Diabetic Retinopathy
Microvascular retinal disease from chronic hyperglycemia — leading cause of new-onset blindness in working-age adults.
Also known as: diabetic retinopathy, DR, NPDR, PDR, non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, DME
Overview
Microvascular complication of diabetes mellitus characterized by progressive retinal microaneurysms, hemorrhages, exudates, ischemia, and ultimately neovascularization. Classified as non-proliferative (NPDR — mild, moderate, severe) and proliferative (PDR — new vessels at the disc, NVD, or elsewhere, NVE). Diabetic macular edema (DME) — fluid in the central macula — can occur at any stage.
Epidemiology
Leading cause of new-onset blindness in US adults aged 20-74. Nearly all patients with type 1 diabetes for >20 years and most with type 2 develop some degree of retinopathy. Prevalence of vision-threatening retinopathy ~5-10% of diabetic patients.
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Risk factors
- Duration of diabetes (strongest predictor)
- Chronic hyperglycemia / elevated A1c
- Hypertension
- Dyslipidemia
- Pregnancy (can accelerate progression — exam at first prenatal visit)
- Renal disease (proteinuria)
- Smoking
- Anemia, sleep apnea
- Rapid intensive glycemic correction in long-standing poor control (transient worsening)
Pathophysiology
Chronic hyperglycemia drives advanced glycation end-product formation, polyol pathway flux, protein kinase C activation, and oxidative stress. These damage retinal capillary pericytes and endothelial cells, leading to microaneurysm formation, increased vascular permeability (edema and exudates), capillary nonperfusion (ischemia), and upregulation of VEGF. VEGF drives macular edema and, when ischemia is widespread, proliferative neovascularization. New vessels are fragile and grow along the posterior hyaloid, causing vitreous hemorrhage and tractional retinal detachment.
Clinical presentation
Symptoms
- Often ASYMPTOMATIC until advanced or DME develops — emphasizes screening
- Blurred or fluctuating vision (often with glycemic swings)
- Floaters or sudden vision loss — vitreous hemorrhage from PDR
- Curtain over vision — tractional retinal detachment
- Central blurring or distortion — diabetic macular edema
Signs / physical exam
- NPDR: microaneurysms (earliest), dot-blot hemorrhages, hard exudates (lipid), cotton-wool spots (nerve fiber infarcts), venous beading, intraretinal microvascular abnormalities (IRMA)
- PDR: neovascularization of the disc (NVD) or elsewhere (NVE), preretinal/vitreous hemorrhage, fibrovascular proliferation, tractional retinal detachment
- DME: retinal thickening within 1 disc diameter of fovea; circinate exudates; cysts on OCT
- Reduced visual acuity in severe disease
- Rubeosis iridis and neovascular glaucoma in advanced ischemia
Classic findings
Dot-blot hemorrhages with hard exudates and microaneurysms in a diabetic; neovascularization of the disc (NVD) in PDR.
Differential diagnosis
- Hypertensive retinopathy — AV nicking, copper/silver wiring, flame hemorrhages; usually no microaneurysms; control BP
- Retinal vein occlusion (CRVO/BRVO) — Sudden vision loss, sectoral or diffuse hemorrhages in distribution of occluded vein
- Sickle cell retinopathy — Peripheral 'sea fan' neovascularization; sickle hemoglobin
- Radiation retinopathy — History of head/orbit radiation; similar microvascular findings
- Ocular ischemic syndrome — Carotid stenosis, midperipheral hemorrhages, neovascularization; carotid imaging
- Age-related macular degeneration — Drusen, CNV affecting macula; usually older nondiabetic patient
Diagnostic workup
Diagnostic criteria
ADA / AAO screening: dilated exam at diagnosis in type 2 DM and within 5 years of diagnosis in type 1 (and at puberty), then annually (or every 1-2 years if no retinopathy and good glycemic control). Pregnant diabetic patients: exam in first trimester and as indicated.
Labs
- A1c, lipid panel, BMP, urine albumin-creatinine — for diabetic care, not specific to DR diagnosis
Imaging
- Dilated fundus examination — primary screening tool
- Optical coherence tomography (OCT) — quantifies retinal thickness and DME
- Fluorescein angiography — identifies capillary nonperfusion, microaneurysms, leakage, and neovascularization
- OCT angiography — non-invasive vascular imaging
- Wide-field fundus photography — increasingly used in screening; teleretinal screening for primary care
- B-scan ultrasound if dense vitreous hemorrhage obscures fundus — rules out retinal detachment
Diagnostic algorithm
| Stage | Key Findings | Management |
|---|---|---|
| Mild NPDR | Microaneurysms only | Optimize glycemic/BP control; annual exam |
| Moderate NPDR | Microaneurysms + dot-blot hemorrhages + exudates | Closer follow-up (6-12 months) |
| Severe NPDR | 4-2-1 rule: 4 quadrants of severe hemorrhages, 2 of venous beading, or 1 of IRMA | Consider early anti-VEGF/PRP; exam every 2-4 months |
| PDR (non-high-risk) | Neovascularization without high-risk features | Anti-VEGF and/or PRP; close follow-up |
| PDR (high-risk) | NVD ≥1/4 disc area, or any NVD with hemorrhage, or NVE with hemorrhage | PRP and/or anti-VEGF; treat promptly |
| DME | Retinal thickening in central macula | Anti-VEGF first-line (center-involving); focal laser for non-center-involving |
Treatment
First-line
- Optimize glycemic control — target A1c individualized but typically <7% (DCCT, UKPDS)
- Blood pressure control — typically <130/80 (UKPDS)
- Lipid management — statin per ASCVD guidelines; fenofibrate has independent benefit on DR progression (ACCORD Eye, FIELD)
- Smoking cessation; treat sleep apnea and anemia
- Adherence to dilated retinal exam schedule
- Patient education on prompt evaluation for new floaters, vision changes, or curtain symptoms
Second-line / adjunct
- Diabetic macular edema (center-involving) — intravitreal anti-VEGF — ranibizumab, bevacizumab (off-label), aflibercept, faricimab — first-line; superior to laser (Protocol T, RIDE/RISE, VIVID/VISTA)
- Diabetic macular edema (non-center-involving) — focal/grid laser per ETDRS
- Intravitreal corticosteroid implant — dexamethasone (Ozurdex), fluocinolone (Iluvien) — for DME refractory to anti-VEGF or pseudophakic patients; cataract and IOP-rise risk
- Proliferative DR — panretinal photocoagulation (PRP) — ablates peripheral ischemic retina to reduce VEGF drive (DRS); high-risk PDR is a class I indication
- Anti-VEGF — non-inferior to PRP for PDR over 2 years (Protocol S), and preferred when DME coexists
- Vitrectomy for non-clearing vitreous hemorrhage, tractional retinal detachment threatening macula, or combined tractional-rhegmatogenous detachment (DRVS)
- Treatment of rubeosis / neovascular glaucoma: anti-VEGF + PRP + glaucoma management
Complications
- Vitreous hemorrhage
- Tractional retinal detachment
- Neovascular (rubeotic) glaucoma — vision-threatening, painful
- Diabetic macular edema with central vision loss
- Cataract progression and earlier need for cataract surgery
- Worsened DR after rapid glycemic correction (transient — emphasize gradual normalization in chronically uncontrolled patients)
PANCE pearls
- Early DR is silent — annual dilated exams or telehealth retinal photos are essential per ADA guidelines.
- Macular edema can occur at any stage of DR — measure with OCT, not just slit-lamp.
- PROLIFERATIVE DR = new vessels (NVD or NVE) and is the indication for PRP and/or anti-VEGF.
- Anti-VEGF is now first-line for center-involving DME and is non-inferior to PRP for PDR, particularly when DME coexists (Protocol S).
- Pregnancy can rapidly accelerate DR — screen at first prenatal visit and as indicated; gestational diabetes alone does not require retinal screening.
- Fenofibrate slowed retinopathy progression independently of lipid effects in ACCORD Eye and FIELD — consider in patients with DR and dyslipidemia.
References
- ADA 2024 — American Diabetes Association. Standards of Care in Diabetes — Retinopathy, Neuropathy, and Foot Care. Diabetes Care 2024;47(Suppl 1):S231-S243
- AAO 2019 — American Academy of Ophthalmology. Diabetic Retinopathy Preferred Practice Pattern. Ophthalmology 2020;127(1):P66-P145
- DCCT/EDIC — DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes. NEJM 1993;329(14):977-986
- ETDRS — Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. ETDRS Report Number 1. Arch Ophthalmol 1985;103(12):1796-1806
- Protocol S — Gross JG et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. JAMA 2015;314(20):2137-2146
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