CNS Vasculitis

Central nervous system (CNS) vasculitis encompasses a group of disorders characterized by inflammation and destruction of blood vessel walls within the brain and/or spinal cord, leading to vessel wall damage, stenosis, occlusion, and/or aneurysm formation with consequent ischemic or hemorrhagic injury to the nervous system. The most important entity in this group is primary angiitis of the central nervous system (PACNS), an idiopathic inflammatory disease confined exclusively to the CNS vasculature without systemic involvement. PACNS accounts for approximately 1% of all systemic vasculitides and has an incidence of approximately 2.4 per 1,000,000 person-years. CNS vasculitis can also occur secondary to systemic vasculitides (polyarteritis nodosa, granulomatosis with polyangiitis/GPA, eosinophilic granulomatosis with polyangiitis/EGPA, microscopic polyangiitis, Behcet disease, giant cell arteritis), systemic autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis), infections (varicella-zoster virus is the most common infectious cause, HIV, syphilis, tuberculosis, fungal infections), drugs (cocaine, amphetamines), and malignancy (lymphomatoid granulomatosis, intravascular lymphoma). The pathogenesis of PACNS involves immune-mediated inflammation of the walls of small and medium-sized leptomeningeal and parenchymal arteries. The inflammatory infiltrate is predominantly composed of lymphocytes (CD4+ T cells predominate) and macrophages, with granulomatous inflammation being the most common histological pattern (approximately 50% of cases show well-formed granulomas with multinucleated giant cells in the vessel wall, similar to giant cell arteritis but affecting smaller vessels and without temporal artery involvement). Lymphocytic vasculitis (approximately 30% of cases) shows a predominantly lymphocytic infiltrate without granuloma formation. Necrotizing vasculitis (approximately 15%) shows fibrinoid necrosis of the vessel wall similar to polyarteritis nodosa. The inflammatory process targets the media and adventitia of affected vessels, causing concentric intimal fibroproliferation (progressive narrowing of the vessel lumen), thrombosis (inflammatory endothelial activation promotes local coagulation), and weakening of the vessel wall (destruction of the elastic lamina can lead to microaneurysm formation). These pathological changes produce the clinical manifestations through two primary mechanisms: (1) ischemic injury from progressive vessel stenosis and thrombotic occlusion, producing multifocal ischemic strokes or transient ischemic attacks in various vascular territories (the hallmark of CNS vasculitis is MULTIFOCAL neurological deficits that cannot be explained by a single vascular territory); and (2) hemorrhagic injury from vessel wall rupture at sites of inflammatory weakening (intracerebral hemorrhage, subarachnoid hemorrhage). The clinical presentation of PACNS is notoriously variable and non-specific, making diagnosis extremely challenging. The most common presenting symptoms include headache (60-80%, typically chronic, progressive, and often severe -- may be thunderclap headache mimicking subarachnoid hemorrhage), cognitive dysfunction (50-70%, ranging from subtle executive dysfunction to severe dementia -- reflecting diffuse cortical microvascular ischemia), focal neurological deficits (40-50%, hemiparesis, aphasia, visual field deficits -- from territorial infarctions), stroke or TIA (30-40%, often in multiple vascular territories -- the multifocal, multi-territory pattern is the clinical hallmark), and seizures (15-30%). Constitutional symptoms such as fever and weight loss are notably ABSENT in PACNS (their presence should prompt evaluation for secondary CNS vasculitis from systemic disease). The diagnosis of PACNS requires a high index of clinical suspicion because no single test is pathognomonic. The diagnostic workup proceeds through several levels. Conventional cerebral angiography (catheter-based DSA) has been the traditional gold standard imaging study, showing characteristic findings of alternating areas of stenosis and dilation (beading pattern) in multiple intracranial vessels. However, angiography has significant limitations: sensitivity is only 50-60% for PACNS because it primarily detects medium-vessel disease and cannot visualize small vessel inflammation (<200 micrometers); the beading pattern is non-specific and can be seen in other conditions including reversible cerebral vasoconstriction syndrome (RCVS -- the most important clinical mimic), atherosclerosis, and intracranial infection. High-resolution vessel wall MRI (HR-VW-MRI) is an emerging technology that can directly visualize vessel wall inflammation (concentric wall thickening and enhancement in vasculitis versus eccentric enhancement in atherosclerosis), potentially improving diagnostic accuracy. Brain and leptomeningeal biopsy remains the gold standard for definitive diagnosis, with sensitivity of approximately 50-75% (false-negative biopsies occur because the disease may be patchy and the biopsy may miss affected areas). Biopsy should include both brain parenchyma and overlying leptomeninges. CSF analysis is abnormal in 80-90% of PACNS cases, typically showing mild lymphocytic pleocytosis (10-100 cells), elevated protein, and normal glucose -- a completely normal CSF makes PACNS unlikely and should prompt reconsideration of the diagnosis (particularly RCVS, which characteristically has normal CSF). Treatment of PACNS requires aggressive immunosuppression. Induction therapy consists of high-dose corticosteroids (IV methylprednisolone 1 g/day for 3-5 days followed by oral prednisone 1 mg/kg/day) combined with cyclophosphamide for severe disease (particularly granulomatous PACNS or disease with large vessel involvement). Maintenance therapy uses steroid-sparing agents (mycophenolate mofetil or azathioprine) with gradual corticosteroid taper over 6-12 months. The total treatment duration is typically 12-24 months, with monitoring for relapse by serial neurological examination, MRI, and CSF analysis. Distinguishing PACNS from RCVS is one of the most critical clinical challenges. RCVS presents with thunderclap headaches (sudden, severe, peaking within 60 seconds), is triggered by specific precipitants (vasoactive drugs, postpartum state, sexual activity), has NORMAL CSF, and shows diffuse vasoconstriction on angiography that REVERSES within 12 weeks. PACNS has insidious chronic headache (not thunderclap), ABNORMAL CSF, and shows focal beading that does NOT reverse. Misdiagnosing RCVS as PACNS leads to unnecessary immunosuppression, while missing PACNS leads to progressive neurological deterioration.