Cerebral Vasculitis

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

Synonyms

Primary angiitis of the central nervous system (PACNS)
Central nervous system angiitis
Cerebral arteritis

Epidemiology & Demographics

Incidence

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

Predominant Gender

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.

Peak Incidence

Fourth decade of life for PACNS

What increases the Risk of Cerebral Vasculitis

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.

Genetics

Multifactorial

Classification

•PACNS: Involvement of the blood vessels in brain or spinal cord without involvement of blood vessels and organs beyond the CNS
•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

Diagnostic Criteria for Primary Angiitis of the CNS

From Hajj-Ali RA, Calabrese LH: Diagnosis and classification of central nervous system vasculitis, J Autoimmun 48-49:149-152, 2014.

1.The presence of an acquired otherwise unexplained neurologic or psychiatric deficit

2.The presence of either classic angiographic or histopathologic features of angiitis within the CNS

3.No evidence of systemic vasculitis or any disorder that could cause or mimic the angiographic or pathologic features of the disease

CNS, Central nervous system.

Physical Findings & Clinical Presentation of Cerebral Vasculitis

•Presentation of cerebral vasculitis is diverse and includes the following:
- 1.Nonspecific symptoms such as insidious headache, weight loss, lethargy, personality changes, delirium, and even dementia.
- 2.Focal neurologic manifestations: Seen in 80% of patients during course of illness, may mimic multiple sclerosis, with a relapsing and remitting course.
- 3.Stroke can occur in 40% of patients; transient ischemic attacks have been reported in 30% to 50% of patients.
- 4.Seizures occur in 25% of patients.
- 5.Other common presentations include intracerebral hemorrhage (11%) and intracranial space-occupying lesions (15%).
•Secondary vasculitis often presents with strokelike symptoms. Sjögren syndrome and Behçet disease can have varied presentations that mimic multiple sclerosis, seizures, movement disorders, encephalopathy, dementia, and aseptic meningitis.

What causes Cerebral Vasculitis?

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.

Differential Diagnosis

•Reversible cerebral vasoconstriction syndrome (RCVS)
•Intracranial artery atherosclerosis
•Cerebral emboli of multiple etiologies
•Intravascular lymphoma
•Sarcoidosis
•Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
•Meningovascular syphilis
•Angioinvasive fungal infections
•Varicella zoster virus vasculopathy
•Tuberculosis meningitis vasculopathy

Differential Diagnosis of PACNS

From Hajj-Ali RA, Calabrese LH: Diagnosis and classification of central nervous system vasculitis, J Autoimmun 48-49:149-152, 2014.

Systemic vasculitides	Behçet syndrome, polyarteritis nodosa, granulomatosis with polyangiitis
Systemic inflammatory diseases	Systemic lupus erythematosus, Sjögren syndrome, Crohn disease, sarcoid granulomatosis, and angiitis
Infections	Viral (e.g., herpes zoster, HIV), bacterial (e.g., tuberculosis, syphilis, neuroborreliosis), fungal (e.g., aspergillosis, nocardiosis, Cryptococcus, histoplasmosis)
Conditions with cerebral angiographic abnormalities	Reversible cerebral vasoconstriction syndrome, premature intracranial atherosclerosis, fibromuscular dysplasia, moyamoya disease and syndrome, small-vessel arterial dissection, angiotropic and intervascular lymphoproliferative disorders, radiation vasculopathy
Brain diseases with MRI lesions that can mimic PACNS	Brain neoplasms (e.g., intravascular lymphoma, gliomatosis cerebri), genetic conditions (e.g., CADA-SIL, HERNS, COL4A1 mutation), posterior reversible encephalopathy syndrome, Susac syndrome, chronic hypertension (“microvascular cerebral ischemia”), demyelinating diseases (e.g., multiple sclerosis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy)
Miscellaneous	Hyperhomocystinemia, thrombocytic purpura, porphyria, antiphospholipid antibody syndrome, Kohlmeier-Degos
Conditions with multifocal cerebral thromboembolism	Atrial fibrillations and cholesterol atheroembolism, endocarditis, left atrial myxoma and other cardiac tumors

CADA-SIL, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; HERNS, hereditary endotheliopathy with retinopathy, nephropathy, and stroke; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging; PACNS, primary angiitis of the central nervous system.

Diagnostic Criteria for RCVS

From Hajj-Ali RA, Calabrese LH: Diagnosis and classification of central nervous system vasculitis, J Autoimmun 48-49:149-152, 2014.

1.Severe and acute headache (often thunderclap) with or without focal deficits or seizures

2.Direct or indirect angiography documenting multifocal segmental cerebral artery vasoconstriction

3.No evidence of aneurysmal subarachnoid hemorrhage

4.Normal or near-normal CSF (protein concentrations)

CSF, Cerebrospinal fluid; RCVS, reversible cerebral vasoconstriction syndrome.

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 dilation.

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 dilations, 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.

How is Cerebral Vasculitis diagnosed?

•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.
•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.
•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.
•Echocardiogram and cardiac telemetry should exclude cardioembolic sources such as atrial fibrillation, cardiac thrombus, and atrial myxoma.
•Consider screening for lymphoma in patients with PACNS, since both Hodgkin and non-Hodgkin 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.

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.

Differentiating Features between PACNS and RCVS

From Hajj-Ali RA, Calabrese LH: Diagnosis and classification of central nervous system vasculitis, J Autoimmun 48-49:149-152, 2014.

	PACNS	RCVS
Gender, mean age at onset	Male, 50 yr	Female, 42 yr
Headache	Insidious subacute onset	Acute onset, often thunderclap
Clinical course	Chronic, relapsing	Monophasic
CSF findings	Lymphocytic pleocytosis and elevated protein	Normal
MRI of brain	Abnormal in 100% ischemic, high-intensity T2/FLAIR lesions	Normal MRI in 20% ischemia, edema, cSAH, ICH
Cerebrovascular abnormalities	Frequently irreversible	Reversible
Histological findings on brain biopsy	Vasculitic changes	No vasculitic pattern

cSAH, Convexity subarachnoid hemorrhage; CSF, cerebrospinal fluid; FLAIR, fluid-attenuated inversion recovery; ICH, intracranial hemorrhage; MRI, magnetic resonance imaging; PACNS, primary angiitis of the central nervous system; RCVS, reversible cerebral vasoconstriction syndrome.

How is Cerebral Vasculitis treated?

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 Treatment

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 Treatment

•Steroids: Oral prednisone is continued at high dose (1 mg/kg/day) for 4 to 6 wk and then tapered slowly over 12 mo.
•Immunosuppressive treatment: Pulse intravenous cyclophosphamide or oral cyclophosphamide should be used in addition to steroids for 3 to 6 mo to induce remission. When stable, milder and relatively safer immunosuppressants such as azathioprine, methotrexate, or mycophenolate are used for 2 to 3 yr.

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

•Neurologic consultation is indicated in patients with neurologic deficits of uncertain etiology, younger age, intractable headaches, or uncertain diagnosis.
•Neurosurgery consultation for brain biopsy is indicated for definitive tissue-based diagnosis.
•Interventional neuroradiology consultation is indicated for four-vessel cerebral angiogram.
•Rheumatology consultation is indicated when either a systemic vasculitis or connective tissue disease is suspected.
•Infectious diseases consultation is recommended when infection is suspected.

Pearls & Considerations

•Cerebral vasculitis is a rare disorder that is difficult to diagnose because of variable presentation.
•Early recognition of the clinical symptoms and signs is important to prevent long-term morbidity and mortality.
•Systemic, infectious, and noninflammatory vasculopathic (like RCVS) causes should be excluded.
•Patients may need chronic immunosuppressive treatment.

Cerebral Vasculitis