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

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 only ~60% — 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 ~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

Overview

• Definition: Syndrome of reversible segmental vasoconstriction of cerebral arteries, presenting with thunderclap headaches
• Epidemiology: More common than PACNS; peak age 20–50; female predominance
• Key feature: All vasoconstriction resolves within 12 weeks (usually by 3 months)
• Previously called Call-Fleming syndrome, benign angiopathy of the CNS, postpartum angiopathy

Triggers

• Postpartum period (most classic association)
• Vasoactive drugs:
  • Triptans, ergotamine
  • SSRIs, SNRIs
  • Cannabis, cocaine, amphetamines, methamphetamine
  • Sympathomimetics (pseudoephedrine, phenylephrine)
  • Nasal decongestants
• Other triggers: Blood products/transfusion, catecholamine-secreting tumors (pheochromocytoma), eclampsia, surgical/anesthetic exposure
• ~25–60% of cases are idiopathic (no identifiable trigger)

Clinical Presentation

• Recurrent thunderclap headaches — sudden-onset, maximal-intensity (peak in seconds); occur over 1–3 weeks; often triggered by Valsalva, exertion, emotion, or bathing
• Headaches typically self-limited (each episode lasts minutes to hours)
• Focal neurological deficits may develop from complications (see below)
• Patients often appear well between headache episodes

Complications

• Convexity subarachnoid hemorrhage (SAH): Sulcal SAH over the convexities (NOT basal cisterns like aneurysmal SAH); occurs early (week 1)
• Intracerebral hemorrhage (ICH): Lobar hemorrhage; occurs early (week 1)
• Ischemic stroke: Watershed or territorial infarcts; occurs later (weeks 2–3, as vasoconstriction peaks)
• PRES (Posterior Reversible Encephalopathy Syndrome): Overlapping condition; ~10–40% of RCVS patients have concurrent PRES
• Temporal pattern: Hemorrhagic complications first (week 1) → ischemic complications later (weeks 2–3)

Diagnostic Workup

Treatment

• Remove the trigger (stop offending drug, manage postpartum state)
• Calcium channel blockers: Verapamil or nimodipine (most commonly used); empiric treatment for headache and vasoconstriction
• Supportive care: Analgesia, avoid Valsalva maneuvers, blood pressure management
• NO STEROIDS — glucocorticoids may worsen RCVS outcomes (associated with more complications in observational studies)
• NO immunosuppression (this is NOT an inflammatory vasculitis)
• Prognosis: Generally good; headaches resolve within weeks; vasoconstriction resolves by 3 months; ~5–10% may have residual deficits from stroke

Head-to-Head Comparison

Overview

• Large-vessel vasculitis affecting branches of the external carotid artery (especially temporal artery) and aorta
• Age: Almost exclusively ≥50 years (peak 70–80 years); rare before age 50
• Sex: Female:male ratio ~2–3:1
• Ethnicity: More common in Northern European descent
• Pathology: Granulomatous inflammation of the arterial wall with giant cells; intimal hyperplasia → stenosis → ischemia

Clinical Presentation

• Headache: New-onset, temporal, often severe; worsened by scalp contact (combing hair, wearing glasses)
• Scalp tenderness: Especially over the temporal artery
• Jaw claudication: Pain with chewing that resolves with rest — most specific symptom (~50% positive predictive value)
• Visual loss: The most feared complication
  • Anterior ischemic optic neuropathy (AION): Most common mechanism; pallid disc edema, altitudinal field cut
  • Central retinal artery occlusion (CRAO): Sudden, painless, monocular blindness
  • Posterior ischemic optic neuropathy: Less common
  • Visual loss occurs in ~15–20% and is often irreversible
  • Risk of bilateral involvement: Without treatment, ~50% of patients with unilateral visual loss develop contralateral involvement within days to weeks
• Temporal artery exam: Tender, thickened, nodular; absent or reduced pulse
• Constitutional symptoms: Fever, malaise, weight loss, fatigue
• Stroke: Vertebrobasilar > carotid territory (vertebral arteries involved in ~15%)

Association with Polymyalgia Rheumatica (PMR)

• ~40–60% of GCA patients have concurrent PMR
• ~15–20% of PMR patients develop GCA
• PMR features: bilateral shoulder/hip girdle pain and stiffness, morning stiffness >1 hour, elevated ESR/CRP
• PMR responds to low-dose steroids (10–20 mg prednisone); GCA requires high-dose steroids

Diagnostic Workup

Temporal Artery Biopsy Pearls

• Skip lesions: Inflammation is patchy → obtain adequate length (≥1–2 cm specimen); examine multiple sections
• Bilateral biopsy increases sensitivity by ~5–14% (consider if first side is negative)
• Biopsy can remain positive for 2–6 weeks after starting steroids — do NOT delay treatment while awaiting biopsy
• False-negative rate: ~10–15% even with adequate specimen

Treatment

• DO NOT wait for biopsy to start treatment — blindness is preventable but irreversible once it occurs
• Without visual symptoms: High-dose prednisone (1 mg/kg/day, typically 40–60 mg/day)
• With visual symptoms or impending visual loss: IV pulse methylprednisolone (1 g/day × 3 days) → then high-dose oral prednisone
• Steroid taper: Very slow over 12–24+ months; guided by symptoms and ESR/CRP; relapse is common during taper
• Tocilizumab (IL-6 receptor inhibitor): FDA-approved for GCA; steroid-sparing agent; GiACTA trial showed superior sustained remission with tocilizumab + 6-month prednisone taper vs. prednisone alone
• Low-dose aspirin: Recommended to reduce ischemic complications (visual loss, stroke)
• Methotrexate: May have modest steroid-sparing benefit (conflicting evidence)

Overview

• Large-vessel vasculitis affecting the aorta and its major branches (subclavian, carotid, vertebral, renal arteries)
• Age: Typically <40 years (peak onset 15–30 years)
• Sex: Female:male ratio ~9:1
• Ethnicity: Higher prevalence in Asia, but occurs worldwide
• Pathology: Granulomatous inflammation of the arterial wall → stenosis, occlusion, or aneurysm formation

Clinical Features

• “Pulseless disease”: Diminished or absent pulses in upper extremities; discrepant blood pressures between arms (>10 mmHg difference)
• Limb claudication: Upper extremity > lower extremity
• Neurological involvement:
  • Stroke/TIA: From carotid or vertebral artery stenosis/occlusion
  • Syncope, dizziness, visual disturbance (vertebrobasilar insufficiency)
  • Headache
• Constitutional symptoms: Fever, malaise, weight loss, arthralgias (especially in early inflammatory phase)
• Hypertension: From renal artery stenosis
• Aortic regurgitation: From aortic root dilation
• Carotid/subclavian bruits

Diagnosis

• CTA or MRA: First-line imaging; shows vessel wall thickening, stenosis, occlusion, or aneurysms of the aorta and branches
• PET/CT: Can detect vessel wall inflammation before stenosis develops (active disease)
• ESR/CRP: Elevated during active phase but may be normal in “burned out” disease
• DSA: Classic “rat-tail” tapering of involved arteries; now largely replaced by CTA/MRA for diagnosis

Treatment

• Glucocorticoids (mainstay for active disease); prednisone 1 mg/kg/day with slow taper
• Steroid-sparing agents: Methotrexate, azathioprine, mycophenolate, tocilizumab
• Vascular intervention: Angioplasty/stenting or bypass surgery for critical stenosis; ideally during disease quiescence

Overview

• Medium-vessel vasculitis with necrotizing inflammation; does NOT involve venules or small vessels
• Age: 40–60 years; male:female ratio ~1.5:1
• Key association: Hepatitis B (HBsAg-positive in ~30% of classic PAN)
• Incidence has declined due to widespread Hepatitis B vaccination

Clinical Features

• Peripheral nervous system >> CNS — PAN predominantly affects peripheral nerves, NOT the brain
• Mononeuritis multiplex: Most characteristic neurological feature (~50–70%); asymmetric involvement of individual named nerves (e.g., foot drop from peroneal nerve, wrist drop from radial nerve)
• Renal involvement: Renal artery vasculitis → renovascular hypertension, renal infarcts; NO glomerulonephritis (this distinguishes PAN from ANCA-associated vasculitis)
• Skin: Livedo reticularis, subcutaneous nodules, ulcers, digital ischemia
• GI: Mesenteric ischemia (abdominal pain, GI bleeding, bowel infarction)
• Musculoskeletal: Myalgias, arthralgias
• Testicular pain: Present in ~25% of males (testicular artery involvement)
• CNS involvement: Uncommon but can include stroke from medium-vessel vasculitis

Diagnosis

• ANCA: Negative (PAN is NOT an ANCA-associated vasculitis — this is a critical distinction)
• Hepatitis B serology: Check in all cases
• Angiography (mesenteric or renal): Microaneurysms at vessel branch points — classic finding; also shows stenosis and occlusions
• Biopsy: Necrotizing vasculitis of medium arteries with fibrinoid necrosis; inflammation of vessel wall in different stages (acute and healed lesions)
• ESR/CRP: Elevated; leukocytosis, anemia, thrombocytosis

Treatment

• Non-HBV PAN: Glucocorticoids ± cyclophosphamide (for severe/life-threatening disease)
• HBV-associated PAN: Short course of steroids + antiviral therapy (entecavir or tenofovir) + plasma exchange; prolonged immunosuppression is avoided (risk of HBV reactivation)

Overview

• Small-vessel vasculitis group associated with antineutrophil cytoplasmic antibodies (ANCA)
• Three main subtypes: GPA (Wegener), MPA, EGPA (Churg-Strauss)
• All can cause glomerulonephritis (unlike PAN)
• Pauci-immune glomerulonephritis on renal biopsy (minimal immune complex deposition)

ANCA Types

Granulomatosis with Polyangiitis (GPA, formerly Wegener)

• ANCA: c-ANCA/PR3 (~90%)
• Classic triad: Upper airway + lower airway + kidney
  • Sinopulmonary: Chronic sinusitis, nasal crusting, epistaxis, saddle nose deformity, subglottic stenosis
  • Pulmonary: Nodules, cavitary lesions, alveolar hemorrhage
  • Renal: Rapidly progressive glomerulonephritis (RPGN) with crescents
• Neurological manifestations (~30–50%):
  • Cranial neuropathies: CN II (optic neuritis), CN VI, CN VII most common
  • Peripheral neuropathy: Mononeuritis multiplex or distal symmetric
  • Pachymeningitis: Thickening of the dura; headache, cranial neuropathies
  • CNS vasculitis: Rare; cerebral infarcts
  • Orbital pseudotumor: Proptosis, orbital pain from granulomatous mass
• Pathology: Necrotizing granulomatous vasculitis

Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

• ANCA: p-ANCA/MPO in ~40–60% (less consistently positive than GPA)
• Classic features:
  • Asthma (present in >95%; typically adult-onset, severe)
  • Eosinophilia (≥1,500/μL or ≥10% of WBC)
  • Peripheral neuropathy (~70%; mononeuritis multiplex is most common neurological feature)
• Three phases:
  1. Prodromal: Allergic rhinitis, asthma, nasal polyps (years before vasculitis)
  2. Eosinophilic: Peripheral eosinophilia, eosinophilic organ infiltration (lungs, GI)
  3. Vasculitic: Small-vessel vasculitis with systemic involvement
• Cardiac involvement: Most common cause of death (eosinophilic myocarditis, pericarditis)
• Pathology: Eosinophilic infiltration + granulomatous inflammation + necrotizing vasculitis

Microscopic Polyangiitis (MPA)

• ANCA: p-ANCA/MPO (~70%)
• Small-vessel vasculitis without granulomas (distinguishes from GPA and EGPA)
• Key features:
  • Rapidly progressive glomerulonephritis (most prominent feature)
  • Pulmonary-renal syndrome: Alveolar hemorrhage + RPGN (overlap with Goodpasture)
  • Peripheral neuropathy: Mononeuritis multiplex; distal sensorimotor neuropathy
  • CNS involvement is rare
• Pathology: Necrotizing vasculitis without granulomas; pauci-immune GN

Comparison Table

Treatment of ANCA-Associated Vasculitis

• Induction (severe/organ-threatening): Cyclophosphamide or rituximab + high-dose glucocorticoids
• RAVE trial: Rituximab non-inferior to cyclophosphamide for induction of remission in ANCA vasculitis; rituximab superior for relapsing disease
• Maintenance: Rituximab (preferred) or azathioprine; continue for ≥18–24 months
• Plasma exchange (PLEX): Consider in pulmonary-renal syndrome or severe renal failure (Cr >5.7 mg/dL); PEXIVAS trial showed no long-term benefit on death/ESRD but may be used acutely
• Mepolizumab: Anti-IL-5; FDA-approved for relapsing/refractory EGPA
• Avacopan: Complement C5a receptor inhibitor; approved as adjunctive therapy for GPA/MPA (ADVOCATE trial — steroid-sparing)

Infectious Causes

Drug-Induced Vasculopathy

• Cocaine: Vasospasm ± vasculitis; ischemic and hemorrhagic stroke; may trigger RCVS
• Amphetamines/methamphetamine: Small and medium vessel vasculitis/vasospasm; can cause necrotizing vasculitis on biopsy
• Mechanism: Sympathomimetic surges → vasoconstriction → vessel wall injury → true vasculitis or vasospasm

Systemic Autoimmune Causes

Chapel Hill Consensus Classification

When to Suspect CNS Vasculitis

• Unexplained multifocal neurological deficits (especially in a young patient)
• Recurrent strokes in multiple vascular territories without conventional risk factors
• Headache + cognitive decline + focal deficits (progressive)
• Ischemic stroke with evidence of systemic inflammation or known autoimmune disease
• Abnormal inflammatory CSF in a patient with stroke or white matter lesions
• Beading on angiography in the appropriate clinical context

Diagnostic Workup Algorithm

Key Decision Points

• Thunderclap headache + normal CSF + beading → RCVS (follow-up angiography at 3 months to confirm resolution)
• Progressive deficits + abnormal CSF + beading → PACNS (proceed to biopsy for confirmation)
• Age >50 + headache + elevated ESR/CRP + jaw claudication → GCA (start steroids immediately; temporal artery biopsy)
• Multisystem involvement + ANCA positive → ANCA-associated vasculitis (PR3 → GPA; MPO → MPA or EGPA)
• Mononeuritis multiplex + Hep B + microaneurysms + ANCA negative → PAN
• Young woman + pulseless + discrepant arm BPs → Takayasu