When do I consider central nervous system (CNS) vasculitis as a differential diagnosis in patients with neurological symptoms?

CNS Vasculitis: Clinical Presentation and When to Consider as a Differential

When to Suspect CNS Vasculitis

Consider CNS vasculitis in patients presenting with ischemic or hemorrhagic stroke, recurrent stroke, stroke with encephalopathic changes, or stroke accompanied by fever, multifocal neurological events, unexplained skin lesions, glomerulopathy, or elevated sedimentation rate. 1, 2

Clinical Presentations That Should Trigger Consideration

Primary CNS Vasculitis (Small-Medium Vessel Disease)

• Headache is the most common initial symptom, followed by encephalopathy and behavioral changes 1
• Cognitive deficits affecting attention, visual memory, verbal memory, executive function, and psychomotor speed 3, 4
• Altered level of consciousness and encephalopathy are more characteristic of small vessel disease 4
• Seizures occur as presenting symptoms in a subset of patients 1, 2
• Focal neurological deficits occur in only 20-30% of patients with primary CNS vasculitis 1
• Intracranial hemorrhage may be the initial presentation 1
• Progressive course with small-vessel strokes developing over weeks to many months 1

Secondary CNS Vasculitis (Associated with Systemic Disease)

• Stroke in the context of systemic symptoms: fever, night sweats, fatigue, weight loss 2
• Multi-organ involvement: pulmonary hemorrhage (hemoptysis), rapidly declining renal function with hematuria and red cell casts, sinusitis, nasal crusting, epistaxis 2
• Peripheral neuropathy: mononeuritis multiplex or paresis of extremities 3, 2
• Skin manifestations: unexplained rashes or lesions 2

Giant Cell Arteritis (Large Vessel)

• New-onset persistent localized headache in the temporal area in patients >50 years 2
• Jaw or tongue claudication 2
• Acute visual symptoms: amaurosis fugax, visual loss, or diplopia (requires immediate evaluation) 2
• Constitutional symptoms with markedly elevated ESR 2

Key Clinical Scenarios for High Suspicion

Red Flag Combinations

• Young stroke patient (<50 years) with multifocal neurological events and no traditional vascular risk factors 4, 5
• Recurrent strokes of different ages on imaging without clear cardioembolic or atherosclerotic source 1
• Stroke with encephalopathy that cannot be explained by stroke location alone 2, 4
• Stroke with fever in the absence of infectious endocarditis 2
• Progressive cognitive decline with multiple small infarcts on MRI 3, 1
• Hemorrhagic stroke in a young patient without hypertension or vascular malformation 1

Systemic Disease Context

• Known systemic vasculitis (ANCA-associated vasculitis, polyarteritis nodosa) presenting with new neurological symptoms 3, 2
• Systemic lupus erythematosus with stroke, especially if antiphospholipid antibodies are present 3
• Hepatitis C infection with cryoglobulinemia and neurological symptoms 3
• Recent varicella zoster infection followed by stroke (VZV vasculitis) 3

Initial Diagnostic Markers That Support Consideration

Laboratory Findings

• Elevated ESR or CRP (though ESR is often normal or only minimally elevated in primary CNS vasculitis) 1, 2
• Positive ANCA (by both immunofluorescence and ELISA) in appropriate clinical context 1, 2
• Positive antiphospholipid antibodies in SLE patients with stroke 3
• Cryoglobulinemia in HCV-infected patients 3

CSF Analysis Findings

• Lymphocytic pleocytosis (rarely exceeding 250 cells/mm³) 1
• Elevated protein 1
• Increased opening pressure 1
• Note: CSF may be entirely normal in some cases of CNS vasculitis 1

Neuroimaging Clues

• Multiple infarcts of variable ages on MRI (present in up to 50% of CNS vasculitis cases) 1
• Mass lesions (5% of cases) 1
• Meningeal enhancement (8% of cases) 1
• Hemorrhage (9% of cases) 1
• MRI abnormalities are present in >90% of CNS vasculitis cases 1

Critical Differential Diagnoses to Exclude First

Common Mimics (More Common Than True Vasculitis)

• Reversible cerebral vasoconstriction syndrome (RCVS): acute-onset severe recurrent headaches with reversible vasoconstriction 4, 6
• Intracranial atherosclerosis: especially in patients with vascular risk factors 4, 7
• Antiphospholipid syndrome: thrombotic events without true vasculitis 3, 7
• Moyamoya disease: progressive stenosis of intracranial vessels 7
• Infectious causes: bacterial meningitis, neurosyphilis, VZV vasculitis 3
• CADASIL: genetic small vessel disease 7
• Multiple sclerosis: can mimic CNS vasculitis with multifocal lesions 7

Important caveat: In one large series, only 17% of patients referred for suspected CNS vasculitis actually had inflammatory vascular disease, with the majority having noninflammatory vasculopathies (42%), coagulopathies (18%), or other causes 7. This underscores the importance of thorough evaluation before initiating immunosuppressive therapy.

When NOT to Consider CNS Vasculitis as Primary Differential

• Isolated headache in SLE patients without high-risk features (fever, immunosuppression, focal signs, altered mental status, meningismus, or active SLE) requires no further investigation beyond standard headache evaluation 3
• Stroke with clear cardioembolic source (atrial fibrillation, recent MI, valvular disease) and no other vasculitis features 7
• Typical atherosclerotic stroke in elderly patients with multiple vascular risk factors and no inflammatory markers 7

Practical Approach for Neurology Trainees

Step 1: Pattern Recognition

• Identify if the presentation fits small vessel (encephalopathy, cognitive decline, seizures) versus medium vessel (focal deficits, discrete strokes) patterns 4

Step 2: Look for Inflammatory Markers

• Check for CSF pleocytosis/elevated protein, elevated ESR/CRP, vessel wall enhancement, or leptomeningeal enhancement 1, 4

Step 3: Assess for Systemic Disease

• Screen for systemic vasculitis symptoms (pulmonary, renal, ENT, skin involvement) 2
• Order ANCA testing if systemic features present 1, 2

Step 4: Rule Out Mimics

• Consider RCVS if thunderclap headaches with reversible vasoconstriction 6
• Evaluate for infectious causes (VZV, syphilis, bacterial) before immunosuppression 3
• Check for antiphospholipid antibodies in young stroke patients 3, 7

Step 5: Advanced Imaging

• Obtain MRI with contrast (abnormal in >90% of cases) 1
• Proceed to MRA or conventional angiography if medium vessel disease suspected 1
• Remember that normal angiography does not exclude small vessel vasculitis 1, 4

Step 6: Consider Biopsy

• Brain biopsy (cortical-leptomeningeal) is the most specific test for small vessel disease, ideally targeting abnormal areas on imaging 1
• A negative biopsy does not exclude vasculitis due to the focal nature of the disease 1

Critical Pitfall to Avoid

Never initiate "blind" immunosuppressive therapy without excluding infectious causes, as septic processes may be responsible for symptoms and immunosuppression could be catastrophic 7. Always ensure adequate workup including infectious evaluation before starting glucocorticoids and cyclophosphamide.