Nonproliferative Diabetic Retinopathy

Nonproliferative diabetic retinopathy (NPDR) is the early stage of diabetic retinopathy, characterised by microvascular damage (pericyte loss, basement membrane thickening, capillary closure, increased permeability) without retinal neovascularisation.

• Present in about one third of people with diabetes; after 20 years almost all type 1 and about 60 percent of type 2 patients have some retinopathy.
• Risk factors: duration of diabetes, poor glycaemic control (HbA1c), hypertension, dyslipidaemia, nephropathy, pregnancy, puberty, smoking, and rapid lowering of glucose after long hyperglycaemia.
• Severity grades:
  • Mild: microaneurysms only.
  • Moderate: more than microaneurysms but less than severe: haemorrhages, hard exudates, cotton wool spots, mild venous beading.
  • Severe (the 4-2-1 rule, any one): more than 20 intraretinal haemorrhages in each of 4 quadrants; definite venous beading in 2 or more quadrants; prominent intraretinal microvascular abnormalities (IRMA) in 1 or more quadrant. About 50 percent progress to proliferative disease within 1 year.

• Usually asymptomatic until macular oedema or ischaemia causes vision loss.
• Microaneurysms (red dots), dot and blot haemorrhages, flame haemorrhages, hard exudates (lipid), cotton wool spots (nerve fibre layer infarcts), venous beading and loops, IRMA (abnormal vessels within the retina that do not cross the vessel border).
• Associated macular oedema (central thickening, hard exudate ring), or macular ischaemia (enlarged foveal avascular zone).
• Other signs of diabetes: cataract, rubeosis, cranial nerve palsy.

• Dilated fundus examination with slit lamp biomicroscopy, retinal photography (two field or seven field).
• Optical coherence tomography for macular thickness.
• Widefield fluorescein angiography for non-perfusion, leakage, and IRMA when staging is uncertain.
• Screening: type 1 diabetes from 5 years after diagnosis (or from age 12), type 2 diabetes at diagnosis, then at least every 1 to 2 years; every trimester in pregnancy.
• Check HbA1c, blood pressure, renal function (urine albumin to creatinine ratio, creatinine) and lipids.

• Systemic risk factor control is the main treatment: HbA1c target about 7 percent (53 mmol/mol) avoiding hypoglycaemia (gradual lowering over months because rapid lowering can transiently worsen retinopathy); blood pressure under 130/80 mmHg (ACE inhibitor such as ramipril 5 to 10 mg daily or an angiotensin receptor blocker such as losartan 50 to 100 mg daily); lipid control with statin (atorvastatin 20 to 40 mg daily); fenofibrate 145 mg daily slows progression; smoking cessation, exercise, weight control.
• Follow up by severity: mild every 12 months; moderate every 6 to 9 months; severe every 3 to 4 months (or treat); pregnancy each trimester and 3 months postpartum.
• Severe NPDR: panretinal photocoagulation (about 1200 to 1600 burns, 200 to 500 micrometre spots, 0.1 seconds) or intravitreal aflibercept 2 mg (monthly for 3 to 5 doses then as needed) reduces progression to proliferative disease; treatment is favoured when follow up is unreliable, in type 2 diabetes with rapid progression, before cataract surgery, and in pregnancy.
• Associated macular oedema is treated according to central involvement and vision: for centre involving oedema, intravitreal aflibercept 2 mg, ranibizumab 0.3 mg or faricimab 6 mg monthly for 4 to 5 doses; for non-centre-involving oedema, focal laser.
• Patient education: report vision change, attend screening, control risk factors; referral to nephrology and cardiology when needed.