Inflammatory disorders that affect the cerebral small vessels

Abstract

This comprehensive review synthesizes the latest advancements in understanding inflammatory disorders affecting cerebral small vessels, a distinct yet understudied category within cerebral small vessel diseases (SVD). Unlike classical SVD, these inflammatory conditions exhibit unique clinical presentations, imaging patterns, and pathophysiological mechanisms, posing significant diagnostic and therapeutic challenges. Highlighting their heterogeneity, this review spans primary angiitis of the central nervous system, cerebral amyloid angiopathy-related inflammation, systemic vasculitis, secondary vasculitis, and vasculitis in autoinflammatory diseases. Key discussions focus on emerging insights into immune-mediated processes, neuroimaging characteristics, and histopathological distinctions. Furthermore, this review underscores the importance of standardized diagnostic frameworks, individualized immunomodulation approaches, and novel targeted therapies to address unmet clinical demands.

Keywords: Cerebral small vessels; Diagnosis; Immunology; Inflammation; Pathogenesis; Therapy; Vasculitis.

Figure 1

Inflammatory disorders that affect the cerebral small vessels. (A) Inflammatory disorders that affect the small vessels restricted to central nervous system. (B) Systemic vasculitis involving the cerebral small vessels. (C) Secondary vasculitis involving the cerebral small vessels. (D) Vasculitis in autoinflammatory diseases. ABRA: Amyloid-β-related angiitis; ADA2: Adenosine deaminase 2; ANCA: Antineutrophil cytoplasmic antibody; CAA: Cerebral amyloid angiopathy; CNS: Central nervous system; CTDs: Connective tissue diseases; EGPA: Eosinophilic granulomatosis with polyangiitis; ER: endoplasmic reticulum; GPA: Granulomatosis with polyangiitis; ICAA: Inflammatory CAA; IL: Interleukin; IKKy: Inhibitor of kappa B kinase γ; MPA: Microscopic polyangiitis; MPO: Myeloperoxidase; NET: Neutrophil extracellular trap; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; OTULIN: OTU deubiquitinase with linear linkage specificity; PACNS: primary angiitis of central nervous system; PR3: Proteinase 3; ROS: Reactive oxygen species; TNFα: Tumor necrosis factor α; TNFR: TNF receptor; TRAF: TNF-receptor associated factor.

Figure 2

Small-vessel primary angiitis of the central nervous system. A 27-year-old female was assessed at Peking Union Medical College Hospital for right-hand clumsiness and speech difficulties for 6 months. Blood tests showed a normal erythrocyte sedimentation rate and high-sensitive C-reactive protein. Her rheumatological workup did not suggest any systemic vasculitis or autoimmune disease. Her CSF was notable for raised concentrations of white blood cells, with a negative pathogen microorganism test. Axial sections of brain MRI demonstrated lesions in the left basal ganglia, the subcortical and deep white matter of the left frontal lobe with perilesional edema (arrows) (A, B). Post-enhancement studies showed multiple nodular and patchy enhancements (arrows) (C). Brain biopsy was undertaken and revealed lymphocytic vasculitis affecting cerebral small vessels (arrow), with segmental necrosis (H&E ×200) (D). Immunohistochemistry showed infiltration of CD3-positive T lymphocytes (arrow) (original magnification ×100) (E). The patient was treated with corticosteroids and cyclophosphamide. Follow-up MRI four months after treatment showed resolution of the lesions (F–H). CD: Cluster of differentiation; CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging; H&E: Hematoxylin and eosin.

Figure 3

Cerebral amyloid angiopathy-related inflammation. A 51-year-old otherwise healthy male was admitted to Peking Union Medical College Hospital with a one-month history of headaches. Lumbar puncture revealed CSF pressure greater than 330 mmH₂O, with an elevated protein level of 1.0 g/L, white blood cell counts, and glucose levels were normal. Brain MRI showed diffuse hyperintensities (arrows) in the white matter bilaterally on fluid-attenuated inversion recovery images (A) and apparent diffusion coefficient (B), with multiple cortical microbleeds (asterisk) (C). Amyloid positron emission tomography showed deposition of amyloid protein in the cortex (D). The patient was considered to have CAA-ri and was treated with corticosteroids and azathioprine. After two months, follow-up brain MRI showed significant improvement in white matter lesions (E), with no significant changes in microbleeds (F). Seven years later, brain MRI indicated an increase in microbleeds (G) with ongoing resolution of white matter lesions (H). CAA: Cerebral amyloid angiopathy; CAA-ri: CAA-related inflammation; CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging.

Figure 4

Eosinophilic granulomatosis with polyangiitis. A 50-year-old female was admitted to Peking Union Medical College Hospital with a one-month history of bilateral leg weakness, numbness, and a rash on her feet (A). During her hospital stay, she developed a sudden worsening of left limb weakness. Her medical history was significant for asthma. Blood work revealed an elevated eosinophil count of 17.99×10⁹/L and erythrocyte sedimentation rate of 57 mm/h. Bone marrow aspiration showed no evidence of hematological disorders, and parasitic screening was negative. Nerve conduction studies showed severe axonal sensorimotor neuropathy. Brain MRI showed the presence of multiple scattered hyperintense lesions in the internal border zone and cortical regions (arrows) on axial diffusion-weighted imaging (B), with corresponding hypoattenuation on apparent diffusion coefficient (C), and hyperintensities on fluid-attenuated inversion recovery images (D). The patient was treated with corticosteroids and cyclophosphamide. A follow-up MRI conducted two months later demonstrated the chronic evolution of the ischemic lesions (arrows) (E). Magnetic resonance angiography did not show any stenosis of major intracranial arteries (F). MRI: Magnetic resonance imaging.

Figure 5

Intracranial vasculitis secondary to tuberculous meningitis (involving large arteries). A 36-year-old female was admitted to Peking Union Medical College Hospital for fever and progressive disturbance of consciousness for 17 days. Brain MRI revealed acute ischemia in bilateral medial frontal lobes and genu of the corpus callosum (A–D). T1 postcontrast image showed patchy meningeal enhancement (arrow) (E). Magnetic resonance angiography indicated severe stenosis of the bilateral middle cerebral arteries and anterior cerebral arteries (arrows) (F). CSF analysis revealed a white blood cell count of 142 cells/mm³, with lymphocytic predominance. Metagenomic next-generation sequencing of CSF detected Mycobacterium tuberculosis. The patient was treated with anti-tuberculosis treatment and corticosteroids, but ultimately the condition worsened, and the patient died. CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging.

Figure 6

Ischemic stroke secondary to Varicella zoster infection (involving small arteries). A 60-year-old male with no significant medical history was admitted to Peking Union Medical College Hospital presenting with an 18-day history of herpes zoster encircling the right abdominal region, accompanied by 5 days of left lower limb weakness. Brain MRI including T1-weighted imaging (A), T2-weighted imaging (B), fluid-attenuated inversion recovery (C), diffusion-weighted imaging (D), and apparent diffusion coefficient imaging (E), showed areas of restricted diffusion within the bilateral basal ganglia (arrows), indicating acute ischemia. CSF analysis showed a white blood cell count of 16 cells/mm³, along with an elevated protein concentration of 3.12 g/L. Metagenomic next-generation sequencing of the CSF identified the presence of Varicella-Zoster Virus. CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging.