Central Nervous System Involvement in ANCA-Associated Vasculitis: What Neurologists Need to Know

Abstract

Objective: To provide a comprehensive review of the central nervous system (CNS) involvement in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including the pathogenesis, clinical manifestations, ancillary investigations, differential diagnosis, and treatment. Particular emphasis is placed on the clinical spectrum and diagnostic testing of AAV. Recent Findings: AAV is a pauci-immune small-vessel vasculitis characterized by neutrophil-mediated vasculitis and granulomatousis. Hypertrophic pachymeninges is the most frequent CNS presentation. Cerebrovascular events, hypophysitis, posterior reversible encephalopathy syndrome (PRES) or isolated mass lesions may occur as well. Spinal cord is rarely involved. In addition, ear, nose and throat (ENT), kidney and lung involvement often accompany or precede the CNS manifestations. Positive ANCA testing is highly suggestive of the diagnosis, with each ANCA serotype representing different groups of AAV patients. Pathological evidence is the gold standard but not necessary. Once diagnosed, prompt initiation of induction therapy, including steroid and other immunosuppressants, can greatly mitigate the disease progression. Conclusions and Relevance: Early recognition of AAV as the underlying cause for various CNS disorders is important for neurologists. Ancillary investigations especially the ANCA testing can provide useful information for diagnosis. Future studies are needed to better delineate the clinical spectrum of CNS involvement in AAV and the utility of ANCA serotype to classify those patients. Evidence Review: We searched Pubmed for relevant case reports, case series, original research and reviews in English published between Sep 1st, 2001 and Sep 1st, 2018. The following search terms were used alone or in various combinations: "ANCA," "proteinase 3/PR3-ANCA," "myeloperoxidase/MPO-ANCA," "ANCA-associated vasculitis," "Wegener's granulomatosis," "microscopic polyangiitis," "Central nervous system," "brain" and "spinal cord". All articles identified were full-text papers.

Keywords: anti-neutrophil cytoplasmic antibodies; central nervous system; granulomatosis with polyangiitis; microscopic polyangiitis; vasculitis.

Figure 1

Pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). The left side of the diagram (with blue background) represents the blood stream and the right (with orange background) the interstitial tissue, separated by a line of endothelial cells. ANCAs are autoantibodies directed against proteins in the cytoplasmic granules of neutrophils. The two antigenic targets are proteinase 3 (PR3) and myeloperoxidase (MPO) normally expressed on the surface or inside the cytoplasm of resting neutrophils (11, 12). The interplay among genetic, environmental, and immunological factors contributes to the high membrane expression and release of PR3 and MPO, leading to the production and proliferation of pathogenic ANCAs. Primed neutrophils are activated by ANCAs and transmigrate the vessel wall, undergoing respiratory bursts, degranulation, and neutrophil extracellular traps (NETs) generation (11), which are further augmented by the alternative complement pathway (13). The neutrophil-mediated processes are the major contributor to the injury and inflammation of the endothelial cells lining the vascular wall in the early phase (14). Monocytes are subsequently recruited at sites of acute inflammation and necrosis, inducing the development of granulomatous inflammation mainly mediated by an exaggerated monocyte/macrophage reaction (11). Potential treatment targets are illustrated by red arrows in the figure, including the T-cell and B-cell dysregulation, environmental triggers (microbes, drugs), aberrant activation of alternative complement pathway and NETs. ANCA, anti-neutrophil cytoplasmic antibody; MPO, myeloperoxidase; PR3, proteinase 3; NET, neutrophil extracellular trap.

Figure 2

Treatment algorithm for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) with central nervous system (CNS) involvement. The algorithm is formulated and terms are defined according to the 2016 European league Against Rheumatism (EULAR)/European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recommendations (61). For AAV with CNS involvement, the remission-induction therapy mainly consists of high-dose steroids and cyclophosphamide (CYC), or rituximab (RTX) for CYC-intolerant patients. Plasma exchange should be considered for those with a serum creatine level of ≥500 μmol/L or diffuse alveolar hemorrhage. Once complete remission is achieved, patients should be switched to the maintenance regimen. A combination of low-dose steroid and an oral immunosuppressive agent including azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF) or RTX is used for at least 24 months (61). For patients refractory to the remission-induction therapy, referral to experts for reevaluation and treatment optimization is warranted (61). Severe relapses with organ- or life-threatening conditions are treated as per new disease, while non-severe relapses are managed with modification of the previous immunosuppressive regimen (61). ^aAAV with severe renal impairment or diffuse alveolar hemorrhage; ^bDrugs are listed in order of the strength of vote. AAV, anti-neutrophil cytoplasmic antibody-associated vasculitides; ANCA, anti-neutrophil cytoplasmic antibodies; AZA, azathioprine; CNS, central nervous system; CYC, cyclophosphamide; MTX, methotrexate; MMF, mycophenolate mofetil; PLEX, plasma exchange; RTX, rituximab.