Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy is deposition of amyloid beta in the walls of small cortical and leptomeningeal vessels, causing lobar intracerebral haemorrhage, cognitive decline and transient focal episodes. It is a leading cause of spontaneous lobar haemorrhage in older adults.

Prevalence rises with age, and neuropathological changes are present in over half of people over 80 and in most with Alzheimer disease. It causes about 5 to 20% of spontaneous intracerebral haemorrhage in older adults.

Genetics and risk factors. The APOE e2 and e4 alleles increase risk of haemorrhage and amyloid deposition respectively. Rare hereditary forms (APP duplication, Dutch type) cause early onset disease.

Variants. Inflammatory CAA (amyloid-beta-related angiitis and CAA-related inflammation) presents subacutely with headache, seizures, cognitive decline and vasogenic oedema, often in younger patients.

Pathophysiology.

Failure of perivascular clearance of amyloid beta leads to vessel wall deposition, loss of smooth muscle and fragile vessels that rupture.

Vessel stiffening and impaired reactivity reduce perfusion, causing white matter disease and small infarcts, and an inflammatory response to amyloid causes the inflammatory variant.

• Acute lobar haemorrhage with headache, focal deficit, seizure or reduced consciousness.
• Progressive cognitive decline and gait impairment.
• Transient focal neurological episodes (amyloid spells): stereotyped, spreading paraesthesia or weakness over minutes, which can be mistaken for TIA or seizure.
• Inflammatory CAA: subacute encephalopathy, seizures and focal signs over days to weeks.

Red flags.

• Acute lobar haemorrhage with expanding haematoma.
• Subacute encephalopathy with seizures and vasogenic oedema (inflammatory CAA).
• Anticoagulant or antiplatelet use with recurrent haemorrhage.

• MRI with gradient echo or susceptibility weighted sequences is central; it shows lobar microbleeds, cortical superficial siderosis or convexity subarachnoid haemorrhage, and white matter changes.
• Criteria for probable CAA in a patient aged 50 or over: at least 2 strictly lobar haemorrhagic lesions (haemorrhage, microbleeds, cortical superficial siderosis), or 1 haemorrhagic lesion plus 1 white matter feature (severe enlarged perivascular spaces in the centrum semiovale or multispot white matter hyperintensities). One lobar lesion is possible CAA; definite CAA needs pathology.
• CT in acute haemorrhage; CT angiography for a vascular lesion when atypical.
• EEG for seizures; lumbar puncture and, rarely, biopsy when inflammatory CAA is suspected and infection is excluded.
• APOE genotyping is not needed for routine diagnosis.

Differential diagnosis. Hypertensive deep haemorrhage, vascular malformation, cavernous malformation, haemorrhagic tumour, vasculitis, venous thrombosis, infection and other causes of subacute encephalopathy.

• No treatment removes amyloid or prevents all recurrence; management is risk reduction.
• Blood pressure: lower to under 130/80 mmHg after haemorrhage, with an ACE inhibitor, a thiazide like diuretic or a calcium channel blocker as tolerated, which reduces recurrence.
• Avoid antiplatelet drugs and anticoagulants when possible after lobar haemorrhage. When atrial fibrillation is present, balance stroke and haemorrhage risk individually; left atrial appendage closure may be considered.
• Avoid anti-amyloid antibody therapy in patients with CAA imaging features because of the risk of amyloid related imaging abnormalities.
• Seizures: levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 2 weeks as needed to a maximum of 1500 mg twice daily, continued for at least 6 months after the last seizure. Monitor mood, behaviour and renal function. Reduce dose when creatinine clearance is 50 to 80 mL/min (500 to 1000 mg twice daily), 30 to 50 mL/min (250 to 750 mg twice daily) and under 30 mL/min (250 to 500 mg twice daily); use with caution in pregnancy and breastfeeding.
• Inflammatory CAA: methylprednisolone 1 g intravenously once daily for 3 days (up to 5), then prednisolone 1 mg/kg orally once daily (maximum 80 mg) with a tapering course over 3 to 6 months. Monitor glucose, blood pressure, mood, bone health and infection, repeating MRI every 2 to 4 weeks at first. Use caution in diabetes, peptic ulcer and active infection; acceptable in pregnancy when needed; no renal adjustment. Add a steroid sparing agent through specialist review for relapse.
• Supportive care: cognitive rehabilitation, falls prevention and treatment of depression.

Monitoring. MRI at 3 to 6 months after a haemorrhage or steroid course, then as clinically needed; review cognition and blood pressure every 6 months.

Referral and escalation. Neurosurgery for large lobar haematoma with mass effect; neurology or stroke service for antithrombotic decisions; specialist centre for suspected inflammatory CAA.

Special groups. Hereditary forms need genetic counselling. Older adults: tailor blood pressure targets to frailty and falls risk.