Neurosarcoidosis

Neurosarcoidosis is involvement of the nervous system by sarcoidosis, a multisystem non-caseating granulomatous disease. It affects 5 to 10% of patients with sarcoidosis and can involve cranial nerves, meninges, brain parenchyma, spinal cord, peripheral nerves and muscle.

The incidence of sarcoidosis is about 5 to 40 in every 100,000 people each year, higher in Black populations and in northern Europe. Neurological disease occurs mostly at 30 to 50 years, and in about half of cases it is the first manifestation.

Patterns. Facial palsy (commonest, in 50 to 70%), optic neuropathy, aseptic meningitis, hydrocephalus, hypothalamic and pituitary disease, parenchymal masses, myelopathy, small fibre neuropathy and myopathy.

Course. Variable; about one third have a monophasic course, one third relapsing and one third chronic. Relapse is common during steroid tapering.

Pathophysiology.

Granulomatous inflammation driven by CD4+ T cells and macrophages, in response to unknown antigens in genetically susceptible people, infiltrates the leptomeninges and perivascular spaces.

The result is cranial neuropathy, parenchymal lesions and vasculopathy.

• Cranial neuropathies: facial palsy (may be bilateral), optic neuritis, hearing loss, diplopia, loss of smell.
• Headache, meningism, hydrocephalus, seizures, cognitive change and encephalopathy.
• Hypothalamic and pituitary dysfunction: diabetes insipidus, hypopituitarism, hyperprolactinaemia, sleep and temperature disturbance.
• Myelopathy (longitudinally extensive lesions), radiculopathy, neuropathy and myopathy.
• Systemic features: cough, dyspnoea, erythema nodosum, uveitis, lymphadenopathy, hypercalcaemia.

Red flags.

• Visual loss, progressive hydrocephalus or reduced consciousness.
• Myelopathy with rapid weakness.
• Fever, immunosuppression or constitutional symptoms (infection, lymphoma, tuberculosis).

• Tissue confirmation of non-caseating granulomas from an accessible site (lymph node, lung, skin, or brain and meningeal biopsy when needed), with exclusion of infection.
• MRI of the brain and spine with contrast: leptomeningeal and dural enhancement, parenchymal lesions, hypothalamic and pituitary lesions, cranial nerve enhancement, longitudinally extensive cord lesions.
• Cerebrospinal fluid: lymphocytic pleocytosis, raised protein, low glucose in some, oligoclonal bands, raised angiotensin converting enzyme (low sensitivity); exclude infection and malignancy.
• Chest imaging (CT), whole body FDG-PET for a biopsy target, serum calcium, angiotensin converting enzyme, soluble interleukin-2 receptor, and ophthalmology review.
• Tuberculosis, HIV and fungal tests, and cerebrospinal fluid cytology and flow cytometry for lymphoma.

Differential diagnosis. Tuberculous meningitis, fungal infection, multiple sclerosis, neuromyelitis optica spectrum disorder, lymphoma, IgG4-related disease, Behçet disease, granulomatosis with polyangiitis and Lyme neuroborreliosis.

• First line: prednisolone 0.5 to 1 mg/kg orally once daily in the morning (usual 40 to 60 mg, maximum 80 mg) for 4 to 8 weeks, then taper by 5 to 10 mg every 2 to 4 weeks to the lowest effective dose. Monitor blood pressure, glucose, mood, infection, weight, bone density and adrenal suppression. Avoid with untreated systemic infection; use caution in diabetes, peptic ulcer, psychosis and osteoporosis; give bone protection and gastric protection as needed.
• Severe disease (optic neuropathy, myelopathy, encephalopathy): methylprednisolone 1000 mg intravenously once daily for 3 to 5 days, then oral prednisolone. Maximum 5 g in a course. Monitor blood pressure, glucose, mood and infection. Avoid with active untreated infection.
• Steroid sparing agent, started early for parenchymal disease or when prednisolone is needed over 10 mg daily: methotrexate 7.5 to 10 mg orally (or subcutaneously) once weekly, increased by 2.5 to 5 mg every 2 to 4 weeks to a usual 15 to 25 mg once weekly, with folic acid 5 mg once weekly on a different day. Maximum 25 mg weekly. Monitor full blood count, liver function and renal function every 2 weeks for 2 months, then every 3 months. Avoid in pregnancy (stop 6 months before conception), severe hepatic or renal impairment (reduce dose when creatinine clearance is under 60 mL/min and avoid when under 30 mL/min), active infection and alcohol excess.
• Azathioprine as an alternative: 50 mg orally daily, increased to 2 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 before starting. Avoid with allopurinol (reduce azathioprine to a quarter), in pregnancy unless needed, and in severe hepatic impairment.
• Refractory or severe 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.
• Hydrocephalus: shunting. Pituitary dysfunction: hormone replacement. Seizures: levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 2 weeks to a maximum of 1500 mg twice daily; monitor mood and renal function; reduce dose in renal impairment.
• Prophylaxis against Pneumocystis infection, vaccination and bone health with combined immunosuppression.

Monitoring. Clinical and MRI review at 3 months, then every 6 months; full blood count, liver and renal function at the intervals given in Management; watch for relapse during tapering.

Referral and escalation. Neurology and respiratory or sarcoidosis services; ophthalmology; endocrinology; neurosurgery for hydrocephalus or biopsy.

Special groups. Pregnancy: avoid methotrexate; use prednisolone and azathioprine. Older adults: higher infection risk with immunosuppression.