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.

Introduction

Cerebral small vessel disease (SVD) is a rapidly evolving field of research that encompasses various pathological processes affecting the small arteries, arterioles, venules, and capillaries of the brain. The clinical manifestations of SVD can be diverse.^[1] While a significant proportion of cases present with acute ischemic or hemorrhagic stroke, others experience chronic symptoms, such as gradually worsening cognitive decline. The spectrum of SVD includes several subtypes, and an etiopathogenic classification has been proposed,^[2] which categorizes the disease into age- and vascular risk factor-associated arteriolosclerosis; cerebral amyloid angiopathy (CAA); inherited or genetic SVD; inflammatory and immunologically mediated SVD; venous collagenosis; and other conditions not included in the previously mentioned categories.

There is an inflammatory component to sporadic SVD, although still not well understood. Population-based studies have confirmed the correlation between peripheral inflammatory markers and imaging changes of SVD.^[3,4] Moreover, pathological research has also confirmed signs of inflammation in the arteriolar wall and perivascular tissues.^[5] It has been observed that leukocytes infiltrate the walls of small arterioles, and there are macrophages and active microglia present in perivascular parenchymal lesions.^[6,7] On the other hand, in the classification of SVD etiologies, the term “inflammatory and immunologically mediated SVD” represents a heterogeneous group with diverse etiologies, where there is a dominant, often very specific inflammatory component that may affect the small vessels. The central mechanisms driving inflammatory SVD include immune complex deposition, endothelial cell injury, and a cytokine storm with complement activation.^[8] However, this category has not been well defined, with considerable conceptual ambiguity and a lack of clear subclassifications.

A thorough investigation is essential to identify the specific pathophysiological mechanisms of inflammatory and immunologically mediated SVD, and how they differ in cause, presentation, and appearance from sporadic SVD, which will guide individualized therapeutic interventions. The primary objective of this article is to review inflammatory disorders involving the cerebral small vessels, encompassing small-vessel primary angiitis of the central nervous system (CNS), systemic vasculitis, secondary vasculitis, and autoinflammatory diseases [Figure 1]. This will facilitate more targeted approaches to the diagnosis and treatment of these conditions.

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.

Inflammatory Disorders that Affect the Small Vessels Restricted to CNS

Small-vessel primary angiitis of the central nervous system (PACNS)

PACNS is a group of clinicopathological entities characterized by vasculitis that affects the cerebral vessels without any evident systemic vasculitis or identifiable underlying cause. It is a rare and often severe form of vasculitis, with an estimated incidence rate of 2.4 cases per million inhabitants.^[9] Diagnosing PACNS is challenging due to its heterogeneous manifestations and the lack of specific diagnostic markers. The condition is categorized into two subtypes based on the size of the affected vessels: the small-vessel variant and the medium-sized vessel variant.^[10] This spectrum includes cases with biopsy-proven vasculitis and normal angiograms, as small vessels involved are below the resolution of vascular imaging techniques. Another category is the angiographically defined variant, where brain biopsies may appear normal, since this subset primarily affects medium-sized vessels that are not easily accessible for biopsy.

The clinical course is highly variable, presenting a spectrum ranging from acute to chronic and insidious symptoms. The most common manifestations, often the initial symptoms, include headache, cognitive impairments, focal neurological deficits, and stroke. Peripheral blood typically shows no specific findings, nor the presence of autoantibodies. Cerebrospinal fluid (CSF) findings typically include a mild increase in white cell count and total protein concentration. Biomarkers in the CSF appear to be promising approaches for increasing diagnostic certainty; however, further research is still needed.^[11] Magnetic resonance imaging (MRI) manifestations are crucial, but not specific, in diagnosing small-vessel PACNS, which may be completely different from those of sporadic SVD. Potential imaging findings include disseminated small acute infarcts, acute or chronic infarcts with white matter hyperintensities (WMHs), parenchymal and leptomeningeal gadolinium enhancement, intracranial hemorrhage, and even tumor-like masses.^[10] In addition, recent 7-T MRI research has shown that diffuse microhemorrhages in the cerebral cortex with atrophy may be an important MRI pattern indicative of small-vessel PACNS.^[11]

There is currently no highly efficient non-invasive method for the diagnosis of small vessel PACNS. The criteria revised by Birnbaum and Hellmann in 2009 emphasize that brain biopsy remains the definitive diagnostic procedure for the small-vessel PACNS.^[12] Histologically, PACNS is distinguished by several patterns of vasculitis, which may have varying prognoses.^[13] Granulomatous vasculitis is the most prevalent pattern, characterized by vasculocentric destructive mononuclear inflammation with well-formed granulomas and/or multinucleated giant cells. Lymphocytic vasculitis is the second most common pattern, featuring a prominent lymphocytic infiltrate within the vessel walls, leading to vascular distortion and/or destruction [Figure 2]. Necrotizing vasculitis is the least common pattern, marked by acute necrotizing inflammation with transmural fibrinoid necrosis, often accompanied by acute inflammation. Although histopathologic findings have been well described, the underlying immunological mechanisms are not well characterized. Unlike systemic vasculitis, there is scant evidence of immune complex or antibody-mediated processes playing a significant role in PACNS.^[14]

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.

It is worth noting that there have been reports of myelin oligodendrocyte glycoprotein antibody-associated disease, hemophagocytic lymphohistiocytosis, and autoimmune encephalitis being biopsied as PACNS.^[15] This underscores the importance of utilizing available non-invasive tests, such as autoantibodies and genetic tests, for differential diagnoses before performing a biopsy for suspected small-vessel PACNS. Furthermore, a negative brain biopsy does not exclude small-vessel PACNS, as the segmental and focal nature of the pathological changes may not be captured in a single biopsy sample.

Considering the scarcity of randomized controlled trials focused on PACNS, treatment protocols are guided by therapeutic principles applied to systemic vasculitis.^[16] Management of acute exacerbations typically begins with intravenous and oral corticosteroids to rapidly suppress inflammation. For the induction phase, potential therapeutic options include immunosuppressive agents such as cyclophosphamide, which has a long history of use in treating vasculitic conditions, and rituximab, a monoclonal antibody targeting cluster of differentiation (CD) 20⁺ B cells, which is increasingly recognized for its efficacy in various autoimmune and inflammatory disorders.

CAA-related inflammation (CAA-ri)

CAA results from the deposition of amyloid-β (Aβ) in cortical or leptomeningeal vessels, which can be identified by positive Congo red staining. CAA-related inflammation, a relatively rare and aggressive subtype of CAA, is characterized by neuropathological evidence of vascular inflammation associated with CAA.^[17] It involves perivascular or transmural inflammatory infiltration triggered by an autoimmune response to the deposited Aβ. Cells, including CD3⁺, CD4⁺, and CD8⁺ T lymphocytes, CD20⁺ B lymphocytes, and CD68⁺ monocytes within the vessel wall, as well as reactive astrocytes in the surrounding parenchyma, can be observed.^[18,19] Current consensus recognizes two pathological subtypes of CAA-ri: non-destructive perivascular inflammation, referred to as inflammatory CAA, and transmural or intramural inflammation, termed amyloid-β related angiitis.^[20,21] The location and intensity of the inflammatory response vary between these two conditions [Figure 1A]. Granulomatous inflammation, a pathological hallmark of amyloid-β related angiitis, along with vascular destructive changes resembling those in PACNS, distinguishes it from inflammatory CAA. These diseases, sharing similar pathological features, represent a continuum ranging from CAA to PACNS.^[22]

CAA-ri typically affects the late middle age population, with an average age of diagnosis around 67 years, younger than that of CAA patients.^[23] The clinical presentation of CAA-ri is typically characterized by subacute cognitive impairments, behavioral changes, headaches, seizures, and focal neurological deficits.^[17,24] Whereas CAA predominantly manifests symptoms directly attributable to an acute hemorrhage or insidious cognitive decline. MRI findings indicative of CAA-ri include patchy or confluent T2 hyperintensity in subcortical white matter lesions, often predominantly asymmetric, as well as multiple strictly lobar cerebral microbleeds and cortical superficial siderosis, which are also characteristic of CAA.^[25] WMHs sometimes extend to the cortex with a mass effect showing hyperintensity in maps of apparent diffusion coefficient suggesting vasogenic edema [Figure 3]. In addition, amyloid positron emission tomography can be valuable in diagnosing CAA-ri by identifying areas with significantly increased amyloid deposition.^[26] Research also indicates that CSF anti-Aβ autoantibodies are elevated in CAA-ri patients during the acute phase, suggesting an immune response triggered by Aβ. Furthermore, these antibodies exhibit a therapeutic response-dependent decline, supporting their dual role as diagnostic biomarkers and indicators of treatment efficacy monitoring.

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.

Although neuropathological examination remains the definitive diagnostic approach to CAA-ri, a reliable diagnosis can be reached from basic clinical and radiographic information alone. The Boston criteria of CAA-ri, introduced in 2011^[27] and updated in 2016^[28] showed good sensitivity and excellent specificity. These criteria of probable CAA-ri define unifocal or multifocal WMHs that are asymmetric and extend to the immediately subcortical white matter, while the possible CAA-ri only requires WMHs that extend to the immediately subcortical white matter.

Immunotherapy can lead to improved outcomes, with high-dose corticosteroids recommended as the first-line therapy. In cases where patients do not respond to corticosteroids or to prevent disease recurrence, immunosuppressants may be used as adjunctive therapy.^[29] A study found that a higher percentage of amyloid-β-related angiitis patients (33.0%) require a combination of steroids and immunosuppressants to achieve better clinical outcomes compared to inflammatory CAA patients, of whom only 12.8% need this combined approach.^[21] There is currently no study giving recommendations on the choice of medication, dosage, and the time span of treatment.

Systemic Vasculitis Involving the Cerebral Small Vessels

Systemic vasculitis refers to a group of disorders characterized by inflammation of blood vessels that can affect multiple organ systems throughout the body, often involving arteries, veins, or capillaries of varying sizes.^[30] Among them, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a subtype of systemic vasculitis characterized by pauci-immune inflammation primarily affecting small- to medium-sized blood vessels [Figure 1B].^[31] B lymphocytes may play a major role in the pathogenesis of AAV by producing pathogenic ANCAs, which primarily target proteinase 3 and myeloperoxidase on innate immune cells, driving the disease process.^[32] The process involves cytokine-mediated priming of neutrophils, followed by the direct action of ANCAs on these primed neutrophils, which, in combination with complement cascade activation, drives vascular inflammation and injury. This group mainly includes two distinct but overlapping diseases: granulomatosis with polyangiitis and microscopic polyangiitis.^[33] AAV commonly affects the kidneys, lungs, upper respiratory tract, skin, eyes, peripheral nerves, and brain. Although CNS involvement occurs in less than 15% of AAV patients throughout the disease course, it contributes significantly to morbidity.^[34] In AAV, the brain parenchyma can be compromised through inflammation, obstruction, or increased permeability of small- to medium-sized cerebral vessels. The precise origin of pathogenic ANCAs– whether they are produced intrathecally or arise from systemic circulation–and the specific roles of the two ANCA serotypes in the diverse CNS manifestations are subjects of ongoing investigation.

Cerebral involvement in AAV typically presents acutely or subacutely. Stroke, although infrequent, can be the initial manifestation of AAV. Timely recognition of AAV as the underlying cause is challenging, especially during the initial emergency room visit. The distal penetrating vessels originating from the cortical and basal perforating substances frequently represent the primary sites of involvement. Infarctions typically appear as isolated or multiple small lesions affecting the white matter. Hemorrhagic events, while less common, primarily involve the brain parenchyma and, occasionally, the subarachnoid space. Brain MRI findings may include ischemic or hemorrhagic lesions, hypertrophic pachymeningitis, as well as varying degrees of WMHs in the periventricular and subcortical regions.^[35]

ANCA testing is a crucial diagnostic tool for patients exhibiting clinical signs indicative of systemic vasculitis. A definitive diagnosis of small-vessel vasculitis is based on histopathological examination, which is considered as the gold standard. Tissue samples are typically obtained from frequently affected organs, such as the kidneys and skin. In cases of suspected CNS involvement, biopsies may be obtained from relevant structures, including the dura, cerebral parenchyma lesions, and overlying leptomeninges. Two primary pathological findings are described: necrotizing vasculitis affecting small to medium vessels, often with necrosis of the vessel walls; and granulomatosis with inflammatory cell infiltration, including monocytes, plasma cells, eosinophils, and polymorphonuclear leukocytes, indicative of a chronic process.^[32]

Although classified as a form of AAV, eosinophilic granulomatosis with polyangiitis, also known as Churg–Strauss syndrome, has distinct pathophysiological mechanisms. It is a rare systemic necrotizing vasculitis characterized by blood and tissue eosinophilia,^[36,37] with ANCA positivity observed in only about one-third of cases. Neurological manifestations of eosinophilic granulomatosis with polyangiitis typically present as multiple and bilateral small infarcts, often occurring in the border zone areas of the white matter [Figure 4]. In addition, ischemic lesions are found in approximately 12% of patients with hypereosinophilic syndrome, suggesting that the pathogenesis of stroke may involve factors beyond vasculitis alone.^[38] Eosinophilia-induced endothelial damage and a prothrombotic state also significantly contribute to the disease process.

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.

Ischemic strokes associated with AAV are often resistant to antiplatelet therapies and are prone to recurrence without appropriate immunosuppressive intervention. It is crucial to initiate treatment promptly in patients highly suspected of having AAV, even in the absence of pathological confirmation. Corticosteroids combined with immunosuppressants form the cornerstone of therapy, which is essential for preventing relapses and achieving remission. Further research is needed to validate the utility of ANCA specificity in classifying CNS manifestations, guiding treatment decisions, and predicting prognosis.

Secondary Vasculitis Involving the Cerebral Small Vessels

Secondary vasculitis refers to inflammation of blood vessels that occurs as a complication of an underlying primary disease, distinguishing it from primary vasculitis. It presents a diverse clinical picture, ranging from localized to generalized manifestations. Common causes include infections, connective tissue diseases (CTDs), drug use, or malignancies [Figure 1C]. Therefore, when vasculitis is identified along with an underlying disease or trigger factor, it is classified as secondary vasculitis.

Infection-induced vasculitis

Infection is a recognized cause of cerebral vasculitis, making accurate diagnosis crucial due to the potential need for targeted therapy.^[39] Vasculitis associated with infection can affect large [Figure 5], medium, and small [Figure 6]-caliber vessels, respectively, leading to arteritis, venulitis, and capillaritis alone or in combination.^[40] Under infectious conditions, in addition to meningitis and encephalitis, it may present with a spectrum of vascular complications, including ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, and venous thrombosis.

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.

Pathogens can injure blood vessels through various mechanisms. They may bind to or directly infect the endothelium, or they may trigger an immune or toxic response that adversely affects the vasculature. Vascular injury could result from direct meningeal infection, compressive inflammatory exudates, septic emboli, or the formation of mycotic aneurysms that rupture. A variety of pathogens, including bacteria,^[41,42,43] viruses,^[44,45,46] fungi,^[47] and parasites^[48] [Supplementary Table 1, http://links.lww.com/CM9/C397], can involve blood vessels during CNS infections, further leading to cerebrovascular complications.

Infection-induced vasculitis is a severe condition, with outcomes closely tied to the timeliness of recognition and treatment. Selected antimicrobial therapy combined with supportive care can be lifesaving. In addition, corticosteroids may help rapidly reduce associated inflammation, thus preserving neurological function. However, the use of corticosteroids in infectious cerebral vasculitis has largely been empirical, and there is a lack of randomized clinical trials to guide their use. Apart from specific conditions such as tuberculosis,^[49,50] bacterial meningitis,^[51] and helminthiases,^[52] corticosteroid therapy is considered on a case-by-case basis and is contingent upon the response to appropriate anti-infective treatments. Corticosteroids are generally not recommended in cases with underlying immunosuppression. The role of antiplatelet medication in reducing stroke risk in patients with infectious vasculitis remains unclear and requires further investigation.^[53]

Vasculitis in CTDs

Vasculitis secondary to CTDs is characterized by the variable involvement of blood vessels, as observed both clinically and histopathologically.^[54] Histopathological hallmarks include fibrinoid necrosis and the infiltration of inflammatory cells within the walls of affected vessels. Complications can include vascular occlusion and aneurysm formation.

Vasculitis secondary to CTDs and systemic vasculitis share several commonalities in pathogenesis and histopathological characteristics, notably their multisystem involvement. Various sizes of vessels and their endothelium are often implicated in CTDs, including rheumatoid arthritis,^[55] systemic lupus erythematosus,^[56,57] polymyositis and dermatomyositis,^[58] systemic sclerosis,^[59] and Sjögren syndrome.^[60,61] The pathological features of vascular involvement may suggest either an inflammatory or thrombotic and occlusive process, depending on the specific autoimmune mechanism involved. Although the exact mechanisms that initiate and sustain immunologically mediated acute endovascular inflammation remain elusive, immune complex deposition is thought to be a primary cause of endothelial injury.^[62] The interaction of circulating immune complexes with Fc receptors on cell surfaces triggers the complement cascade. This, in turn, leads to a cascade of events, including the release of proinflammatory cytokines and hydroxyl radicals, potentially resulting in necrosis and damage to the vessel walls.

In addition to vascular damage caused by autoantibodies, systemic inflammation significantly impacts the integrity of cerebral small vessels. In systemic CTDs, there are often brain changes even when there is no direct neurological involvement.^[63] Studies have shown that patients with systemic lupus erythematosus exhibit a high burden of SVD markers on MRI,^[64] particularly WMHs and enlarged perivascular spaces. Further emphasizing the connection between autoimmune conditions and cerebrovascular risk, a comprehensive meta-analysis found that both rheumatoid arthritis and systemic lupus erythematous are associated with a significantly increased risk of strokes, raising the likelihood by 60% to 100% compared to the general population.^[65]

Drug-induced vasculitis

The abuse of substances such as amphetamines,^[66] cocaine,^[67] and opioids^[68] has increasingly been recognized as a potential trigger for the onset of cerebral vasculitis.^[69,70] Determining the exact prevalence of cerebral vasculitis in the context of substance abuse is challenging due to the underreporting associated with the covert nature of substance use and the nonspecific clinical presentation of vasculitis. However, there is a growing body of evidence indicating an upward trend in incidence, particularly among younger populations and in areas with high rates of drug use. The mechanisms through which these substances elicit cerebral vasculitis are not fully understood but are hypothesized to involve a combination of direct toxic effects on the vasculature, immune-mediated reactions, and secondary infections.

The pathological hallmark of cerebral vasculitis is characterized by the infiltration of inflammatory cells into vessel walls, resulting in intimal thickening, luminal narrowing, and, in severe cases, thrombosis and infarction.^[71,72] This damage can be extensive and severe, especially when these substances are administered parenterally. Treatment typically involves immunosuppressive therapy and addressing the underlying substance abuse through rehabilitation programs.

The introduction of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis for patients with various malignancies. However, while ICIs offer considerable therapeutic benefits, they can also trigger immune-related adverse events affecting multiple organ systems, including the CNS.^[73,74] Cerebral vasculitis, a rare but severe complication, requires prompt diagnosis and intervention to prevent potentially life-threatening outcomes. The occurrence of ICI-induced cerebral vasculitis is infrequent, with only a few cases reported in the literature.^[75] Several hypotheses have been proposed.^[76] First, like classic paraneoplastic autoimmunity mechanisms, the anti-tumor immune responses stimulated by ICIs may cross-react with CNS autoantigens. Second, ICIs might amplify two independent immune responses: one targeting the tumor and the other the nervous system. Third, therapeutic antibodies could recognize their target molecules, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death ligand 1 (PD-L1), present on endothelial cells, thereby inducing localized injury through complement-dependent or cell-mediated cytotoxic pathways.

Clinical manifestations and imaging findings are not specific to ICI-induced cerebral vasculitis and must be differentiated from metastatic brain lesions. Management typically involves the immediate discontinuation of the ICIs and the initiation of immunosuppressive therapy. Corticosteroids are generally the first-line treatment, with additional immunosuppressants or biological agents used for cases resistant to initial therapy.

Paraneoplastic vasculitis

Paraneoplastic syndromes are remote effects of cancer that can impact the nervous system. Although the neurological manifestations primarily include paraneoplastic cerebellar degeneration, limbic encephalitis, and paraneoplastic sensory neuropathy, vasculitis is comparatively uncommon. Paraneoplastic vasculitis is predominantly observed in patients with lymphoma, particularly Hodgkin lymphoma, and less frequently in non-Hodgkin lymphoma.^[77] Its occurrence is relatively rare in solid tumors.

A comprehensive review by the Mayo Clinic found that 10 (5.9%) of 168 patients with primary CNS vasculitis also had a history of lymphoma: 6 with Hodgkin lymphoma and 4 with non-Hodgkin lymphoma.^[78] Notably, in 8 of these 10 cases, the lymphoma was active at the time of the vasculitis diagnosis, suggesting a potential paraneoplastic immunological mechanism. Several pathogenic mechanisms have been proposed to explain the association between vasculitis and cancer. Tumor cells can trigger immunological reactions against vascular endothelium, release cytokines that cause endothelial injury, or induce delayed hypersensitivity reactions through the deposition of cancer proteins on vessel walls. They may also invade vessel walls, damage endothelial cells via circulating immune complexes, or act as sensitizing agents. Furthermore, concomitant factors such as infections or drugs can contribute to immune complex-mediated disorders, which may even appear early in the course of the neoplastic disease. For paraneoplastic syndromes, the primary treatment strategy involves the early detection of the underlying tumor and the subsequent initiation of targeted therapy aimed at the malignancy.

Vasculitis in Autoinflammatory Diseases

Autoinflammatory diseases are a group of hereditary disorders of the innate immune system, characterized by recurrent episodes of inflammation that may be localized or systemic. Vasculitis can be a concurrent feature in some autoinflammatory diseases [Figure 1D].^[79] CNS vasculitis and vasculopathy have been reported in patients with a deficiency of adenosine deaminase 2 (DADA2),^[80] familial Mediterranean fever,^[81] deficiency of interleukin-1 receptor antagonist,^[82] and pyogenic arthritis, pyoderma gangrenosum, and acne.^[83] In addition, sporadic case reports have documented CNS vasculitis in patients with Aicardi–Goutières syndrome^[84] and those with haploinsufficiency of A20.^[85]

DADA2 was initially described as a monogenic form of systemic vasculitis resembling polyarteritis nodosa but showed poor responsiveness to conventional treatments such as corticosteroids or immunosuppressants. In 2014, the deficiency of adenosine deaminase 2 (ADA2), caused by mutations in the ADA2 gene, was identified, marking the recognition of DADA2 as a distinct autosomal recessive autoinflammatory disease.^[80] ADA2 is predominantly expressed by myeloid cells, though not exclusively. Proposed functions of ADA2 include modulation of monocyte phenotype polarization, regulation of neutrophil extracellular traps, and modulation of innate immunity. Tumor necrosis factor α^[86] and type I interferon^[87] are pivotal cytokines in the pathogenesis.^[88] Monocyte differentiation in DADA2 patients has been reported to be skewed, resulting in a reduction of anti-inflammatory M2 macrophages and an increase in pro-inflammatory M1 macrophages. ADA2 is also involved in regulating neutrophil activity, and its absence may lead to overactive neutrophil responses causing endothelial damage. Likely, dysregulation of vascular endothelial homeostasis in the presence of pro-inflammatory macrophages leads to vessel stenosis, aneurysm formation, and vessel rupture.^[89] This process predominantly affects small- to medium-sized vessels and can manifest in various locations.

The clinical presentation of DADA2 ranges from nonspecific symptoms, such as fever and weight loss, to features that mimic systemic vasculitis. A livedoid rash is a key dermatological hallmark indicative of the disease. DADA2 is primarily characterized by immunodeficiency due to innate immune dysfunction and vasculopathy, with lacunar strokes in the basal ganglia and brainstem being notable manifestations.^[90] Treatment with tumor necrosis factor inhibitors has proven effective in preventing stroke and alleviating systemic inflammation. For young adults presenting with recurrent lacunar strokes, immunodeficiency, elevated inflammatory markers, and cutaneous changes, early consideration of DADA2 is warranted.^[91] Decreased serum ADA2 levels and mutations in the ADA2 gene can aid in confirming the diagnosis.

Conclusions

This review highlights the complexities of inflammatory disorders affecting cerebral small vessels, including PACNS and CAA-ri, systemic vasculitis, secondary vasculitis, and vasculitis in autoinflammatory diseases. These conditions share vascular inflammation as a hallmark but differ in their pathophysiological mechanisms, and clinical features. Accurate diagnosis requires the integration of clinical, imaging, and histopathological data. Compared with sporadic SVD, patients with inflammatory disorders often lack traditional vascular risk factors, are generally younger, and present with acute or subacute onset with a stepwise progression of symptoms. Brain imaging is not specific but often reveals lesions suggestive of small vessel involvement, including small subcortical infarcts, hemorrhages, WMHs, and signs of blood barrier disruption. It is essential to detect subtle inflammatory clues, such as systemic multi-organ involvement, elevated inflammatory markers, the presence of autoantibodies, or inflammatory responses in CSF. For patients with diagnostic uncertainty, a tissue biopsy may be necessary to provide definitive evidence of vascular wall inflammation. This multidisciplinary approach is critical for distinguishing these conditions and guiding effective treatment strategies, which vary based on the underlying etiology.

In recent years, significant progress has been made in understanding these conditions, yet substantial challenges remain. The absence of standardized diagnostic criteria and reliable biomarkers hampers early and precise identification, while the heterogeneity of these disorders complicates the development of unified treatment guidelines. Future research should focus on establishing standardized classifications, improving diagnostic tools, and exploring molecular mechanisms to develop targeted therapies and improve patient outcomes. Addressing these gaps will be critical to advancing both clinical practice and research in this field.

Funding

The study was supported by grants from the National Natural Science Foundation of China (No. 82271368), and the National High-Level Hospital Clinical Research Funding (No. 2022-PUMCH-D-007).

Conflicts of interests

None.

Supplementary Material

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