Fig. 1Clinical features of diabetic retinopathy (DR). (A) Pseudo-colored fundus (left) and fluorescein angiography (right) images from ultra-widefield ophthalmoscopy. Note the elevated leakage of fluorescein dye in the macular area in non-proliferative DR (NPDR) and from aberrant neovascularization (NV) in proliferative DR (PDR). Dark areas in fluorescein angiography represent vascular non-perfusion (NP). (B) Cross-sectional macular images from optical coherence tomography (OCT). Note the recurrence of diabetic macular edema (DME) at 3 months after intravitreal anti-vascular endothelial growth factor injection. (C) Superficial and deep retinal vessel images from OCT angiography. Note the microaneurysms and enlargement of the foveal avascular zone in NPDR. HE, hard exudate; VH, vitreous hemorrhage.
Fig. 2Schematic of key cellular and molecular events in the progression of diabetic retinopathy. Hyperglycemia initiates oxidative stress, epigenetic modifications, and inflammation in vascular endothelial cells (ECs). Neuroglial degeneration precedes microvascular changes. Pericyte loss from vessel walls sensitizes ECs to microenvironmental stimuli. Infiltrating macrophages secrete vascular endothelial growth factor (VEGF) A and placental growth factor (PlGF). A positive feedback loop between angiopoietin-2 (Ang2) and a forkhead box transcription factor, forkhead Box O1 (FOXO1), in ECs further destabilizes vessel integrity. These events form a cycle of vessel damage, leading to the breakdown of the blood-retina barrier. Retinal hypoxia resulting from vessel occlusion induces extra-retinal neoangiogenesis accompanied by fibrovascular membrane formation. Throughout these processes, signal transduction via the mitogen-activated protein kinase (MAPK) and the phosphatidyl inositol 3-kinase (PI3K)/Akt pathways downstream of VEGF receptor (VEGFR) 2 in ECs is pivotal in retinal angiogenesis and vascular leakage. Tie2, tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains 2.
Table 1Classification of diabetic retinopathy and recommended eye care
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DR severity |
Defining features |
Management |
Follow-up |
No DR |
No microvascular abnormalities |
Control blood glucose levels, serum lipid levels, and blood pressure |
1–2 yr |
Mild NPDR |
Microaneurysms only |
Control blood glucose levels, serum lipid levels, and blood pressure |
6–12 mo |
Moderate NPDR |
Microaneurysms and other signs (dot and blot hemorrhages, hard exudates, cotton wool spots), but not severe NPDR |
Control blood glucose levels, serum lipid levels, and blood pressure |
3–6 mo |
Severe NPDR |
Intraretinal hemorrhages (≥20 in each of 4 quadrants), definite venous beading (in at least 2 quadrants), or apparent IRMA (in at least 1 quadrant), but not PDR |
Consider PRP |
<3 mo |
PDR |
Neovascularization of optic disc or elsewhere, preretinal hemorrhage, or vitreous hemorrhage |
Strongly consider PRP, consider vitrectomy for persistent vitreous hemorrhage or tractional retinal detachment |
<1 mo (variable) |
DME |
Retinal thickening in the macula |
Consider focal laser photocoagulation, anti-VEGF therapya, or corticosteroid therapy for center-involving DME |
1–3 mo |