Neuro-Behçet Disease

Neuro-Behçet disease is nervous system involvement by Behçet disease, a variable vessel vasculitis with oral and genital ulcers, uveitis and skin lesions. It takes two forms: parenchymal (brainstem, diencephalon and spinal cord inflammation) and non-parenchymal (cerebral venous thrombosis, arterial disease).

Behçet disease is most common along the old Silk Road (prevalence up to 100 to 400 in every 100,000 in Turkey), and is rare in northern Europe (about 1 in 100,000). Neurological involvement affects 5 to 10% of patients, typically 3 to 6 years after onset, and is more frequent in men aged 20 to 40 years.

Parenchymal form. Brainstem and diencephalic lesions, myelopathy and meningoencephalitis, about 75% of neurological involvement.

Non-parenchymal form. Cerebral venous sinus thrombosis with raised intracranial pressure, and rarely arterial thrombosis.

Course. Acute, relapsing or secondary progressive in the parenchymal form; the venous form usually has a monophasic course. Progressive disease carries a poor outcome.

Pathophysiology.

Immune mediated vasculitis and perivascular inflammation, with neutrophil and T cell infiltration, affect small veins and venules, in genetically susceptible people (HLA-B51).

Hypercoagulability and endothelial dysfunction produce venous thrombosis.

• Parenchymal: headache, fever, brainstem syndromes (ophthalmoplegia, ataxia, dysarthria, pyramidal weakness), hemiparesis, cognitive and behavioural change, myelopathy.
• Non-parenchymal: headache, papilloedema, visual loss, seizures and focal signs from venous thrombosis.
• Systemic: recurrent oral ulcers, genital ulcers, uveitis, skin lesions (erythema nodosum, pustules), pathergy and arthritis.
• Cognitive impairment and psychiatric features in chronic disease.

Red flags.

• Reduced consciousness, progressive brainstem signs or myelopathy.
• Papilloedema with visual loss (venous thrombosis).
• Haemoptysis (pulmonary artery aneurysm, which needs urgent specialist care, and anticoagulation is hazardous).

• Behçet disease criteria (recurrent oral ulcers plus genital ulcers, eye, skin or pathergy findings), with neurological features not explained by other causes.
• MRI of the brain and spine with contrast: brainstem and diencephalic lesions extending to the basal ganglia ("flame shaped" brainstem lesion), longitudinally extensive cord lesions; MR venography for venous thrombosis.
• Cerebrospinal fluid: neutrophilic or lymphocytic pleocytosis, raised protein and interleukin-6; oligoclonal bands are uncommon.
• Exclude infection, multiple sclerosis, neurosarcoidosis, lymphoma, CNS vasculitis and drug induced disease (ciclosporin neurotoxicity).
• Chest CT angiography for pulmonary artery aneurysm before anticoagulation; HLA-B51 and pathergy test as supportive.

Differential diagnosis. Multiple sclerosis, neurosarcoidosis, primary angiitis of the central nervous system, neuro lupus, brainstem infection (Listeria), lymphoma, neuromyelitis optica spectrum disorder and idiopathic cerebral venous thrombosis.

• Acute parenchymal attack: methylprednisolone 1000 mg intravenously once daily for 3 to 7 days, followed by prednisolone 1 mg/kg orally once daily (maximum 60 mg) tapered over 2 to 3 months. Maximum 7 g of methylprednisolone in a course. Monitor blood pressure, glucose, mood, infection and bone density. Avoid with active untreated infection; use caution in diabetes, peptic ulcer and psychosis.
• Long term immunosuppression to prevent relapse: azathioprine 50 mg orally daily, increased to 2.5 mg/kg daily. Maximum 3 mg/kg daily. Monitor full blood count and liver function weekly for 4 weeks, then every 3 months; check thiopurine methyltransferase activity. Avoid with allopurinol (reduce azathioprine to a quarter) and in severe hepatic impairment; acceptable in pregnancy with specialist advice.
• Severe or refractory disease: infliximab 5 mg/kg intravenously at weeks 0, 2 and 6, then every 8 weeks. Maximum 10 mg/kg for each infusion. Screen for tuberculosis and hepatitis B before the first dose; monitor infusion reactions, infection and full blood count. Avoid in heart failure (NYHA class III or IV), active infection and demyelinating disease; use caution in pregnancy.
• Avoid ciclosporin because it is neurotoxic and can worsen neurological disease.
• Cerebral venous thrombosis: corticosteroids and immunosuppression; the role of anticoagulation is debated and is decided by specialists after exclusion of pulmonary artery aneurysm.
• Treat headache, seizures, spasticity and bladder dysfunction symptomatically; rehabilitation.
• Eye, oral, skin and genital disease are managed with rheumatology, ophthalmology and dermatology.

Monitoring. Clinical and MRI review every 3 months in the first year, then every 6 months; blood counts and liver tests at the intervals given in Management; watch for relapse as steroids are tapered.

Referral and escalation. Neurology and rheumatology; ophthalmology; intensive care for coma or brainstem failure.

Special groups. Pregnancy: prednisolone and azathioprine acceptable; avoid infliximab unless needed. Men: higher risk of severe neurological disease.