Primary Angiitis of the Central Nervous System

Primary angiitis of the central nervous system is an inflammatory vasculitis restricted to the brain, spinal cord and leptomeninges. It is rare, heterogeneous and fatal without treatment.

The estimated incidence is about 2 to 3 cases in every million people each year. It affects adults of any age, with a mean age near 50 years, and slightly more men.

Classification. Small vessel angiography negative disease (biopsy proven), large and medium vessel angiography positive disease, amyloid-beta-related angiitis, and granulomatous, lymphocytic and necrotising histological types.

Diagnostic criteria. An acquired unexplained neurological deficit, angiographic or histological evidence of vasculitis in the central nervous system, and no systemic vasculitis or other condition that mimics it.

Pathophysiology.

T cell and macrophage mediated inflammation of the vessel wall causes luminal narrowing, thrombosis and ischaemia, and occasionally haemorrhage.

The trigger is unknown; infection (varicella zoster virus) and amyloid beta may be involved in subsets.

• Headache, often subacute and progressive (about 60 to 70%).
• Cognitive decline, confusion and personality change.
• Multifocal strokes or TIAs, focal deficits, seizures and myelopathy.
• Fever and systemic features are usually absent.

Red flags.

• Recurrent multifocal infarcts in different territories.
• Rapid cognitive decline or encephalopathy with abnormal CSF.
• Intracerebral haemorrhage with vascular narrowing.

• MRI is abnormal in over 90%, usually with multifocal infarcts of different ages, with or without enhancement.
• Cerebrospinal fluid shows lymphocytic pleocytosis or raised protein in about 80 to 90%; a normal CSF and MRI make the diagnosis unlikely.
• Catheter angiography or CT angiography shows multifocal segmental narrowing in large vessel disease, but sensitivity is only moderate and a normal result does not exclude small vessel disease.
• Brain and leptomeningeal biopsy of an abnormal region confirms the diagnosis, with sensitivity of about 75%.
• Exclude infection (varicella zoster virus, HIV, syphilis, tuberculosis), systemic vasculitis and autoimmune disease (ESR, CRP, ANA, ANCA, complement), malignancy and lymphoma, and RCVS.

Differential diagnosis. Reversible cerebral vasoconstriction syndrome, intracranial atherosclerosis, infection related vasculitis, systemic lupus, Behçet disease, neurosarcoidosis, intravascular lymphoma, CADASIL, moyamoya disease and embolic disease.

• Start treatment promptly after infection is excluded and biopsy is planned or done.
• Methylprednisolone 1 g intravenously once daily for 3 days, then prednisolone 1 mg/kg orally once daily (maximum 80 mg), tapered over 6 to 12 months once remission is reached. Monitor blood pressure, glucose, mood, infection and bone health. Use caution in diabetes, peptic ulcer and active infection; acceptable in pregnancy when needed; no renal adjustment.
• Cyclophosphamide 0.6 to 0.75 g/m2 intravenously every 2 to 4 weeks for 6 pulses (or 2 mg/kg orally once daily for 3 to 6 months). Maximum single intravenous dose about 1.2 g. Monitor full blood count before each dose and at the nadir (days 10 to 14), urinalysis, renal function and liver function. Give mesna and fluids to protect the bladder. Reduce the dose by 20 to 30% in older adults and when creatinine clearance is under 30 mL/min; offer fertility preservation; contraindicated in pregnancy; avoid live vaccines.
• Maintenance after remission: azathioprine 2 mg/kg orally once daily (maximum 2.5 mg/kg daily) for 18 to 24 months. Monitor full blood count and liver enzymes every 2 weeks for 2 months, then monthly for 3 months, then every 3 months. Check thiopurine methyltransferase activity before starting; reduce the dose to one quarter when taking allopurinol and in renal impairment; avoid in pregnancy unless the benefit outweighs risk.
• Relapse or intolerance: rituximab or mycophenolate through specialist review, with doses set by the treating team.
• Supportive care: prophylaxis against Pneumocystis infection, bone protection and gastroprotection during prolonged steroids, antiplatelet therapy only when infarcts are present and haemorrhage is excluded, and seizure treatment as needed.

Monitoring. MRI at 3 months, then every 6 months for 2 years, with clinical and laboratory assessment; relapse occurs in about one quarter of patients.

Referral and escalation. Specialist neurology and rheumatology care in a centre with neuropathology; neurosurgery for biopsy; intensive care for refractory seizures or raised pressure.

Special groups. Women of childbearing age: contraception and fertility counselling before cyclophosphamide. Older adults: reduced cyclophosphamide dose.