this reason, imaging with FA is still necessary to plan focal laser photocoagulation for diabetic macular edema, since it can image a wider area with greater sensitivity for leaking microaneurysms.26

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