27.2 Retinopathy in Systemic Disease
Key Takeaways
- Proliferative diabetic retinopathy is defined by new vessel formation and is treated with panretinal photocoagulation or anti-VEGF therapy.
- Grade 4 hypertensive retinopathy adds papilloedema to haemorrhages and exudates and defines accelerated (malignant) hypertension.
- Retinitis pigmentosa causes night blindness and tunnel vision with bone-spicule pigmentation, and is associated with Refsum disease, Usher syndrome and abetalipoproteinaemia.
3. Retinopathy in Systemic Disease
Diabetic Retinopathy
Diabetic retinopathy is a chronic microangiopathy driven by chronic hyperglycaemia, capillary pericyte loss, basement membrane thickening, microvascular occlusion, and VEGF-driven neoangiogenesis.
| Classification (NHS DESP) | Defining Fundoscopic Features | Clinical Significance & Action |
|---|---|---|
| R0: None | Normal fundus; no microvascular lesions | Annual digital photographic screening |
| R1: Background (Mild NPDR) | • Microaneurysms (small, circular red dots)<br>• Retinal dot/blot haemorrhages<br>• Hard exudates (discrete lipid deposits) | Low risk of progression; annual screening; optimize glycemic (HbA1c) and BP control |
| R2: Pre-Proliferative (Moderate–Severe NPDR) | Signs of progressive retinal ischaemia (The 4-2-1 Rule):<br>• Multiple blot haemorrhages in all 4 quadrants<br>• Venous beading in ≥ 2 quadrants<br>• IRMA (Intraretinal Microvascular Abnormalities) in ≥ 1 quadrant<br>• Multiple cotton wool spots (nerve fibre layer infarcts) | High risk of rapid progression to proliferative disease; routine ophthalmology clinic referral |
| R3: Proliferative Diabetic Retinopathy (PDR) | • Neovascularization at the Disc (NVD)<br>• Neovascularization Elsewhere (NVE)<br>• Preretinal or vitreous haemorrhage<br>• Tractional retinal detachment | High risk of catastrophic irreversible blindness; urgent ophthalmology referral for Panretinal Photocoagulation (PRP) laser or intravitreal anti-VEGF |
| M1: Diabetic Maculopathy | • Hard exudates, blot haemorrhages, or retinal thickening/oedema within 1 disc diameter of the fovea<br>• Decreased visual acuity (≤ 6/12) in presence of macula lesions | Leading cause of visual loss in Type 2 diabetes; treated with intravitreal anti-VEGF or focal macular laser |
Hypertensive Retinopathy: Keith-Wagener-Barker Classification
Arterial hypertension damages retinal arterioles through vasoconstriction, intimal hyperplasia, hyalinization, and endothelial necrosis:
- Grade 1: Generalized retinal arteriolar narrowing, tortuosity, and increased light reflex (producing the classic "silver wiring" and "copper wiring" appearance).
- Grade 2: Grade 1 plus Arteriovenous (AV) nipping / nicking (Salus' sign: deflection, tapering, or banking of venules as they cross rigid, sclerotic arterioles).
- Grade 3: Grade 2 plus signs of acute vascular decompensation: "flame-shaped" retinal haemorrhages (superficial nerve fibre layer), cotton wool spots (axoplasmic flow stasis in microinfarcted nerve fibres), and hard exudates radiating circumferentially around the fovea in a "macular star" pattern.
- Grade 4 (Malignant / Accelerated Hypertension): Grade 3 plus bilateral optic disc oedema / papilloedema. Represents a medical hypertensive emergency (diastolic blood pressure typically > 120–130 mmHg). Mandates immediate hospital admission and controlled blood pressure reduction with intravenous antihypertensives (e.g. labetalol, nicardipine, or sodium nitroprusside), cautiously lowering mean arterial pressure by no more than 20% to 25% over the first 2 to 4 hours to prevent cerebral, myocardial, or retinal hypoperfusion.
Papilloedema vs. Optic Neuritis
- Papilloedema: Defined specifically as bilateral optic disc swelling secondary to raised intracranial pressure (ICP).
- Clinical Triad of Raised ICP: Morning headache (worsened by coughing, bending, or Valsalva), nausea/vomiting, and transient visual obscurations (momentary graying or blacking out of vision lasting seconds, typically triggered by standing up or postural shifts).
- Examination: Loss of spontaneous retinal venous pulsations (SVPs), blurring of disc margins (initially nasal), hyperaemic elevated disc, splinter haemorrhages at the disc margin, and an enlarged physiological blind spot on visual field testing. Crucial Exam Pearl: Central visual acuity and pupillary light reflexes are characteristically preserved in early and acute papilloedema (in stark contrast to optic neuritis or ischemic optic neuropathy).
- Mandatory Investigation: Urgent neuroimaging (MRI brain with MR venography) must be performed to exclude an intracranial space-occupying lesion or cerebral venous sinus thrombosis before considering a lumbar puncture (to prevent fatal tentorial or cerebellar tonsillar herniation / coning).
- Optic Neuritis: Idiopathic inflammatory demyelination of the optic nerve (strongly associated with multiple sclerosis). Typically unilateral, presenting in young adults with subacute painful visual loss (worse with extraocular eye movements), marked impairment of colour vision (dyschromatopsia, red desaturation), and a profound Relative Afferent Pupillary Defect (RAPD). Fundoscopy is completely normal in two-thirds of cases (retrobulbar neuritis).
Retinal Signs of Systemic Infection and Inflammation
The fundus is the only place where small vessels and neural tissue can be inspected directly, and MRCP uses described fundoscopic findings as a shortcut to a systemic diagnosis.
| Finding described in the stem | Systemic diagnosis to consider |
|---|---|
| Roth spots (white-centred retinal haemorrhages) | Infective endocarditis, leukaemia, severe anaemia, vasculitis |
| Cotton wool spots in a patient with HIV | HIV retinopathy (non-infective, CD4-dependent) |
| "Pizza pie" or "cheese and ketchup" retinitis with haemorrhage | Cytomegalovirus retinitis, CD4 below 50 cells/mm3 |
| Choroidal tubercles | Miliary tuberculosis |
| Candida chorioretinitis with vitreous "fluffy balls" | Candidaemia, intravenous drug use, central venous catheter |
| Posterior uveitis with candle-wax drippings and periphlebitis | Sarcoidosis |
| Retinal vasculitis with occlusion in a young adult | Behcet disease, systemic lupus erythematosus |
| Bilateral optic disc swelling with normal acuity and enlarged blind spot | Raised intracranial pressure or idiopathic intracranial hypertension |
Cytomegalovirus retinitis is a sight-threatening AIDS-defining illness requiring urgent ganciclovir or valganciclovir alongside antiretroviral therapy, and immune recovery uveitis can follow the start of ART.
Drug-Induced Retinal and Optic Toxicity
| Drug | Ocular toxicity | Monitoring |
|---|---|---|
| Hydroxychloroquine | Bull's-eye maculopathy | Baseline and annual screening after five years, earlier with renal impairment or tamoxifen |
| Ethambutol | Dose-related optic neuritis with red-green colour loss | Baseline visual acuity and colour vision; warn the patient |
| Amiodarone | Corneal verticillata (usually asymptomatic); rarely optic neuropathy | Symptom-driven |
| Vigabatrin | Irreversible concentric visual field constriction | Regular perimetry |
| Isotretinoin | Night blindness, dry eye | Symptom-driven |
| Sildenafil | Transient blue-tinged vision | None |
| Corticosteroids | Posterior subcapsular cataract, raised intraocular pressure | Pressure checks in prolonged use |
Inherited and Metabolic Retinal Disease
Retinitis pigmentosa should trigger a search for a syndromic cause: Refsum disease (phytanic acid accumulation, deafness, ataxia, ichthyosis, treated by dietary phytanic acid restriction), Usher syndrome (sensorineural deafness), Kearns-Sayre syndrome (mitochondrial, with external ophthalmoplegia and heart block) and abetalipoproteinaemia (acanthocytes, fat malabsorption, vitamin E deficiency). A cherry-red spot without arterial occlusion suggests a lysosomal storage disorder such as Tay-Sachs or Niemann-Pick disease, whereas with a pale retina and sudden painless visual loss it indicates central retinal artery occlusion. Angioid streaks point to pseudoxanthoma elasticum, Paget disease of bone or sickle cell disease.
A 56-year-old man with an 11-year history of type 2 diabetes mellitus attends the hospital eye clinic for his routine annual digital retinal screening review. His most recent HbA1c is 76 mmol/mol (9.1%), and blood pressure is 154/92 mmHg. He reports no visual complaints and his corrected visual acuity is 6/6 in both eyes. Dilated digital fundus photography reveals multiple microaneurysms, scattered intraretinal blot haemorrhages across three quadrants, and a prominent fine, delicate network of frond-like, tortuous new vessels arising directly from the surface of the optic disc (neovascularization of the disc, NVD) extending across more than one-third of the disc diameter. There are no retinal hard exudates or oedema within one disc diameter of the fovea. According to the UK National Diabetic Eye Screening Programme (NDESP) classification, what is the correct grade of retinopathy, and what is the most appropriate guideline-directed management?
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