Cerebral Vasculitis

• Chloe Mander Nunneley, M.D.
• Joseph S. Kass, M.D., J.D

 Basic Information

Definition

Cerebral vasculitis refers to a group of heterogeneous disorders characterized by pathologic inflammation and leukocytoclastic changes in the blood vessel walls.

Synonyms

1. Primary angiitis of the central nervous system (PACNS)

2. Central nervous system angiitis

3. Cerebral arteritis

Epidemiology & Demographics

Incidence

2.4 cases per 1,000,000 person-yr for PACNS

Peak Incidence

Fourth decade of life for PACNS

Predominant Sex

Males are affected twice as often as females by PACNS. For secondary vasculitis of the CNS, sex predominance varies by underlying autoimmune condition.

Predominant Age

Usual age of presentation of PACNS is in the third and fourth decades of life, but it can present in age ranging from 17 to 70 yr.

Genetics

Multifactorial

Risk Factors

Infections, connective tissue disorders, systemic vasculitis, and substance abuse are the prominent risk factors for secondary cerebral vasculitis. No risk factors have been clearly established for PACNS.

Classification

1. •

   PACNS (see Table E1 for full diagnostic criteria): involvement of the blood vessels in brain or spinal cord without involvement of blood vessels and organs beyond the CNS.

2. •

   Secondary CNS vasculitis: involvement of the brain or spinal cord blood vessels by a systemic disorder such as systemic vasculitis, connective tissue disorders, infections, malignancy, or substance abuse.

Physical Findings & Clinical Presentation

1. •

   Presentation of cerebral vasculitis is diverse and includes the following:

   1. 1.

      Nonspecific symptoms such as insidious headache, weight loss, lethargy, personality changes, delirium, and even dementia.

   2. 2.

      Focal neurologic manifestations: seen in 80% of patients during course of illness, may mimic multiple sclerosis, with a relapsing and remitting course.

   3. 3.

      Stroke can occur in 40% of the patients; transient ischemic attacks have been reported in 30% to 50% of patients.

   4. 4.

      Seizures occur in 25% of patients.

   5. 5.

      Other common presentations include intracerebral hemorrhage (11%) and intracranial space-occupying lesions (15%).

2. •

   Secondary vasculitis often presents with stroke-like symptoms. Sjögren’s syndrome and Behçet’s disease can have varied presentations that mimic multiple sclerosis, seizures, movement disorders, encephalopathy, dementia, and aseptic meningitis.

Etiology

The exact etiology of primary cerebral vasculitis is unknown. It has been associated with various infectious agents such as herpes zoster, mycoplasma, HIV, and unknown viruses. Amyloid angiopathy has been described with primary cerebral vasculitis.

Diagnosis

Differential Diagnosis (See Table E2 for complete differential diagnosis)

1. •

   Reversible cerebral vasoconstriction syndrome (RCVS) (see Table E3 for full diagnostic criteria)

2. •

   Intracranial artery atherosclerosis

3. •

   Cerebral emboli of multiple etiologies

4. •

   Intravascular lymphoma

5. •

   Sarcoidosis

6. •

   Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

7. •

   Meningovascular syphilis

8. •

   Angioinvasive fungal infections

9. •

   Varicella zoster virus vasculopathy

10. •

    Tuberculosis meningitis vasculopathy

Workup

Brain biopsy (lesional area on MRI preferred but if not surgically feasible, then usually nondominant temporal lobe tip along with overlying leptomeninges) is the gold standard diagnostic method and is required for definitive diagnosis. Vessel histology may be granulomatous, lymphocytic, or necrotizing and will reveal vessel wall damage.

A brain MRI with and without contrast has a sensitivity approaching 100%, although it has a very low specificity. Thus, a normal brain MRI virtually excludes the diagnosis of cerebral vasculitis. The most common lesions are ischemic strokes, occurring in 53% of cases. Strokes are often multiple and bilateral, affecting different vascular territories of variable sizes and in various stages of evolution; they can involve the cortex, subcortical areas, and leptomeninges. High-intensity T2-weighted subcortical lesions are very common but not specific. Mass lesions are seen in 5%, meningeal enhancement in 8%, and intracranial hemorrhages in 9% of cases.

Cerebral angiography, either by direct four-vessel angiography or by indirect magnetic resonance or CT angiography, may show beading: diffuse, bilateral, and alternating areas of stenosis and dilatation. This finding may indicate vasculitis, but it is not specific for vasculitis. Other nonspecific angiographic findings in CNS vasculitis include tapering of the lumen of a single vessel or many vessels and fusiform arterial dilatations, multifocal vascular occlusions, development of collateral circulation, or delayed contrast-medium enhancement and washout time. Furthermore, the resolution of angiography further limits its sensitivity in that it does not capture morphologic changes in small arteries and arterioles, so a cerebral vasculitis limited to these small-caliber vessels will be normal on angiography (Fig. E1).

Laboratory Tests

1. •

   Lumbar puncture: Cerebrospinal fluid (CSF) should show elevated protein, lymphocytic pleocytosis, and negative microbial cultures. Opening pressure may be elevated. Consider obtaining CSF cytology and flow cytometry.

2. •

   Basic laboratory testing: should include CBC with differential, blood urea nitrogen and serum creatinine, hepatic functions and enzymes, erythrocyte sedimentation rate (ESR), RPR (for syphilis), HIV, C-reactive protein (CRP), and urinalysis with microscopy to look for signs of renal vasculitis. ESR and CRP are typically normal in PACNS.

3. •

   Specific serologic tests to evaluate for systemic autoimmune causes: ANA, rheumatoid factor, anti–double-stranded DNA, anti SS-A, anti SS-B, anti–neutrophil cytoplasmic antibodies (both c-ANCA and p-ANCA), complement 3 and 4, cryoglobulins, and testing for HIV, hepatitis B (associated with polyarteritis nodosa), and hepatitis C (associated with mixed cryoglobulinemia). Markers of systemic autoimmune diseases are typically negative in PACNS.

4. •

   Echocardiogram and cardiac telemetry should exclude cardioembolic sources such as atrial fibrillation, cardiac thrombus, and atrial myxoma.

5. •

   Consider screening for lymphoma in patients with PACNS, since both Hodgkin’s and non-Hodgkin’s lymphoma have an association with PACNS.

Imaging Studies

Brain MRI with and without contrast is the neuroimaging of choice. Abnormal findings are seen in virtually 100% of the patients. Cerebral cortex and deep white and gray matter changes are commonly reported (Fig. E2). Angiography has poor sensitivity at detecting small vessel changes. Many patients, in fact, have a normal angiogram, and a vasculopathic appearance of intracerebral vessels on a four-vessel cerebral angiogram does not by itself distinguish an inflammatory vasculitis from a noninflammatory vasculopathy like RCVS (see Table E3 for RCVS diagnostic criteria and Table E4 for features distinguishing PACNS and RCVS).

Treatment

There are no randomized controlled trials evaluating treatment of cerebral vasculitis. Treatment strategies are similar to those for systemic vasculitis.

Nonpharmacologic Therapy

Patients with permanent deficits are provided with physical and occupational therapy.

Acute General Rx

1. •

   Steroids: For suspected cases, empiric therapy with glucocorticoids is started after exclusion of infectious causes. Intravenous methylprednisolone 1 g daily for 3 days is preferred, followed by oral therapy for chronic therapy.

Chronic Rx

1. •

   Steroids: Oral prednisone is continued at high dose (1 mg/kg/day) for 4 to 6 weeks and then tapered slowly over 12 months.

2. •

   Immunosuppressive treatment: Pulse intravenous cyclophosphamide or oral cyclophosphamide should be used in addition to steroids for 3 to 6 months to induce remission. When stable, milder and relatively safer immunosuppressants such as azathioprine, methotrexate, or mycophenolate are used for 2 to 3 years.

Disposition

Course and prognosis of the disease are variable and depend on the extent of neurologic involvement, severity of deficits, and response to treatment. Neurologic deficits may resolve acutely, slowly, or not at all. Some patients have symptomatic improvement with resolution of headache or altered mental status. Some have improvement in laboratory values, and others have improved MRI scans.

Referral

1. •

   Neurologic consultation is indicated in patients with neurologic deficits of uncertain etiology, younger age, intractable headaches, or uncertain diagnosis.

2. •

   Neurosurgery consultation for brain biopsy is indicated for definitive tissue-based diagnosis.

3. •

   Interventional neuroradiology consultation is indicated for four-vessel cerebral angiogram.

4. •

   Rheumatology consultation is indicated when either a systemic vasculitis or connective tissue disease is suspected.

5. •

   Infectious diseases consultation is recommended when infection is suspected.

Pearls & Considerations

Comments

1. •

   Cerebral vasculitis is a rare disorder that is difficult to diagnose because of variable presentation.

2. •

   Early recognition of the clinical symptoms and signs is important to prevent long-term morbidity and mortality.

3. •

   Systemic, infectious, and noninflammatory vasculopathic (like RCVS) causes should be excluded.

4. •

   Patients may need chronic immunosuppressive treatment.

Suggested Readings

• H. de Boysson, et al.: Primary angiitis of the central nervous system: description of the first fifty-two adults enrolled in the French cohort of patients with primary vasculitis of the central nervous system. Arthritis Rheumatol. 66:1315–1326 2014 24782189

• R.A. Hajj-Ali, L.H. Calabrese: Diagnosis and classification of central nervous system vasculitis. J Autoimmun. 48-49:149–152 2014 24491822

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