Overview

• Definition: Idiopathic vasculitis restricted to the CNS (brain and spinal cord parenchyma + leptomeninges)
• Epidemiology: Rare (~2.4 per 1,000,000 person-years); mean age 50; slight male predominance
• Pathology: Granulomatous, lymphocytic, or necrotizing inflammation of small and medium leptomeningeal/parenchymal vessels
• No systemic involvement by definition — if systemic vasculitis markers are positive, consider secondary causes

Clinical Presentation

• Triad: Headache + multifocal neurological deficits + cognitive decline
• Course: Progressive or relapsing-remitting over weeks to months
• Headache: Most common symptom (~60%); insidious, persistent, NOT thunderclap
• Cognitive dysfunction: ~50% — attention, memory, executive function
• Focal deficits: Hemiparesis, aphasia, ataxia, cranial neuropathies
• Seizures: ~15–25%
• Stroke: Multifocal ischemic and/or hemorrhagic events
• Systemic symptoms (fever, weight loss, rash, arthralgia) are typically absent — their presence suggests secondary vasculitis

Diagnostic Workup

Serum ESR/CRP

• Serum ESR/CRP are typically NORMAL in PACNS — unlike systemic vasculitides
• Elevated ESR/CRP should prompt search for secondary causes (GCA, ANCA-associated vasculitis, infection)

CSF Analysis

• Abnormal in ~90% of cases — this is a KEY differentiator from RCVS
• Lymphocytic pleocytosis (typically 10–150 cells/μL)
• Elevated protein (often 100–500 mg/dL)
• Glucose usually normal; oligoclonal bands may be present
• A completely normal CSF makes PACNS very unlikely

MRI Brain

• Abnormal in >90% but findings are nonspecific
• Multifocal white matter lesions, cortical/subcortical infarcts of varying ages
• Leptomeningeal or parenchymal enhancement
• Mass-like lesions (tumefactive variant — can mimic CNS lymphoma or glioma)
• May involve both cortex and deep white matter; bilateral but asymmetric

Conventional Angiography (DSA)

• “Beading” pattern: Alternating areas of stenosis and dilation in multiple vascular territories
• Sensitivity ~40–90% (variable, often low for small-vessel disease) — misses small-vessel disease (vessels <500 μm not visualized on angiography)
• Specificity is also limited — beading can be seen in RCVS, atherosclerosis, infection, radiation vasculopathy
• A normal angiogram does NOT rule out PACNS

Brain + Leptomeningeal Biopsy

• Gold standard for diagnosis
• Sensitivity ~50–75% (false negatives due to skip lesions and sampling error)
• Open biopsy of non-dominant temporal tip (leptomeninges + cortex + white matter)
• Target MRI-enhancing lesion if possible to increase yield
• Also excludes mimics: lymphoma, sarcoidosis, infection

Calabrese Diagnostic Criteria

• All 3 criteria must be met:
  1. Acquired neurological deficit unexplained by other causes
  2. Classic angiographic findings (beading) OR histopathologic evidence of CNS vasculitis on biopsy
  3. No evidence of systemic vasculitis or any condition that could mimic PACNS
• Important: Must exclude infections (VZV, syphilis, TB), drugs (cocaine), systemic autoimmune disease, and RCVS

Treatment

• Induction: Cyclophosphamide + high-dose glucocorticoids (IV pulse methylprednisolone 1 g/day × 3–5 days, then oral prednisone taper)
• Cyclophosphamide typically given as monthly IV pulses for 3–6 months
• Maintenance: Azathioprine or mycophenolate mofetil once remission achieved
• Duration: Maintenance therapy continued for ≥12–24 months; high relapse rate if stopped early
• Monitor for cyclophosphamide toxicity: hemorrhagic cystitis (use mesna), infection, bone marrow suppression, malignancy risk