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Eye Diseases > Retina

Diabetic Retinopathy

Evidence-based assessment and management of diabetic retinopathy. Comprehensive guide covering etiology, ICDR classification, pathogenesis, diagnosis, and treatment protocols for optometry practice.

Optic discNVD(neovascularisation)FoveaMicro-aneurysmsHard exudates(circinate)Cotton woolspotIRMADot/blothaemorrhage

Diabetic retinopathy fundus features: microaneurysms (first ophthalmoscopic sign), dot/blot haemorrhages, hard exudates (circinate near fovea), cotton wool spots (NFL infarcts), IRMA, and neovascularisation of the disc (NVD — PDR).

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus and the leading cause of preventable vision loss in working-age adults globally. It results from chronic hyperglycaemia-induced damage to the retinal microvasculature — capillary pericyte loss, basement membrane thickening, and endothelial dysfunction.

DR is broadly classified into non-proliferative DR (NPDR) — the earlier, vascular change stage — and proliferative DR (PDR), characterised by pathological neovascularisation driven by retinal ischaemia and VEGF.Diabetic macular oedema (DMO) can occur at any stage and is the primary cause of visual impairment in working-age diabetic patients.

Approximately 35% of people with diabetes have DR; nearly all Type 1 DM patients develop some DR after 20 years. In Singapore, where diabetes affects ~13% of adults, DR is a major public health concern addressed through the Singapore Diabetic Retinopathy Screening (SDRS) programme.

  • Type 1 Diabetes Mellitus (T1DM): Autoimmune destruction of pancreatic beta cells → absolute insulin deficiency; after 20 years, virtually all T1DM patients have some degree of DR; ~50% develop PDR
  • Type 2 Diabetes Mellitus (T2DM): Insulin resistance + progressive beta-cell failure; >60% develop DR after 20 years; lower PDR rate than T1DM but far greater absolute burden due to higher prevalence; many have pre-existing DR at diagnosis (delayed diagnosis is common)
  • Gestational diabetes: Can cause or accelerate DR in women with pre-existing diabetes during pregnancy; gestational DM itself carries lower ocular risk but requires monitoring
  • Secondary diabetes: Chronic pancreatitis, haemochromatosis, cystic fibrosis-related diabetes, Maturity Onset Diabetes of the Young (MODY) — same retinal consequences as primary DM when chronic hyperglycaemia is present
  • Common final pathway: Regardless of type, chronic hyperglycaemia is the essential driver — duration and glycaemic control determine risk
  1. Chronic hyperglycaemia activates four key biochemical pathways: (1) Polyol pathway — aldose reductase converts glucose to sorbitol → osmotic and oxidative stress; (2) AGE formation — advanced glycation end-products cross-link proteins, stiffen vessel walls; (3) PKC activation — protein kinase C alters vascular permeability and VEGF signalling; (4) Hexosamine pathway — altered gene expression → inflammation and oxidative stress.
  2. Pericyte loss — the earliest histological change; pericytes normally support endothelial cells and regulate capillary tone; their selective loss leads to microaneurysm formation (saccular outpouchings of weakened capillary walls).
  3. Breakdown of inner blood-retinal barrier (BRB) — tight junction disruption between retinal capillary endothelial cells → plasma proteins and lipoproteins leak into retina → hard exudates; fluid accumulation → retinal oedema → DMO when involving the macula.
  4. Capillary non-perfusion and retinal ischaemia → cotton wool spots (NFL infarcts from arteriolar occlusion); venous beading (irregular venous calibre); IRMA (intraretinal microvascular anomalies — shunt vessels bypassing non-perfused areas, lying flat within retina, not crossing ILM).
  5. VEGF upregulation — ischaemic retina releases VEGF-A → dual effect: (a) pathological neovascularisation of disc (NVD) and elsewhere (NVE) → PDR; (b) further increase in vascular permeability → worsening DMO.
  6. Proliferative complications — new vessels grow on inner retinal surface and into vitreous; accompanied by fibrous tissue → contraction → tractional retinal detachment; friable new vessels rupture → vitreous haemorrhage; new vessels on iris (rubeosis iridis) → angle NVE → neovascular glaucoma.

International Clinical DR Severity Scale (ICDR) — Preferred Practice

DR StageKey Fundus Features
No apparent retinopathyNo diabetic fundus abnormalities detected
Mild NPDRMicroaneurysms only
Moderate NPDRMore than microaneurysms; haemorrhages, hard exudates, cotton wool spots; less than severe NPDR
Severe NPDRAny ONE of (4-2-1 rule): ≥20 intraretinal haemorrhages in each of 4 quadrants; venous beading in ≥2 quadrants; prominent IRMA in ≥1 quadrant; no neovascularisation
PDRNeovascularisation (NVD and/or NVE) ± preretinal or vitreous haemorrhage ± fibrovascular proliferation

Diabetic Macular Oedema (DMO) — Classified Separately at Any DR Stage

DMO TypeDefinition
Centre-Involving DMO (CI-DMO)Retinal thickening or hard exudates within 1 disc diameter of the foveal centre; directly threatens central VA; requires treatment
Non-Centre-Involving DMORetinal thickening outside the central subfield; may not affect VA initially; monitor closely

PDR High-Risk Characteristics (HRC) — DRS-defined criteria for immediate PRP:

  • NVD ≥ ¼–⅓ disc area (DA)
  • Any NVD with vitreous or preretinal haemorrhage
  • NVE ≥ ½ DA with vitreous or preretinal haemorrhage
  • Duration of diabetes: Most important risk factor; >90% of T1DM patients of 25 years duration have DR; T2DM risk accumulates with years
  • Poor glycaemic control (HbA1c >7%): Dose-response relationship; DCCT demonstrated 76% reduction in DR development with intensive glycaemic control in T1DM; UKPDS showed 25% reduction in T2DM
  • Hypertension: Accelerates both NPDR-to-PDR conversion and DMO; systolic BP control to <130 mmHg reduces DR progression; UKPDS tight BP control reduced DR risk by 35%
  • Dyslipidaemia: High LDL and triglycerides → hard exudate deposition near fovea; fenofibrate (FIELD/ACCORD-Eye trials) reduces DR progression by ~30%
  • Nephropathy: Microalbuminuria strongly correlates with DR severity; shared microvascular pathogenesis; ACE inhibitors/ARBs protective for both
  • Pregnancy: Rapid DR progression during pregnancy, especially in pre-existing poorly controlled T1DM; baseline ophthalmic assessment pre-conception and each trimester
  • Puberty: Onset of puberty resets cumulative risk exposure; rapid acceleration of DR risk in adolescence
  • Anaemia: Reduces oxygen delivery to already-ischaemic retina; haemoglobin levels should be optimised
  • Obesity: Independent risk factor for T2DM and its vascular complications; weight loss improves HbA1c and reduces DR risk
  • Smoking: Increases cardiovascular and microvascular disease risk; counsel cessation in all diabetic patients

NPDR Signs

  • Microaneurysms: Tiny red dots (<125 µm); saccular outpouchings of capillary wall; first ophthalmoscopic sign of DR; leak on FFA
  • Dot and blot haemorrhages: Slightly larger dark red dots; in outer plexiform and inner nuclear layers; round, well-demarcated
  • Flame-shaped haemorrhages: Superficial nerve fibre layer haemorrhages; less specific for DR
  • Hard exudates: Bright yellow, waxy deposits with distinct edges; lipoprotein leakage from incompetent vessels; circinate (ring) pattern around leaking microaneurysms; threaten vision when approaching fovea
  • Cotton wool spots (soft exudates): Fluffy white patches; NFL infarcts from arteriolar occlusion; transient (disappear over 4–6 weeks); indicate ischaemia and transition to severe NPDR
  • Venous beading: Irregular, sausage-like calibre of retinal veins; key feature of severe NPDR (4-2-1 rule)
  • IRMA: Dilated, tortuous intraretinal vessels that cross non-perfused areas; flat on FFA; do not cross ILM (distinguishes from NVE); indicator of severe NPDR

PDR Signs

  • Neovascularisation of the disc (NVD): Fine, frond-like new vessels at or within 1 disc diameter of the optic disc; leaks profusely on FFA; hallmark of PDR
  • Neovascularisation elsewhere (NVE): New vessels on retinal surface away from disc; extend into vitreous; bleed readily
  • Preretinal haemorrhage: Blood between retina and posterior vitreous face; boat-shaped (gravity-dependent layer); obscures detail beneath
  • Vitreous haemorrhage: NVD/NVE rupture → blood in vitreous; loss of fundus red reflex; sudden visual loss
  • Fibrovascular proliferation: White fibrous tissue alongside or replacing neovascularisation; traction on retina → TRD

DMO Signs

  • Retinal thickening: Greyish haze or elevation at macula; best seen with contact lens biomicroscopy or OCT; may be subtle on slit-lamp alone
  • Circinate hard exudate rings: Around leaking microaneurysms near fovea; indicates lipid deposition from macular oedema
  • Cystoid spaces (OCT): Fluid in inner nuclear layer and outer plexiform layer; “petaloid” pattern on OCT cross-section

Other Signs

  • Rubeosis iridis (NVI): Fine new vessels on iris surface and angle; risk of neovascular glaucoma; seen at slit-lamp with dilated pupil or gonioscopy
  • Diabetic cataract: Snowflake cortical opacities (T1DM); earlier nuclear sclerosis (T2DM); impairs fundus view
  • Asymptomatic (early to moderate NPDR): The majority of patients have no visual symptoms — regular screening is essential as DR is often advanced before symptoms appear
  • Gradual blurred vision: CI-DMO causing foveal thickening; gradual onset; may fluctuate with blood glucose levels
  • Metamorphopsia (distortion): CI-DMO causing fluid displacement of photoreceptors; Amsler grid may reveal distortion before VA drops
  • Sudden onset of floaters: Vitreous haemorrhage from ruptured NVD/NVE; cobwebs, red haze, or black spots; urgent ophthalmology referral
  • Sudden painless visual loss: Dense vitreous haemorrhage obscuring vision; macular tractional retinal detachment; sudden, severe, painless
  • Dark shadow or curtain in vision: Tractional or combined tractional-rhegmatogenous RD; progresses from periphery if extra-macular initially
  • Peripheral visual field loss: Extensive PRP laser scarring (a known complication of treatment); macular-sparing peripheral RD
  • Reduced night vision: Peripheral rod photoreceptor loss from ischaemia or PRP; rarely noticed until significant

Vitreous / Posterior Segment

  • Vitreous haemorrhage: NVD/NVE rupture → sudden, painless visual loss; may self-resolve (weeks to months) or require vitrectomy
  • Tractional retinal detachment (TRD): Fibrovascular membrane contraction → retinal traction; macular TRD = surgical emergency; extra-macular TRD may be observed
  • Combined tractional-rhegmatogenous RD: TRD causes a retinal break → simultaneous TRD + RRD; more complex surgical management
  • Macular ischaemia: FAZ enlargement from capillary drop-out; irreversible central visual loss; no effective treatment

Macular

  • Persistent CI-DMO: Progressive photoreceptor damage; ellipsoid zone disruption on OCT indicates irreversible loss; requires anti-VEGF ± steroid treatment
  • Hard exudate subfoveal migration: Lipid deposits in subretinal space/fovea → permanent photoreceptor damage

Anterior Segment

  • Neovascular glaucoma (NVG): Rubeosis iridis → angle NVE → secondary closed-angle glaucoma; IOP severely elevated; refractory; poor prognosis if established
  • Cataract: Earlier onset nuclear sclerosis; snowflake cortical cataract in T1DM; impairs fundus monitoring
  • Diabetic nephropathy: Shares microvascular pathogenesis; microalbuminuria strongly predicts DR severity; ACE inhibitors/ARBs reduce progression of both conditions; co-manage with nephrology; end-stage renal disease (ESRD) accelerates PDR
  • Cardiovascular disease: DM → 2–4× increased risk of coronary artery disease, stroke, peripheral arterial disease; aggressive management of lipids, BP, antiplatelet therapy essential; cardiovascular death is the major cause of mortality in T2DM
  • Diabetic peripheral neuropathy: Co-existing microvascular complication; sensory neuropathy → reduced awareness of foot injury; autonomic neuropathy → gastroparesis affecting glycaemic control; painful neuropathy reduces quality of life
  • Diabetic foot / peripheral arterial disease: Shared small and large vessel disease; foot ulcers and amputations; poor wound healing — co-manage with vascular surgery and podiatry
  • Hypertension: Present in majority of T2DM patients; BP control to <130/80 mmHg reduces DR progression; UKPDS: 10 mmHg systolic reduction → 35% reduction in DR events
  • Dyslipidaemia: Elevated triglycerides strongly associated with hard exudate formation near fovea; fenofibrate 145 mg/day (FIELD trial, ACCORD-Eye) reduced DR laser requirement by ~30%; statins essential for cardiovascular risk
  • Pregnancy: DR can worsen rapidly during pregnancy (especially T1DM); ophthalmology review before conception and each trimester; tight glycaemic control pre-conception; gestational DM — lower ocular risk but monitor for worsening pre-existing DR
  • Obstructive sleep apnoea (OSA): Intermittent hypoxaemia worsens retinal ischaemia; associated with accelerated DR progression; CPAP treatment may slow DR progression in observational studies
  • Thyroid disease: Hypothyroidism → worsened dyslipidaemia → increased hard exudate risk; thyroid function should be assessed in all T1DM patients
  • Dilated fundus examination: Gold standard for DR staging; 90D or 78D lens at slit-lamp; binocular indirect ophthalmoscopy for peripheral retina; full dilation essential (tropicamide 1%)
  • Digital fundus photography: ETDRS 7-field protocol (research gold standard); 2-field SDRS protocol (macula-centred + disc-centred) for Singapore screening; wide-field (200°) imaging detects more peripheral lesions; used for grading and teleconsultation
  • OCT (optical coherence tomography): Essential for DMO detection, staging, and treatment monitoring; quantify central subfield thickness (CST); identify intraretinal fluid (IRF), subretinal fluid (SRF), hard exudate; assess ellipsoid zone integrity (photoreceptor prognosis)
  • OCT-Angiography (OCT-A): Non-invasive vascular imaging; quantify FAZ (foveal avascular zone) size; detect capillary non-perfusion; identify NVE (flow on inner retinal slab); does not show leakage (FFA still needed for that)
  • Fluorescein angiography (FFA): Gold standard for capillary non-perfusion mapping, NVD/NVE leakage confirmation, microaneurysm characterisation; invasive (IV sodium fluorescein); nausea risk; increasingly replaced by OCT-A for most indications
  • HbA1c: Assess glycaemic control; target <7% (53 mmol/mol); correlates with DR risk and progression
  • Blood pressure measurement: Essential at every visit; target <130/80 mmHg; elevated BP accelerates DR
  • Lipid profile: LDL, HDL, triglycerides; elevated TG → hard exudate risk; guide fenofibrate and statin management
  • Visual acuity (ETDRS chart): Baseline and monitoring; best corrected VA essential for DMO treatment decisions; VA alone underestimates DMO severity
  • IOP measurement: Rule out NVG in PDR; elevated IOP with rubeosis iridis = emergency

1. Systemic Optimisation (most important — prevents and slows DR)

  • Glycaemic control: HbA1c target <7%; DCCT (T1DM): intensive control reduced DR development by 76%, progression by 54%; UKPDS (T2DM): 25% reduction in microvascular complications per 1% HbA1c reduction
  • Blood pressure: Target <130/80 mmHg; ACE inhibitors or ARBs preferred (renoprotective and reduce DR progression); UKPDS: tight BP control reduced DR 35%
  • Lipid management: Statins for cardiovascular risk; fenofibrate 145 mg/day to reduce DR progression (FIELD/ACCORD-Eye trials)
  • Lifestyle: weight management, aerobic exercise, smoking cessation, dietary optimisation

2. No DR / Mild NPDR — Monitoring

  • Annual dilated fundus examination or fundus photography
  • Systemic optimisation; patient education on DR symptoms (floaters, sudden vision loss)
  • No ocular treatment required

3. Moderate NPDR — Monitoring & Optimisation

  • 6–12 monthly monitoring (frequency based on control and trajectory)
  • Optimise systemic risk factors; refer endocrinology if HbA1c not at target
  • Treat any concurrent CI-DMO (see below)

4. Severe NPDR — Close Monitoring ± Early Treatment

  • 3–4 monthly monitoring; 50–75% convert to PDR within 1–2 years
  • Consider early PRP in high-risk patients: monocular, poor follow-up adherence, planned intraocular surgery, pregnancy
  • Treat CI-DMO

5. CI-DMO Treatment

  • Intravitreal anti-VEGF (first-line): Ranibizumab 0.5 mg (RISE/RIDE: +10–12 ETDRS letters at 2 years), aflibercept 2 mg (VIVID/VISTA: superior to laser), bevacizumab 1.25 mg (off-label, cost-effective); monthly loading × 3–6 doses then PRN or treat-and-extend
  • Intravitreal steroid (second-line or adjunctive): Dexamethasone implant (Ozurdex 0.7 mg) — effective for non-responders; preferred in pseudophakic patients (cataract side effect avoided); fluocinolone acetonide implant (Iluvien 0.19 mg) for chronic refractory DMO; monitor IOP
  • Focal / grid macular laser: Now largely superseded by anti-VEGF for CI-DMO; still used for non-CI-DMO threatening the centre, or adjunctively to reduce injection burden
  • Non-CI-DMO: Systemic optimisation; close observation; focal laser if approaching centre

6. PDR Treatment

  • Pan-retinal photocoagulation (PRP): 1200–1600 laser burns over 2+ sessions; destroys ischaemic peripheral retina → reduces VEGF demand → NVD/NVE regression; DRS Trial: PRP reduced risk of severe VA loss by >50%; standard treatment for PDR and HRC-PDR
  • Intravitreal anti-VEGF (alternative/adjunctive): Ranibizumab non-inferior to PRP for PDR at 2 years (DRCR.net Protocol S); rapid NVD/NVE regression; used pre-vitrectomy to reduce bleeding; note: risk of TRD if discontinued abruptly in eyes with fibrovascular proliferation
  • Vitrectomy (PPV): Indications — non-clearing vitreous haemorrhage (>3 months), macular TRD, combined TRD/RRD; pars plana vitrectomy with membrane peeling, endolaser PRP, tamponade (gas/silicone oil)

7. Neovascular Glaucoma (NVG)

  • Urgent intravitreal anti-VEGF → rubeosis regression within days; PRP to treat underlying ischaemia; IOP lowering (topical beta-blockers, CAIs, alpha-agonists); trabeculectomy or aqueous tube shunt if refractory

Singapore Optometry Scope Note: Optometrists in Singapore play a key role in DR screening within the Singapore Diabetic Retinopathy Screening (SDRS) programme — including fundus photography, OCT imaging, IOP measurement, and DR grading. Optometrists may document DR stage and DMO presence, and initiate timely ophthalmology referral according to SDRS referral criteria. Therapeutic-endorsed optometrists may prescribe lubricants and manage co-existing ocular surface conditions. Intravitreal injections (anti-VEGF, steroids), laser photocoagulation (PRP, focal/grid), and vitreoretinal surgery require ophthalmology. Counsel all diabetic patients on the importance of annual eye examination, systemic risk factor optimisation, and prompt reporting of new visual symptoms (floaters, sudden vision loss, distortion).

  • No DR / Mild NPDR: Excellent with good systemic control; DCCT/UKPDS demonstrate that tight glycaemic and BP control prevents DR development and slows progression
  • Severe NPDR: High-risk; 50–75% convert to PDR within 1–2 years without treatment; close follow-up and timely PRP in high-risk cases can prevent severe visual loss
  • PDR without treatment: Risk of severe visual loss (VA <5/200); DRS Trial demonstrated PRP reduces severe VA loss by >50% in high-risk PDR
  • CI-DMO with anti-VEGF treatment: ~50% of patients gain ≥10 ETDRS letters at 2 years (RISE/RIDE); VA gain is greater with earlier treatment (before photoreceptor damage)
  • Macular ischaemia (FAZ enlargement on OCT-A): Poor visual prognosis; no effective treatment for the ischaemia itself; VA may remain poor despite treatment of oedema
  • Vitreous haemorrhage: 50% clear within 3 months; remainder require vitrectomy; outcomes depend on underlying retinal status
  • Macular TRD: Surgical emergency; prognosis depends on duration and whether ellipsoid zone is intact pre-operatively
  • Key favourable prognostic factors: Early detection through regular screening; tight HbA1c, BP, lipid control; prompt treatment of CI-DMO; timely PRP/anti-VEGF for high-risk PDR; intact ellipsoid zone on OCT
  • Key poor prognostic factors: Long disease duration; poor systemic control; macular ischaemia; delayed presentation; bilateral PDR; macular TRD; NVG at presentation
ConditionKey Differentiator from DR
Hypertensive RetinopathyArteriolar narrowing, AV nicking, copper/silver wiring; haemorrhages flame-shaped, peripapillary; no true microaneurysms; associated with severe/chronic hypertension; no DM required
Branch Retinal Vein Occlusion (BRVO)Haemorrhages, oedema, CWS confined to sector of occluded vein; acute onset; no bilateral symmetry; FFA shows filling defect along vein; may co-exist with DR
Central Retinal Vein Occlusion (CRVO)Haemorrhages in all 4 quadrants ("stormy sunset"); disc oedema; tortuous dilated veins; acute onset; distinguished by bilateral CRVO being rare vs bilateral DR being common
Radiation RetinopathyClinically identical to DR (microaneurysms, exudates, NVE); diagnosis by history of radiotherapy to orbit/brain; no systemic DM required; may occur years post-radiation
Sickle Cell Retinopathy"Sea-fan" peripheral neovascularisation (fan-shaped, not disc-based); salmon patch haemorrhages; black sunburst lesions; predominantly peripheral; Hb electrophoresis confirms SC or SS disease
Ocular Ischaemic Syndrome (OIS)Dilated tortuous veins; mid-peripheral haemorrhages (not posterior pole predominant); low or normal IOP (despite severe ischaemia); carotid bruit; FFA shows prolonged arteriovenous transit; carotid imaging confirms
Eales DiseaseYoung adult males; peripheral retinal vasculitis → ischaemia → neovascularisation → vitreous haemorrhage; TB or autoimmune association; no DM; FFA shows peripheral non-perfusion
Macular Telangiectasia Type 2 (MacTel)Juxtafoveal (perifoveal) telangiectasias, temporal parafoveal greying; crystalline deposits; right-angle venules; OCT shows foveal cavitation; minimal haemorrhages; no DM required
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