What is the recommended diagnostic work‑up and initial management for suspected central nervous system (CNS) vasculitis?

CNS Vasculitis: Diagnostic Work-Up and Initial Management

For suspected CNS vasculitis, begin with MRI brain with and without contrast as your initial imaging study, followed by laboratory evaluation including ANCA testing, ESR, and CSF analysis, with brain biopsy reserved for cases where diagnosis remains uncertain after noninvasive testing. 1

Clinical Recognition

Suspect CNS vasculitis in patients presenting with:

• Ischemic or hemorrhagic stroke, particularly recurrent stroke or stroke with encephalopathic changes 1, 2
• Headache followed by encephalopathy and behavioral changes (the most common presentation pattern) 3, 1
• Focal neurological deficits (occurring in only 20-30% of patients, contrary to common assumptions) 3, 1, 2
• Seizures or intracranial hemorrhage as presenting symptoms 1, 2
• Progressive course with small-vessel strokes developing over weeks to months 2
• Stroke accompanied by fever, multifocal neurological events, unexplained skin lesions, glomerulopathy, or elevated sedimentation rate 1, 2

Initial Imaging: MRI Brain

MRI brain with and without contrast is your first-line imaging modality, showing abnormalities in >90% of CNS vasculitis cases 1, 2:

• Multiple infarcts of variable ages (present in up to 50% of cases) 1, 2
• Mass lesions (5% of cases) 1, 2
• Meningeal enhancement (8% of cases) 1, 2
• Hemorrhage (9% of cases) 1, 2
• Include susceptibility-weighted imaging (SWI) to detect hemorrhages, which may be a sensitive marker 4

Laboratory Evaluation

Obtain the following tests systematically:

• ANCA testing using both indirect immunofluorescence AND ELISA (Level of evidence 1A, Grade A recommendation) 1
• Erythrocyte sedimentation rate (though characteristically normal or only minimally elevated in primary CNS vasculitis) 1, 2
• Cerebrospinal fluid analysis looking for:
  • Increased opening pressure 1
  • Elevated protein values 1
  • Lymphocytic pleocytosis (rarely exceeding 250 cells/mm³) 1
  • Oligoclonal bands (particularly in infectious and connective tissue disorder-associated vasculitis) 5
  • Low glucose levels (mostly in infectious vasculitis) 5

Critical pitfall: Normal ESR and other acute-phase reactants do NOT exclude primary CNS vasculitis 1. Do not be falsely reassured by normal inflammatory markers.

Vascular Imaging

After MRI brain, proceed to vascular imaging:

MRA Head (Preferred Noninvasive Option)

• Time-of-flight MRA is abnormal in 81% of patients with angiographic findings of vasculitis 1
• Noninvasive and radiation-free 3
• Major limitation: Limited specificity due to overlap with atherosclerosis and reversible cerebral vasoconstriction syndrome, and limited sensitivity for small vessel involvement 3, 1

Cerebral Angiography (DSA)

Reserve DSA for cases where noninvasive imaging is inconclusive 1:

• Remains the gold standard with submillimeter resolution 3, 1
• Shows characteristic arterial beading and alternating areas of constriction and dilatation 1
• Critical limitation: Low specificity with significant overlap with atherosclerosis and reversible cerebral vasoconstriction syndrome 3, 1
• Limited sensitivity as vascular involvement can be below angiography resolution 3, 1

CTA Head (Alternative)

• Can characterize intracranial vessel luminal characteristics 3, 1
• Limited resolution for distal small arteries 3

Do NOT use: CT head, CT perfusion, CTA neck, CTV head, or carotid ultrasound—no relevant literature supports their use in initial CNS vasculitis evaluation 3

Brain Biopsy

Proceed to cortical-leptomeningeal biopsy when diagnosis remains uncertain after noninvasive testing (Level of evidence 3, Grade C recommendation) 1:

• Most specific diagnostic test for diffuse or multifocal CNS vasculitis 1
• Target abnormal areas identified on MRI or angiography to increase diagnostic yield 1
• Critical caveat: Due to the focal nature of primary cerebral arteritis, a negative biopsy does NOT exclude the diagnosis 1
• In one cohort, biopsies confirmed vasculitis in 7 of 10 PACNS patients and 4 of 4 inflammatory CAA patients 5

Distinguishing Primary vs. Secondary CNS Vasculitis

Your workup must answer: Is this primary angiitis of the CNS or secondary to systemic disease? 6

Features Suggesting Secondary CNS Vasculitis:

• Known history of connective tissue disorder (all CTD-associated vasculitis patients in one cohort had known CTD at presentation) 5
• Fever (more common in infectious and CTD-associated vasculitis) 5
• Positive antiphospholipid antibodies in SLE patients 2
• Cryoglobulinemia in hepatitis C-infected patients 2
• Recent varicella zoster infection 2

Features Suggesting Inflammatory CAA:

• Older age compared to PACNS 5
• Microhemorrhages more common than in PACNS 5
• Higher relapse rates than PACNS 5

Diagnostic Algorithm Summary

1. Clinical assessment for characteristic presentation patterns 1, 2
2. MRI brain with and without contrast (including SWI) 1, 4
3. Laboratory testing: ANCA (both methods), ESR, CSF analysis 1
4. MRA head for noninvasive vascular evaluation 1
5. Cerebral angiography (DSA) if noninvasive imaging inconclusive 1
6. Brain biopsy (targeting abnormal areas) if diagnosis uncertain 1
7. Integrate all findings to establish primary vs. secondary diagnosis and guide treatment 1

Initial Management Considerations

Manage patients with primary small and medium vessel vasculitis in collaboration with or at centers of expertise (Level of evidence 3, Grade D recommendation) 1:

• Induction therapy: Glucocorticoids plus cyclophosphamide most commonly used 1, 6, 5
• Rituximab may be an alternative to cyclophosphamide 6
• All patients should receive maintenance immunosuppression based on available evidence 6
• Intravenous methylprednisolone was the predominant induction therapy (63.6% in one cohort) 5
• Maintenance options: Cyclophosphamide, rituximab, azathioprine, or mycophenolate mofetil, often with concurrent prednisone 5

Critical distinction: Some patients with transient/nonprogressive arteriopathies stabilize or improve without specific treatment, making accurate diagnosis essential before committing to aggressive immunosuppression 1