1. Kanski's Clinical Ophthalmology: A Systematic Approach (10th ed.)
2. The Wills Eye Manual

Diabetic Retinopathy

Definition & Overview

Pathogenesis

1. Pericyte loss - pericytes surround retinal capillaries and provide structural support; their selective loss under hyperglycaemia is the hallmark early change
2. Basement membrane thickening - increases capillary permeability and rigidity
3. Endothelial cell damage - loss of the blood-retinal barrier
4. Capillary closure / non-perfusion - leads to retinal ischaemia
5. VEGF upregulation - ischaemia drives Vascular Endothelial Growth Factor (VEGF) release, promoting pathological new vessel formation

Risk Factors

Staging / Classification

ETDRS Classification with Management Guidelines

Descriptive Categories (Widely Used in Practice)

• Background DR (BDR): Microaneurysms, dot/blot haemorrhages, hard exudates - earliest signs
• Diabetic maculopathy: Significant macular changes - oedema (most common cause of visual loss in type 2) or ischaemia
• Pre-proliferative DR (PPDR): CWS, venous beading, IRMA, moderate-severe haemorrhages - indicates progressive ischaemia
• Proliferative DR (PDR): NVD and/or NVE; driven by VEGF
• Advanced diabetic eye disease: Tractional RD, persistent VH, neovascular glaucoma

Clinical Features (Signs)

1. Microaneurysms

• Earliest ophthalmoscopic sign of DR
• Saccular outpouchings of capillary walls, from focal weakness after pericyte loss
• Appear as tiny red dots, typically at the posterior pole
• On FA: hyperfluorescent dots in early frames; late leakage
• On OCT: located in middle retinal layers

2. Retinal Haemorrhages

• Dot and blot haemorrhages: Arise from the venous end of capillaries; located in compact middle retinal layers; round/oval red spots
• Flame-shaped haemorrhages: From superficial precapillary arterioles in the nerve fibre layer; shaped by the NFL architecture
• Dark round ("blot") haemorrhages: Represent haemorrhagic retinal infarcts; located in middle layers; their extent is a significant marker for progression to PDR

3. Hard Exudates

• Caused by chronic localised leakage from microaneurysms and abnormal capillaries
• Intraretinal deposits of lipids and lipoproteins - bright yellow-white waxy lesions
• Located at the outer plexiform layer
• Arranged in circinate (ring) patterns around leaking microaneurysms
• When at the macula: threaten central vision

4. Cotton-Wool Spots (CWS)

• Superficial white fluffy patches from localised ischaemia of the NFL - accumulation of axoplasmic debris (cytoid bodies)
• Marker of increasing retinal ischaemia - signal progression toward PPDR
• Transient; resolve in weeks to months

5. Venous Changes (PPDR)

• Venous beading: Sausage-like segmental dilatation of veins - indicates severe ischaemia
• Venous loops and reduplication
• Venous dilatation and tortuosity

6. Intraretinal Microvascular Abnormalities (IRMA)

• Dilated capillary channels within the retina that bypass areas of capillary non-perfusion
• Flat on FA (no leakage beyond retina - distinguishes from NVE)
• Marker of severe NPDR / impending PDR

7. New Vessels (PDR)

• NVD (new vessels on the disc): On or within 1 disc diameter of optic disc; arise from optic disc surface or adjacent retina
• NVE (new vessels elsewhere): Arise from retinal surface; may be flat initially then elevated; associated with fibrous tissue proliferation

8. Rubeosis Iridis (NVI)

• New vessels on the iris surface; arise at the pupil margin and spread to the angle
• Sign of severe ischaemia and high risk of neovascular glaucoma

9. Diabetic Maculopathy

• Focal: Localised area of retinal thickening with hard exudates associated with microaneurysm clusters
• Diffuse: Generalised macular thickening from extensive leakage
• Ischaemic: Foveal avascular zone (FAZ) enlargement; poor prognosis; no treatment modifies ischaemia

• Retinal thickening within 500 μm of fovea
• Hard exudates within 500 μm of fovea with adjacent thickening
• Retinal thickening ≥1 disc area, any part within 1 disc diameter of fovea

Investigations

1. Fundus Examination

• Dilated fundus examination using 90D or 60D lens at slit lamp - gold standard for grading
• Indirect ophthalmoscopy for peripheral retinal examination

2. Fluorescein Angiography (FA)

• Differentiates dot haemorrhages from microaneurysms (MA leaks, haemorrhage does not)
• Identifies areas of capillary non-perfusion (ischaemia)
• Detects foveal ischaemia (FAZ enlargement)
• Identifies NVD/NVE (early hyperfluorescence with late leakage)
• Guides focal/grid laser therapy
• Distinguishes IRMA (no leakage) from NVE (leakage)

3. Optical Coherence Tomography (OCT)

• Investigation of choice for DME - quantifies retinal thickness, detects subretinal fluid, cystoid changes
• Identifies vitreomacular traction
• Guides anti-VEGF therapy and monitors response
• OCT Angiography (OCTA): Non-invasive assessment of the FAZ and capillary non-perfusion; detects significant central macular ischaemia

4. Systemic Investigations

• Fasting blood glucose + HbA1c - glycaemic control assessment
• Blood pressure
• Lipid panel (elevated lipids worsen hard exudate formation)
• Renal function (urea, creatinine)
• BMI, urinalysis

5. Additional Ocular Investigations

• Gonioscopy - before dilation, to check for NVI/NVA in suspected PDR
• B-scan ultrasound - when vitreous haemorrhage obscures the fundus view; rules out tractional retinal detachment

Treatment

A. Medical / Systemic Control (Cornerstone)

• Tight glycaemic control (target HbA1c per UKPDS/DCCT trials) - reduces incidence and slows progression
• Blood pressure control - target <130/80 mmHg; reduces progression
• Lipid control - statins/fenofibrate reduce hard exudate deposits
• Treatment of anaemia, renal disease

B. Diabetic Macular Oedema (DME) Treatment

1. Anti-VEGF Therapy (First Line for Centre-Involving DME)

• Ranibizumab (Lucentis) - 0.3 mg intravitreal
• Aflibercept (Eylea) - 2 mg intravitreal; superior for eyes with VA ≤6/15
• Faricimab (Vabysmo) - newest agent; dual mechanism: neutralises angiopoietin-2 AND VEGF-A (YOSEMITE and RHINE studies); as effective as aflibercept and ranibizumab; 4 initial monthly injections then treat-and-extend up to 16-week intervals
• Bevacizumab (Avastin) - off-label but widely used; comparable to ranibizumab for VA >6/15

2. Intravitreal Corticosteroids (Second Line)

• Dexamethasone implant (Ozurdex) - biodegradable 0.7 mg implant
• Fluocinolone acetonide implant (Iluvien) - long-acting (3 years)
• Off-label: triamcinolone acetonide 1-4 mg
• Side effects: cataract formation, raised IOP

3. Laser Photocoagulation (Adjunctive)

• No longer first-line; reserved for:
  • Off-centre thickening with exudates threatening the fovea
  • Extrafoveal microaneurysms causing significant oedema
  • When anti-VEGF/steroids are contraindicated (e.g. pregnancy)
• Focal laser: Burns applied to leaking microaneurysms 500-3000 μm from foveola; 50-100 μm spot, 0.02-0.1 sec, mild grey reaction
• Modified grid laser: Focal treatment of leaking foci
• Subthreshold macular laser (micropulse): Short pulses (100-300 μs on, 1700-1900 μs off); minimises collateral damage while stimulating RPE; no visible burn

C. Proliferative DR (PDR) Treatment

1. Panretinal Photocoagulation (PRP) - Mainstay

• Indicated for high-risk PDR characteristics:
  • NVD >1/3-disc area
  • Any NVD with preretinal haemorrhage or VH
  • NVE >1/2-disc area with preretinal haemorrhage or VH
  • Any NVI or NVA
• Mechanism: destroys ischaemic retina → reduces VEGF production → regression of new vessels
• Technique: 1200-1600 burns, 500 μm spot, 0.05-0.1 sec, ~2 mm apart, from posterior retina to periphery
• Complications: loss of peripheral/night vision, macular oedema, decreased colour vision, exacerbation of pre-existing DME

Clinical tip: PRP remains the mainstay of PDR treatment in most healthcare systems.

2. Anti-VEGF Therapy for PDR

• Alternative to PRP; preferred initial therapy when:
  • DME is co-present
  • View to peripheral retina is limited by VH
• Agents: ranibizumab, aflibercept, bevacizumab
• Caution: patients lost to follow-up show worse anatomic and visual outcomes than PRP-treated patients
• Recent 2025 meta-analysis (PMID 39128789) confirms anti-VEGF and PRP have comparable visual outcomes in PDR, with anti-VEGF having lower risk of visual field loss

3. Vitrectomy (Pars Plana Vitrectomy - PPV)

1. Dense, non-clearing or recurrent vitreous haemorrhage causing significant vision loss
2. Tractional retinal detachment involving or progressing within the macula
3. Macular epiretinal membranes or vitreomacular traction causing significant symptoms
4. Dense premacular haemorrhage
5. Chronic DME unresponsive to other treatment
6. Severe neovascularisation and fibrous proliferation unresponsive to laser or anti-VEGF

Note: Young type 1 diabetics have more aggressive PDR and may benefit from earlier vitrectomy or anti-VEGF therapy. B-scan US is required if dense VH obscures fundus view.

Complications

Ocular Complications

Systemic Associations

• Diabetic nephropathy - DR and nephropathy share the same microangiopathic process
• Cardiovascular disease - patients with PDR have significantly elevated cardiovascular risk
• Diabetic neuropathy

Screening Protocol

"The risk of severe visual loss can be reduced to less than 5% with effective screening and implementation of ETDRS trial conclusions and anti-VEGF clinical trials." - Kanski's Clinical Ophthalmology, 10th Ed.

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