John N. Ratchford, MD
DESCRIPTION
Central nervous system (CNS) vasculitis is a syndrome of subacute onset caused by inflammation of small- and medium-sized blood vessels of the brain, spinal cord, and leptomeninges. Primary angiitis of the central nervous system (PACNS) exclusively involves the CNS. PACNS is also referred to as primary CNS vasculitis, isolated CNS vasculitis, or granulomatous angiitis of the nervous system. Secondary CNS vasculitis is the result of a systemic vasculitis involving the CNS.
EPIDEMIOLOGY
Incidence
- PACNS
- Very rare with no epidemiologic studies of its incidence
- Mean age of onset is 45, range 3–71 years
- Males and females approximately equally affected
- Secondary CNS vasculitis
- Annual incidence of systemic vasculitis is 39 per million with only 1–2 per million involving the CNS.
Prevalence
Unknown
RISK FACTORS
Risk factors are associated with specific conditions that can cause a systemic vasculitis.
Genetics
No known genetic associations
GENERAL PREVENTION
None
PATHOPHYSIOLOGY
- In most cases the inflamed vessels cause tissue ischemia and necrosis, resulting in small infarcts or hemorrhages which present with focal neurologic symptoms.
- Headache and encephalopathy are common.
ETIOLOGY
- Etiology of PACNS is unknown. Infectious agents have been proposed as a cause, but not proven.
- CNS vasculitis can occur as a complication of infection by varicella zoster virus (VZV), HIV, West Nile virus, and other viruses.
- Many systemic vasculitides can cause secondary CNS vasculitis. Deposition of antigen–antibody immune complexes containing activated complement in blood vessel walls has been implicated in initiating the vascular injury.
COMMONLY ASSOCIATED CONDITIONS
HISTORY
- Commonly presents with subacute onset headache, confusion, and focal neurologic findings due to ischemic or hemorrhagic stroke.
- Symptoms can include hemiparesis, aphasia, ataxia, movement disorders, visual changes, and brainstem syndromes.
- Seizures occur in about 30%.
- Should be considered when stroke (especially recurrent) is seen in a young patient without identifiable stroke risk factors or a hypercoagulable state.
- Patients should be queried for symptoms suggestive of a systemic syndrome, including fever, malaise, weight loss, rash, arthritis, and peripheral neuropathy.
PHYSICAL EXAM
- A detailed examination of the CNS should be performed.
- Examination of the skin, eyes, sinuses, lungs, testicles, and peripheral nervous system should be undertaken to look for signs of a systemic syndrome.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- CBC with differential, hepatic function panel, ESR, ANA, c-ANCA, p-ANCA, SSA/SSB, cryoglobulin, complement, syphilis serology, anticardiolipin antibody, lupus anticoagulant, Lyme serology, and an HIV test will help to evaluate for a systemic syndrome.
- In PACNS, CSF generally shows an elevated protein. A lymphocytic pleocytosis is present in 68%, but CSF can be normal. CSF testing should help rule out infection or leptomeningeal metastases.
Follow-Up & Special Considerations
None
Imaging
Initial Approach
- Brain MRI generally shows single or multifocal infarcts and/or hemorrhages. Nonspecific T2-weighted lesions are commonly present.
- MR angiography is insensitive in small-vessel vasculitides, but could identify abnormalities in vasculitides involving large vessels.
Follow-Up & Special Considerations
- Catheter angiography classically demonstrates multifocal areas of stenosis or “beading” in small- and medium-sized vessels, but this is not specific to vasculitis.
- Reported sensitivity of angiography ranges from 10% to 60% in proven cases, so a negative angiogram does not rule out CNS vasculitis (1).
Diagnostic Procedures/Other
- In PACNS a biopsy of the cortex and leptomeninges is generally required to make the diagnosis and rule out other possibilities prior to initiating intensive immunosuppression. In one series of suspected PACNS, biopsy revealed an alternate diagnosis in 50% of cases (2).
- In a suspected systemic vasculitis, biopsy of skin, peripheral nerve, muscle, or other affected organs may confirm the diagnosis.
- Electromyography and nerve conduction studies may show mononeuritis multiplex or a diffuse sensorimotor polyneuropathy in a systemic vasculitis.
Pathological Findings
- The classic pathology of PACNS is a segmental granulomatous vasculitis with multinucleated giant cells, but this is not constant.
- Monocytes, histiocytes, lymphocytes, and plasma cells can be found infiltrating the walls of small vessels.
- Specific other pathological findings may suggest polyarteritis nodosa, Churg–Strauss, Wegener's granulomatosis, or sarcoidosis.
- Stains for infectious agents and neoplasm should be done.
DIFFERENTIAL DIAGNOSIS
- PACNS
- CNS vasculitis secondary to polyarteritis nodosa, Wegener's granulomatosis, Churg–Strauss, Behçet's disease
- Temporal arteritis or Takayasu's arteritis
- Neuropsychiatric lupus and related conditions
- Reversible cerebral vasoconstriction syndrome (causes acute, severe headache, focal neurologic symptoms; normal CSF; reversible angiographic findings; can be drug-induced, migraine-related, postpartum, or idiopathic)
- Antiphospholipid antibody syndrome
- Infection: Bacterial, fungal, or TB meningitis; encephalitis; vasculitis due to VZV; neurosyphilis; CNS Lyme; HIV; progressive multifocal leukoencephalopathy
- Atherosclerosis or cerebral emboli
- Neurosarcoidosis
- Multiple sclerosis
- Moyamoya disease
- Cocaine-related vasculopathy
- Intravascular lymphoma
- Leptomeningeal metastases
- Hashimoto encephalopathy
MEDICATION
First Line
- Treatment should be specific to the syndrome causing CNS vasculitis.
- PACNS, induction phase (3,4)
- Prednisone 1 mg/kg/day, tapered slowly
- When needed, oral cyclophosphamide 1–2 mg/kg/day (maintain hydration; risks include myelosuppression, hemorrhagic cystitis, infection, infertility, and malignancy)
- Alternatives:
- An initial IV methylprednisolone 15 mg/kg/day pulse × 3 days, followed by oral steroids
- Monthly IV cyclophosphamide pulses
- PACNS, maintenance phase
- Continue cyclophosphamide 6–12 months after remission
- Could then switch to azathioprine or mycophenolate mofetil
- Taper prednisone slowly
- Similar regimens have been used in pediatric patients (5)
Second Line
Experience with other treatments is limited; methotrexate can be considered.
ADDITIONAL TREATMENT
General Measures
Issues for Referral
Management often requires involvement of neurology, rheumatology, radiology, neurosurgery, and others.
Additional Therapies
Physical, occupational, and speech therapy may be needed.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
None
SURGERY/OTHER PROCEDURES
Brain biopsy is often required for diagnosis.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
- Initial management generally focuses on ruling out neurologic emergencies such as stroke or CNS infection.
- Patients with an intracerebral hemorrhage or large stroke may require ICU monitoring.
Admission Criteria
Patients often will be admitted following a stroke or transient ischemic attack, or for workup of progressive neurologic symptoms (e.g., encephalopathy).
IV Fluids
IV fluids should be administered when appropriate. Do not use hypotonic IV fluids in patients with a large stroke or intracerebral hemorrhage as this could exacerbate cerebral edema.
Nursing
Nurses should periodically evaluate the patient's neurologic status
Discharge Criteria
Per physician judgment
FOLLOW-UP RECOMMENDATIONS
- Patients should be followed closely for a change in neurologic status and for response to treatment.
- Repeat brain MRI may be useful to evaluate for treatment responsiveness.
Patient Monitoring
- Cyclophosphamide requires frequent blood monitoring and should only be prescribed by providers familiar with its use.
- Patients receiving chronic corticosteroids should continue to be monitored and treated for potential steroid side effects.
DIET
No restrictions
PATIENT EDUCATION
- Patients should be educated about common symptoms and signs of stroke and the importance of urgent evaluation if a stroke develops.
- Reinforce the importance of adhering to the recommended schedule for blood testing in outpatients on cyclophosphamide and other immunosuppressants.
- Advise immunosuppressed patients to contact their provider if symptoms of infection develop.
- A strategy for avoiding pregnancy should be developed for those taking teratogenic medications.
PROGNOSIS
Prognosis is poor in PACNS with a significant number of patients dying within 6 weeks and most dying within 1 year. However, the course can be more benign with periods of remission in some. Prognosis in secondary CNS vasculitis depends on the success of treating the underlying disorder.
COMPLICATIONS
- Patients can experience disease progression or recurrences despite treatment.
- Infection can occur in patients being treated with immunosuppressive medications.
- Immunosuppression can rarely result in secondary malignancies.
