Diagnosis of childhood immune-mediated CNS vasculitides …

E Ann Yeh MD MA FRCPC

General Neurology

Updated 09.25.2024
Released 06.12.2018
Expires For CME 09.25.2027

Diagnosis of childhood immune-mediated CNS vasculitides

Author: E Ann Yeh MD MA FRCPC

See Contributor Disclosures

Editor: Francesc Graus MD PhD

Diagnosis of childhood immune-mediated CNS vasculitides

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Introduction

Overview

Interest in pediatric-onset inflammatory disorders of the CNS has grown in recent years, related partially to the increasing use of MRI in the pediatric population as well as an increased awareness that recurrent inflammatory disorders of the CNS may include etiologies outside of demyelinating disorders and the knowledge that disorders once deemed to be due to possible infection may have immune-related etiologies. With this has come attention to pediatric-onset CNS immune-mediated vasculitides, a heterogeneous group of disorders that may result from either autoimmune (aberrant activation of the adaptive immune system) or autoinflammatory (aberrant activation of the innate immune system) etiologies, with clinical presentations that vary according to the size of the vessels involved and the presence or absence of accompanying systemic (extra-CNS) manifestations. These heterogeneous disorders represent an important subgroup of inflammatory disorders of the CNS given the potential for irreversible injury and, therefore, a high potential for long-term cognitive or motor disability. The incidence and prevalence of childhood immune-mediated CNS vasculitides is unknown, although one adult study confirms the rarity of primary CNS vasculitis, with an incidence of 1:1,000,000 persons per year (67). With this in mind, the author provides details of known clinical CNS vasculitic syndromes and an overview of the clinical and diagnostic approach. Included in the article is a review of primary (or isolated) CNS vasculitides, a discussion of CNS vasculitides associated with systemic involvement, and an examination of monogenic autoinflammatory disorders associated with CNS vasculitis. In the vast majority of disorders, no specific biomarker of disease is known, and the final diagnosis is based on recognizable syndromic characteristics. Therefore, familiarity with the related presentations can improve a timely diagnosis.

Key points

	• Childhood CNS immune-mediated vasculitides include a broad spectrum of rare immune-mediated disorders, defined pathologically by inflammation of the vascular wall and resulting in tissue ischemia, necrosis, and inflammation.
	• Childhood CNS vasculitides, which may remain isolated within the CNS or be associated with systemic involvement, are traditionally classified based on the size of the primary vessel involved (small-vessel or medium-large vessel vasculitis).
	• Irreversible neurologic impairment occurs commonly in this population. As these disorders may be amenable to treatment, prompt recognition by the practicing clinician has the potential to improve clinical outcomes.
	• In the vast majority of disorders, no specific biomarker of disease is known, and the final diagnosis is based on recognizable syndromic characteristics. Next-generation sequencing techniques may prove useful in the future in uncharacterized CNS vasculitides.
	• Treatment is based on a few open label studies and on small case series and reports but mainly is derived from evidence obtained from adult patients. Data are reviewed in this article regarding specific agents and therapeutic management approaches.

Historical note and terminology

In 1988, a case series of eight adults found to have primary vasculitis of the CNS was published together with proposed diagnostic criteria (15). The criteria were revised in 1992 in a new publication from Calabrese and colleagues (14). The criteria proposed in 1992 are widely used for adults and children but have not been validated. They include the following: “(1) the presence of an acquired, otherwise unexplained neurologic or psychiatric deficit; (2) the presence of either classic angiographic or histopathological features of angiitis within the CNS; and (3) no evidence of systemic vasculitis or any disorder that could cause or mimic the angiographic or pathological features of the disease” (14). These criteria were formulated prior to the advent of knowledge about specific antibody-mediated processes leading to inflammatory CNS insults, such as NMDAR encephalitis, and growing knowledge about monogenic etiologies of CNS inflammation. It is possible that the coming years will see a significant evolution in the understanding of the etiopathogenesis of these clinically described syndromes.

Clinical manifestations

Vasculitis syndromes

(1) Primary angiitis of the CNS in childhood (cPACNS). cPACNS has been defined as an immune-mediated disorder affecting vessels of the CNS, without evidence of systemic involvement (15; 14). cPACNS is defined pathologically according to the Alrawi criteria, which require fulfillment of all of the following: (1) minimum of two layers of lymphocytes within or around the walls of parenchymal, leptomeningeal, or dural vessels; (2) structural alterations of the vessel wall with or without necrosis; (3) neuronophagia; (4) parenchymal edema; (5) exclusion of alternate diagnoses (05). cPACNS are traditionally classified based on the primary vessel size affected into angiography-negative small-vessel (SV)cPACNS and angiography-positive large-medium-vessel (LM) cPACNS, for the internal carotid artery, the circle of Willis, and its branches (09). Adult diagnostic criteria have been modified slightly for clinical diagnosis in the pediatric population and include: (1) new neurologic or psychiatric symptoms; (2) angiographic or histologic features of CNS vasculitis; and (3) no evidence of a systemic condition associated with these findings (09). Notably, these diagnostic criteria do not require exclusion of other CNS diagnoses.

(1.1) SVcPACNS. Symptoms described in association with SVcPACNS include the subacute onset of cognitive or behavioral deficits (in 54% to 100% of patients) or headache (62% to 89%) (24; 34). Acute presentations with seizures (79% to 85%), encephalopathy (up to 47% of children), or multifocal neurologic deficits (sensory deficits: 47%; motor deficits: 37%; language deficits: between 52% and 84%) are frequent (24; 34). Twenty percent of children may present with visual impairment from optic nerve involvement, and 15% with movement disorders (34). Disease course can be chronic-unremitting or characterized by periods of remission and relapses (34; 08). Brain MRI in SVcPACNS shows multifocal parenchymal inflammatory involvement of the brain or spinal cord in more than 90% of affected children. The optic nerve can also be affected in approximately one fifth of patients. Brain lesions are variable in number and size, ranging from extensive areas of signal change involving both white and gray matter to nonspecific punctate white matter lesions (08). Inflammatory lesions are typically hyperintense on T2/FLAIR-weighted imaging, variably hypointense on T1-weighted sequences, and do not generally present with diffusion restriction except in cases with a significant ischemic component (24; 34; 08). Lesional contrast enhancement is reported in 70% to 90% of children (24; 34). Leptomeningeal enhancement, reported in up to one third of pediatric patients, in particular should prompt consideration of SVcPANS (provided that CNS infection has been excluded) (24; 08). Inflammatory abnormalities of the brain may present interval progression, remain quiescent, or, infrequently (less than 12% of cases), resolve over time or after immunotherapy (34; 08). Spinal cord abnormalities are seen in approximately 20% of children with SVcPACNS who undergo a spinal cord MRI. Abnormalities may include increased intramedullary T2 signal as well as enhancement of the nerve roots (03). Importantly, due to the small size of the vessels involved, MR and formal angiograms are by definition normal in SVcPACNS (08).

(1.2) LMcPACNS. LMcPACNS include (1) nonprogressive LMcPACNS (transient cerebral arteriopathy, focal cerebral arteriopathy, and postvaricella angiopathy), and (2) progressive LMcPACNS, with new or progressive findings at 3 months from initial angiography (09). The clinical characteristics of childhood LMcPACNS have been described in a retrospective cohort study of 62 children with angiography-proven disease (09). LMcPACNS typically presented with transient ischemic attacks or acute ischemic stroke or subarachnoid hemorrhage. Acute hemiparesis (80%), hemisensory deficit (79%), and fine motor deficits (73%) were the most frequently reported presentations. Concentration difficulties or cognitive dysfunction were reported in 29% and 37% of patients, respectively, with mood or personality changes in 26%. Headache was present in 56% of patients, and seizures in 15% of patients. Constitutional symptoms like fever and malaise were uncommon (10%) (09). Systemic and CSF inflammatory markers are unreliable in LMcPACNS. Acute-phase disease may be associated with increased erythrocyte sedimentation rate or C-reactive protein (51% and 74% of patients, respectively) (09). CSF examination may reveal increased leukocytes or increased protein levels in approximately one third of pediatric patients (09). Molecular testing on CSF and viral serology are required to rule out infectious or parainfectious vasculopathies.

Conventional angiography or MR angiography demonstrate stenosis or occlusion of the involved medium-to-large vessels. MRI findings in these patients consist of brain parenchymal infarcts in recognizable vascular territories (09). Accompanying decreased cerebral blood flow in the affected hemisphere may be demonstrated by perfusion MRI (56). Contrast enhancement and thickening of the vessel wall is described in children with acute LMcPACNS; however, its specificity for LMcPACNS as determined in adult cohorts is low (08). Case reports in children with LMcPACNS described vessel wall enhancement reducing after corticosteroid therapy and re-emerging in progressive cases (56).

(2) CNS vasculitides associated with systemic involvement. Below, we briefly review CNS vasculitis associated with systemic autoimmune or autoinflammatory conditions, also summarized in Table 1.

Table 1. List of Most Common Systemic Rheumatologic Diseases That May Be Associated with CNS Vasculitis and Systemic Vasculitides with Possible CNS Involvement

Systemic rheumatologic diseases
	• Systemic lupus erythematosus • Antiphospholipid antibody syndrome (primary and secondary) • Sjögren syndrome • Behçet syndrome • Linear scleroderma, morphea, or en coup de sabre • Sarcoidosis (neurosarcoidosis) • Macrophage activation syndrome or hemophagocytic lymphohistiocytosis (as a complication of systemic juvenile idiopathic arthritis, systemic lupus erythematosus, or other systemic autoimmune disease)
Systemic vasculitides
	• IgA vasculitis (Henoch-Schonlein purpura) • Kawasaki disease • Antineutrophil cytoplasmic antibody-associated vasculitides:
		- Granulomatosis with polyangiitis (formerly Wegener granulomatosis) - Microscopic polyarteritis - Eosinophilic granulomatosis (formerly Churg-Strauss syndrome)
	• Takayasu arteritis • Polyarteritis nodosa • Cogan syndrome

(2.1) Systemic lupus erythematosus. Systemic lupus erythematosus is a multisystem chronic disease of unknown etiology associated with dysregulation in different immune pathways, with 10% to 15% of cases diagnosed before the age of 16 years (pediatric-onset systemic lupus erythematosus or juvenile systemic lupus erythematosus). Incidence is 0.9 to 25.7 per 100,000 children per year, depending on geographical region (61). The diagnosis of systemic lupus erythematosus is based on clinical judgment after excluding alternative diagnoses. Classification criteria, validated also in pediatric cohorts, are based on both clinical and immunological parameters (25). Seventy percent to 100% of children with systemic lupus erythematosus are antinuclear antibody positive (77). Differential diagnosis of a child positive for antinuclear antibodies and multisystem disease includes infections or other rheumatic diseases.

CNS-related damage is the major determinant of chronic disability in children with systemic lupus erythematosus, with a mortality of 28% (77). Neurologic or psychiatric manifestations of neuropsychiatric systemic lupus erythematosus may be the presenting feature in 16% to 21% of cases of systemic lupus erythematosus (77) and may develop in up to 95% of affected children over the course of the disease (77; 73). In children, NPSLE manifestations may include seizures (4% to 84%), headache (10% to 72%), neuropsychiatric abnormalities (mood disorder, anxiety, or psychosis) (5% to 57%), cognitive abnormalities (acute confusional state or cognitive dysfunction) (0% to 55%), cerebrovascular disease (2% to 39%), peripheral neuropathy with or without dysautonomia (5% to 15%), transverse myelitis (1% to 5%), cranial neuropathy (less than 1% to 2%), aseptic meningitis (less than 1%), or chorea (less than 1%) (77; 73). The pathogenesis of neuropsychiatric systemic lupus erythematosus is multifactorial and includes immune-mediated injury (vasculitis, autoantibody-mediated injury, T-cell mediated damage, cytokines or chemokine release), thrombosis or hemorrhage from coagulation disturbances (in particular, in patients with association with antiphospholipid antibodies), environmental factors (such as opportunistic CNS infections due to dysimmunity), or drug-induced manifestations (29). Accordingly, brain MRI findings in NPSLE are diverse. The most commonly observed changes are supratentorial white matter hyperintensities of various number and size (ranging from punctate nonspecific lesions to larger focal white matter hyperintensities) and observed in up to 33% of pediatric-onset systemic lupus erythematosus (03). The etiopathogenesis of the focal white matter hyperintensities seen in systemic lupus erythematosus is unclear. In adult patients, they may appear during periods of disease activity and partially or completely resolve after immunotherapy (29). Such lesions often affect the hemispheric white or gray matter junction but may also involve the deep white matter, the cortical gray matter, or the infratentorial structures (03). Vascular-type lesions may range from large ischemic areas or watershed infarcts due to thromboembolism, to lacunar lesions or microbleeds due to multifactorial occlusion, narrowing, or thrombosis of small vessels. Intraparenchymal or subarachnoid hemorrhages and calcifications have also been reported. Other MRI findings include focal or diffuse atrophy, seen in up to 18% of pediatric cases, and focal or diffuse cortical T2/FLAIR hyperintensities (compatible with postictal changes or with antibody-mediated changes), reported in approximately 4% of pediatric cases (03). Basal ganglia T2/FLAIR hyperintensities have also been described. Pediatric-onset systemic lupus erythematosus has also been anecdotally associated with demyelinating changes (03). Despite the presence of symptoms, up to 59% of patients with neuropsychiatric systemic lupus erythematosus may present with a normal brain MRI scan (03). Where present, myelopathy is often characterized by longitudinally extensive patterns with predominant central gray matter involvement, affecting most commonly the thoracic cord. Swelling and contrast enhancement are common associated findings (03; 62).

One must exclude other diagnoses, as outlined below (see “Differential diagnosis”) (69). CSF analysis in children with NPSLE can demonstrate lymphocytic pleocytosis with normal protein and glucose levels (03). Biomarkers for CNS involvement, such as antibodies to neuronal components or mediators of neuronal injury, are promising in children with systemic lupus erythematosus but have not demonstrated improvement over current detection methods (44).

(2.2) Kawasaki disease. Kawasaki disease is a self-limited multisystem medium vessel vasculitis of childhood. Current diagnostic criteria for Kawasaki disease include the presence of fever lasting 5 or more days and at least four of the following: (1) bilateral conjunctivitis, (2) oral mucous membrane changes, (3) peripheral extremity changes, (4) polymorphous rash, or (5) cervical lymphadenopathy (07). Pathological changes include inflammation of the vessel wall with destruction of the media and aneurysms or thrombi formation. Symptomatic neurologic involvement is reported in less than 5% of pediatric patients. Aseptic meningitis with seizures and encephalopathy, cranial nerve palsies, and, less frequently, stroke or subarachnoid hemorrhage from aneurysm rupture have been the most commonly reported complications (06). Brain MRI abnormalities may range from leptomeningeal enhancement or nonspecific subdural effusions to diffuse leukoencephalopathy, cerebral infarctions, atrophy, or a reversible T2/FLAIR-hyperintense lesion in the subcortical white matter or splenium of the corpus callosum (06; 35). Cerebrovascular lesions from occlusion of medium-large vessels have also been reported (66).

(2.3) Henoch-Schonlein purpura (IgA vasculitis). Henoch-Schonlein Purpura IgA vasculitis is a self-limited systemic nongranulomatous small vessel vasculitis that occurs almost exclusively in childhood, with an average age at onset of 7 years (65). Diagnostic criteria require the presence of purpura or petechiae (mandatory) plus one of the following: (1) abdominal pain, (2) consistent histopathology (IgA deposits), (3) arthritis or arthralgia, or (4) renal involvement (57). Histopathologically, Henoch-Schonlein Purpura is characterized by a leukocytoclastic vasculitis with IgA deposits affecting capillaries and venules (50; 65). Typical systemic manifestations include purpuric rash, arthritis or arthralgia, abdominal pain, and nephritis with proteinuria (57). Nervous system involvement is rare, described in less than 10% of the patients (10). Manifestations include seizures, encephalopathy, focal neurologic signs, ischemic or hemorrhagic stroke, and peripheral neuropathies (10). However, nonspecific manifestations like headache and subtle behavioral changes are described in up to 31% of pediatric patients. Brain MRI may show evidence of small vessel vasculitis with confluent areas of cortical and subcortical T2/FLAIR hyperintensity and variable contrast enhancement. Where acute ischemia is present, diffusion-weighted imaging may reveal diffusivity restriction. Conventional cerebral angiography is generally normal or shows nonspecific irregularities of the small vessels secondary to tissue edema and inflammation (10). Secondary posterior reversible encephalopathy syndrome complicating disease course is also reported (23). IgA vasculitis has been associated with activated phosphoinositide 3-kinase delta syndrome (APDS), an inborn error of immunity.

(2.4) Behçet syndrome. Behçet syndrome is a chronic relapsing autoinflammatory syndrome of unknown etiology. Diagnosis is made with the presence of oral ulcers at least three times in a year in addition to the presence of at least two of the following: (1) recurrent genital ulcerations, (2) eye lesions (uveitis or retinal vasculitis), (3) skin lesions (erythema nodosum, pseudofolliculitis, papulopustular lesions, acneiform nodules), or (4) positive pathergy test (01). Four percent to 26% of cases are diagnosed before 16 years of age, with an average age at onset of 4 to 12 years (54; 26). Histological findings in systemic tissue or CNS ranges from classic leukocytoclastic vasculitis affecting arteries of all sizes to a nonspecific perivascular inflammation or interstitial infiltration of arteries and veins with mononuclear or neutrophilic predominance. Venous and arterial thrombosis, hemorrhagic phenomena, and aneurysm formation are also described. Neurologic manifestations, not typically described at disease onset (54), occur in 7% to 31% of pediatric patients over the course of the disease (54a; 26). Headache is the most frequently reported neurologic symptom (21% to 25%), followed by aseptic meningitis with or without secondary papilledema (2% to 13%), neuropsychiatric symptoms (5%), hemiparesis or paraparesis (4%), raised intracranial pressure due to cerebral sinodural venous sinus thrombosis (4%), seizures (3%), nuclear cranial nerve palsy (2%), cranial neuropathy (2%), optic neuritis (less than 1%), peripheral neuropathy (less than 1%), and venous thrombosis (less than 1%) (26). Retinal vasculitis is described in 6.4% of children (26). Brain MRI may demonstrate inflammatory T2/FLAIR hyperintense, T1 iso- or hypointense changes, commonly enhancing and not generally diffusion-restricted (neuro-Behcet) in up to 11% of affected children (13). Pons, midbrain, diencephalon, and basal ganglia are preferentially affected. Neuro-Behcet lesions may reduce in size in the chronic phases or after immunotherapy, and atrophy may be present (75). Where medium-large vessels are involved, brain MRI may show ischemic or hemorrhagic changes, and MR or conventional angiography may be consistent with abnormalities of the arteries lumen or cerebral venous sinus thrombosis (38).

(2.5) Sjogren syndrome. Sjogren syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands and autoantibody production (anti-nuclear antibodies, extractable nuclear antigens, rheumatoid factor). Current diagnostic criteria, validated in adult populations, are based on the presence of anti-SSA/Ro antibody and biopsy positive for focal lymphocytic sialadenitis as well as on hypofunction of salivary and lacrimal glands on confirmatory testing (68). A distinction is made between the primary form in which no known systemic autoimmune disorder, such as rheumatoid arthritis or systemic lupus erythematosus, can be demonstrated and the secondary form in which such association exists. Other systemic features may include peripheral neuropathy or polyradiculoneuropathy, arthritis, or kidney and lung involvement. These extraglandular manifestations result from necrotizing vasculitis of small- or medium-sized vessels, autoantibody-mediated mechanisms, or lymphocytic infiltration of the target organs. Up to 6% of the patients may present with disease onset during childhood (76).

In children, neurologic involvement is described in small case series or reports in approximately 20% to 35% of cases (40). This is more frequently characterized by meningoencephalitis or peripheral neuropathy. When present, spinal cord involvement is characterized by transverse myelitis or longitudinally extensive transverse myelitis. Overlap cases with anti-AQP4-positive neuromyelitis optica spectrum disorders have been reported in children.

(2.6) Childhood-onset eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). Childhood-onset eosinophilic granulomatosis with polyangiitis (eGPA) is a small vessel necrotizing granulomatous vasculitis accompanied by asthma and hypereosinophilia (27). eGPA is rare in children, accounting for less than 2% of all cases of systemic vasculitis (27). The American College of Rheumatology criteria for eGPA, validated in adults, require four of the six following clinical findings: (1) asthma, (2) eosinophilia, (3) mononeuropathy or polyneuropathy, (4) non-fixed pulmonary infiltrates on x-ray, (5) paranasal sinus abnormality, or (6) biopsy containing a blood vessel with extravascular eosinophils (49). CNS disease has been described in small cohort studies or case series or reports in up to 11% of the affected children. Manifestations may include headache and cerebrovascular accidents (27). Although it is described in up to 69% of adult patients, only 40% of pediatric patients with eGPA show peripheral nervous system involvement (27).

Granulomatosis with polyangiitis (formerly Wegener granulomatosis), microscopic polyarteritis, and polyarteritis nodosa are extremely rare in children and will not be discussed (32). Systemic vasculitides that may present CNS involvement are summarized in Table 1.

(2.7) Rheumatoid arthritis. Rheumatoid arthritis has been anecdotally associated with medium-large vessel CNS vasculitis manifesting with stroke, mainly in adult patients, and will not be discussed in this topical review.

(3) CNS vasculitides secondary to acquired conditions or inherited immunodeficiencies. Inflammatory vascular changes may be found in cerebral vessels secondary to various acquired or inherited conditions or processes. Examples of acquired conditions are drug-induced CNS vasculitis (DRESS syndrome), radiation-induced CNS vasculitis, infection-associated CNS vasculitis (eg, HSV or hepatitis C), and cryoglobulinemia with vasculitis secondary to B-cell lymphoproliferative disorders (71). Cases of CNS vasculitis have also been described in primary immunodeficiencies. Immune system defects may lead to recurrent and severe infections and, in a minority of patients, to predisposition to autoimmunity or inflammatory conditions. Common variable immunodeficiency, the second most frequent primary immunodeficiency syndrome in children, is a group of heterogeneous conditions linked by lack of antibody production. Systemic or CNS vasculitis can complicate the clinical course of a small percentage of patients (up to 1% of cases) (30). Large-vessel CNS vasculitis with propensity to hemorrhages has been described in adults and children with Wiskott-Aldrich syndrome--a rare, X-linked, primary immune deficiency that leads to the classic triad of eczema, microthrombocytopenia, and combined immunodeficiency (47). CNS vasculitis has been described in adult and pediatric patients with hyperimmunoglobulin E syndrome (04), selective IgA deficiency (45), or chronic mucocutaneous candidiasis (52). CNS vasculitis has been described as a complication of various infectious diseases, most recently in the context of the COVID-19 pandemic, including inflammation of the CNS, some of which follows a CNS vasculitis-like pattern after COVID-19 (42). Cases of CNS vasculitis affecting arteries and veins of different sizes have also been described in children with familial hemophagocytic lymphohistiocytosis, even as the sole manifestation of disease (11).

(4) CNS vasculitis in the context of autoimmune encephalitis. Growing reports have shown pathological evidence for vasculitic changes in encephalitic processes, including MOG-IgG antibody-related disorders in a child (58), and, in the adult population, reports have shown pathological evidence in one form of limbic encephalitis, anti-adenylate Kinase 5 encephalitis (72).

(5) Monogenic autoinflammatory disorders associated with CNS vasculitis. These are a rare group of syndromes characterized by episodes of unprovoked inflammation due to monogenic dysregulation of the innate immune system. In deficiency of ADA2, loss-of-function mutations of the CECR1 gene encoding ADA2 lead to a proinflammatory status with immunodeficiency as well as to a concurrent endothelial defect. This results in vasculitis and vasculopathy affecting the CNS and systemic vessels (55; 78; 28). This condition may present phenotypic overlap with polyarteritis nodosa (PAN) and should be suspected in children with otherwise unexplained cerebrovascular pathology and recurrent episodes of localized or systemic inflammation such as recurrent fevers, cutaneous lesions, abdominal involvement, or neutropenia (55; 28). Neurologic manifestations may include early-onset lacunar strokes, mainly occurring during episodes of active inflammation; peripheral nerve/cranial nerve involvement; or less frequently encephalopathy, mainly occurring during episodes of active inflammation (78; 28). Diffuse brain volume loss in the absence of neuroimaging evidence of large-medium vessel pathology has also been described (28).

Other monogenic autoinflammatory disorders have been associated with CNS vasculitis. Familial Mediterranean fever, characterized by recurrent episodes of fever and painful polyserositis, can present with features overlapping with systemic vasculitides, such as Henoch-Schonlein purpura (IgA vasculitis associated with activated phosphoinositide 3-kinase delta syndrome), polyarteritis nodosa or Behcet syndrome, and present with neurologic features of either small or medium vessel vasculitis (60; 22). Large vessel CNS vasculitis has been described in a neonatal case of deficiency of interleukin-1 receptor antagonist (02) and in a pediatric case with pyogenic arthritis, pyoderma gangrenosum, and acne (37). CNS vasculitis has been described in a case of an infant with autoinflammation and phospholipase Cγ2‐associated antibody deficiency and immune dysregulation (APLAID) (PLCG2 gene) (51) as well as in a child with X-linked lymphoproliferative disease (43). Confirmatory genetic testing is required for the diagnosis of monogenic autoinflammatory disorders. Next-generation sequencing techniques may prove useful in otherwise uncharacterized CNS vasculitides associated with inappropriate innate immunity response.

Prognosis and complications

Long-term longitudinal studies characterizing the functional and neurocognitive outcomes of childhood CNS vasculitides are lacking. Broadly speaking, the clinical course of CNS vasculitides may be monophasic or relapsing; vasculitic changes associated with infectious etiologies such as varicella zoster, have been implicated in monophasic cerebrovascular syndromes, affecting large vessels of the CNS, whereas a relapsing course characterizes other syndromal vasculitic entities, including large-medium vessel PACNS, CNS systemic lupus erythematosus, or monogenic autoinflammatory CNS vasculitides (77; 10; 53). Long-term prognosis depends on extent of CNS involvement and response to treatment. Significant neurologic sequelae including cognitive and behavioral impairment, treatment-refractory epilepsy, and motor disability are common. An open-label cohort study of 19 pediatric patients with cPACNS treated with a standardized immunosuppressive protocol showed moderate to severe irreversible neurologic impairment in 30% of the children at 24 months (34). Full recovery was achieved by 46%, and 21% participants presented remission after discontinuation of therapy (34).

In a retrospective assessment of 80 children with LMcPACNS (n=59) and 21 children with SVcPACNS (n=21), 24% of children with SVcPACNS and 5% of children with LMcPACNS were found to have full-scale IQ below 70, with deficits found in working memory and processing speed an average of 2.82 years after onset (20).

Biological basis

The pathological hallmark of CNS vasculitis is an inflammatory infiltrate of the vessel wall. The pathophysiology of CNS vasculitides is largely unknown and, most likely, multifactorial. Vascular damage is thought to arise from distinct but interacting mechanisms, such as direct cytotoxic damage, soluble inflammatory factors, autoantibodies, and, in selected cases, inherited vascular abnormalities (31). One publication has implicated the alternative complement cascade in primary CNS vasculitis in a small adult population, specifically pointing to regulators of the C3 and C5 convertases and components of the terminal cascade in a proteomic study (48), although this was not confirmed by another group evaluating an array-based multiplex system (PACNS n=20, non-inflammatory n=16) (17). Consequences of immune-mediated vascular injury may include thrombotic events presenting with either stroke or transient ischemic attack or with ischemic microangiopathy, depending on the size, number, and location of the vessels involved. Seizures or nonfocal neurologic manifestations, such as encephalopathy, or neuropsychiatric manifestations may derive from inflammatory injury to the vessel wall, with increased permeability of the blood-brain barrier and tissue edema, intrathecal formation of antibodies and immune complexes, production of inflammatory mediators, and consequent perturbation of neuronal and microglial function (31). In adult primary angiitis of the CNS, promising biomarkers include those that may point to injury of the cytoskeleton of the neuron even prior to a clinical attack, such as CSF neurofilament light chain (59). Still, other work has pointed to serum markers that can help to differentiate primary angiitis of the CNS from other entities such as circulating endothelial cells, where active primary angiitis of the CNS has been shown to be associated with markedly higher circulating endothelial cells levels than a healthy control population (19).

Differential diagnosis

Confusing conditions

Children presenting with new acute or subacute onset of focal neurologic signs, neuropsychiatric changes, or seizures should be assessed via thorough history and neurologic examination, with explicit attention to possible infectious, inflammatory, metabolic, and structural etiologies. In addition to inquiring about a history of previous neurologic events and developmental delay, eliciting a history focused on systemic manifestations or frequent infections may be helpful in formulating a differential diagnosis in these cases. Consideration of a large-vessel CNS vasculitis should occur in the event of the hyperacute onset of neurologic deficits. Table 2 provides a broad differential diagnosis for the child with suspected vasculitis.

Table 2. Differential Diagnosis of CNS Vasculitis

Acquired demyelinating syndromes
	• Multiple sclerosis • Anti-MOG-associated syndromes • Acute disseminated encephalomyelitis
Anti-neuronal antibody-associated syndromes (syndromes described in children): Cell surface antigens:
	• Anti-NMDAR encephalitis • Anti-GABAA ionotropic receptor 1 encephalitis • Anti-D2 receptor encephalitis
*Intracellular antigens:*
	• Anti-glutamic acid decarboxylase encephalitis
Neurosarcoidosis Rasmussen encephalitis Infectious or post-infectious encephalitides Metabolic disorders Malignancies (intravascular lymphoma, gliomatosis cerebri) Monogenic disorders (hereditary immune dysregulation and other syndromes)
	• Aicardi-Goutieres syndrome / Interferonopathies • Neonatal onset multisystem inflammatory disease (NOMID) • Muckle-Wells syndrome • IgA vasculitis • X-linked lymphoproliferative disorder • ADA2 deficiency/DADA2
Inherited or acquired cerebrovascular conditions
	• Fibromuscular dysplasia • Dissection • Channelopathies with vasospasm • Inherited cerebral arteriopathies • Moyamoya disease • Hemoglobin disorders • Thromboembolism

Diagnostic workup

CNS vasculitides can manifest with a wide range of neurologic and psychiatric features and often pose diagnostic and therapeutic challenges. Diagnosis is dependent on careful history and physical examination together with specific laboratory autoantibody testing and evaluation of brain structure and function. As initial presentation of systemic rheumatologic disorders may be in the CNS alone, one must consider the possibility of underlying or coexisting systemic disorders even in the face of a purely CNS presentation.

Laboratory work-up. Laboratory work-up with CSF analysis may reveal evidence for ongoing CNS inflammatory activity. Elevated CSF protein concentration, pleocytosis, oligoclonal bands, and elevated IgG index all support an immune-mediated etiology. Serum evaluation for evidence for systemic inflammation or evidence for biomarkers of known rheumatologic or antibody-mediated disorders can help to narrow the differential diagnosis (Table 3).

Table 3. Laboratory Investigations

	Test	Relevance
Blood chemistry	CBC, differential, liver and kidney function tests, folate, B vitamins, lactate dehydrogenase	General, organ involvement
Inflammatory markers	ESR, CRP	Systemic inflammatory status or disease activity
Infection markers	Serology. Bacterial or mycobacterial, fungal, parasite blood cultures	Infection (viral, bacterial, fungal)
Non-organ-specific autoantibodies	ANA (anti-dsDNA), ENA (anti-Sm, anti-RNP, anti-La, anti-Ro), ANCA (p/c-ANCA, MPO, PR3), RF, aPL (lupus anticoagulant, anticardiolipin antibody, anti-beta2-glycoprotein I, false-positive test result for rapid plasma reagin)	Systemic lupus erythematosus, other rheumatologic conditions
Other	IgA, IgG, IgM, lymphocyte immunophenotyping, C3, C4, CH50, AP50; in selected cases: CICs, cryoglobulins, total hemolytic complement	Immune system function, immunodeficiency, or dysregulated immunity
	Calcium, calcium ionized, 24-hour urine collection for urinary calcium:creatinine ratio, PTH, calcitonin, angiotensin converting enzyme, sIL2R (CD25)	Neurosarcoidosis
	CBC, differential, liver function tests, fibrinogen, D-dimer, ferritin, fasting triglycerides, LDH, sIL2R (CD25), sCD163. For screening between primary and secondary hemophagocytic lymphohistiocytosis: perforin protein expression, CD107a levels (NK degranulation assay), NK cell cytotoxicity assay, (EBV serology) Genetic testing for immune deficiency, hemophagocytic lymphohistiocytosis, or interferonopathy (when indicated by bloodwork, CSF, or typical imaging features in selected cases)	Hemophagocytic lymphohistiocytosis
Hypercoagulable work-up	PT, aPTT, fibrinogen, protein C, protein S, activated protein C resistance (factor V gene Leiden mutation), prothrombin gene mutation, factor VIII, antithrombin III, von Willebrand factor antigen, homocysteine, MTHFR gene mutation, aPL, haptoglobin, peripheral blood smear, hemoglobin analysis	Thrombophilic conditions, hyperhomocysteinemia, sickle-cell disease
Organ-specific autoantibodies	Thyroid peroxidase or microsomal autoantibodies	Hashimoto encephalopathy
	MOG antibodies	MOG-associated demyelinating syndromes
	AQP4 antibodies	NMOSD
	GQ1b antibodies	Bickerstaff brainstem encephalitis
	Antibodies against antineuronal cell-surface and intracellular antigens	Limbic encephalitis and other antibody-associated encephalitis
CSF	Opening and closing pressures
	Glucose, protein, cell count and differential
	Lymphocyte immunophenotyping (in selected cases)
	Oligoclonal banding and IgG index	Intrathecal antibody synthesis, CNS inflammation
	CSF cytopathology (in selected cases)	Abnormal lymphocytes, malignant cells (intravascular lymphoma, gliomatosis cerebri)

	CSF gram stain and culture, CSF PCR studies	Examination for infectious agents (viral, bacterial, fungal)
	CSF angiotensin converting enzyme	Neurosarcoidosis

MRI imaging. Differentiating a vasculitic process from other inflammatory processes of the CNS based solely on MRI features is challenging. Previous studies have shown poor sensitivity and specificity for distinguishing vasculitides in adults from multiple sclerosis using MRI criteria, such as Barkhof criteria (39). However, a study evaluating the value of differentiating multiple sclerosis from other inflammatory or vasculitic processes of the CNS using the “central vein” sign on 3T imaging has suggested that the central vein sign can discriminate cases of adults with multiple sclerosis from inflammatory vasculopathies with a diagnostic accuracy of 100% (46). Susceptibility-weighted imaging may be of benefit in distinguishing CNS vasculitis from multiple sclerosis: those with CNS vasculitis are more likely to exhibit evidence for microbleeds, cortical superficial siderosis, and tortuosity of the vascular route (33).

Small-vessel disease is rarely associated with changes visible on conventional angiography or MRA. However, as it is useful in the diagnosis of large-medium vessel disorders, MR angiogram may be of benefit. As concordance of time-of-flight (TOF) MRA with digital subtraction angiography (DSA) is high in adult patients with primary CNS vasculitis (1.5 T, kappa=0.82 [95% CI 0.75-0.93]; 3T, kappa=0.87[95% CI 0.78-0.91]), DSA likely provides little added benefit in most cases (18). Notably, however, angiography may be negative in most cases of CNS vasculitis: in one adult study of CNS vasculitis, only 5 of 34 positive biopsies were also found to be positive on digital-subtraction angiography (63).

Vessel wall imaging has shown some promise in large vessel CNS vasculitis. In an adult population with large vessel CNS vasculitis who received vessel wall imaging (n=10), all patients showed concentric contrast enhancement of arterial walls in multiple vascular territories (21). Further, a pattern of vessel wall enhancement including secondary and tertiary segments of large vessels may associate with a diagnosis of primary angiitis of the CNS (70). Degree of enhancement at baseline has been found to be predictive of outcome in one study of adult CNS vasculitis (36). In other work, number of vascular segments with affected vessel walls was higher in relapsing than nonrelapsing cases (74). Future studies are needed to confirm utility of these modalities in children with suspected vasculitides.

The imaging features associated with distinct syndromes associated with CNS vasculitis have been discussed in the dedicated sections.

Other investigations. EEG may demonstrate diffuse or focal slowing, interictal epileptiform discharges, or ictal events (seizures), whereas mental status examination may reveal deficits in processing speed, attention, concentration, and memory (34; 28).

Management

Immunosuppression is usually required for disease control in children with CNS vasculitis. First-line immunotherapy typically includes combinations of high-dose intravenous corticosteroids, intravenous immune globulin, or plasma exchange. Protocols vary, but children with persistent symptoms after use of first-line therapies have been treated in an open-label fashion with immunosuppressant medications (mainly cyclophosphamide or mycophenolate mofetil) (08; 64; 34). Rituximab, azathioprine, methotrexate, cyclosporine A, infliximab, and tocilizumab have also been described in case reports or series (34; 12).

Selected patients with LMcPACNS or neuropsychiatric systemic lupus erythematosus with antiphospholipid antibodies may also be treated with anticoagulation or anti-platelet therapy, or both (09; 08). Children with systemic syndromes and CNS involvement may receive maintenance treatment according to the specific syndrome and the extra-CNS organ involvement. Usually, this involves an oral prednisone wean over weeks to months (starting at 1 to 2 mg/kg per day). Specific treatments for systemic vasculitides, including mechanistically targeted treatment with biological drugs, is outside of the scope of this review. However, it is of note that specific, targeted therapies have been described in relation to monogenic disorders, such as interferonopathies (16), DADA2 (41), and IgA vasculitis (22). Information regarding these treatments can be found in articles devoted to the specific underlying illnesses. Neurocognitive and psychiatric counseling as well as physical and symptomatic therapies for chronic neurologic symptoms, such as seizures, spasticity, bowel or bladder dysfunction, and pain, may be required.

Outcomes

Response to immunotherapy is variable. This variability is likely due to heterogeneity in etiology: promise has accompanied the presence of established monogenic disorders, which may have specific targetable immune pathways. Broad immunosuppressive therapies have the potential for significant complications, but one must weigh the risks and potential benefit of preventing progressive CNS injury in this population. The most frequent complications of prolonged steroid treatment observed in children with cPACNS include weight gain (up to 100% of cases), cataracts (5%), avascular necrosis (5%), or vertebral fractures (15%). Five percent to 8% of children treated with immunosuppressive medications may develop serious infection or pancytopenia requiring hospital admission (34). Treatment-related complications and monitoring suggestions are provided in Table 4.

Table 4. Common Treatments for Childhood CNS Vasculitis

Medication, dosing, and schedule	Mechanism of action	Side effects and risks	Monitoring
Induction
First-line
Intravenous methylprednisolone 20 to 40 mg/kg/day, up to 1 g for 3 to 5 days	Impact on the differentiation, function, and survival of leukocytes; suppression of the synthesis of known proinflammatory cytokines; inhibition of immune cell trafficking.	Common: hot flashes, palpitations, insomnia, mood alterations, gastrointestinal symptoms, hypertension. Rare: cardiac arrhythmias.	Pre- and postinfusion cycle: renal and liver function tests, glucose and electrolytes. During infusion, monitor blood pressure and heart rhythm.
Step-up treatment for refractory cases
IVIg 2 g/kg divided over 1 to 5 days.	Neutralization of cytokines, complement and autoantibodies; modulation of innate immune effector cells and B cells.	Common: headache Less common: aseptic meningitis, renal toxicity, homolysis Rare: hypersensitivity reactions or anaphylaxis (especially if IgA deficient) Extremely rare: risk of transmission of blood borne pathogens.	Prior to first dose: IgA levels and testing for pre-existing infections in selected cases. Prior to every dose: CBC, differential, Coombs test, renal function and liver enzymes.
Plasmapheresis Standard protocol Frequency: every other day Exchange solution: 5% albumin Exchange volume: 1 TPV OR Intensified protocol Frequency: daily Exchange solution: 5% albumin with one unit of FFP* at the end of each procedure Exchange volume: 1 TPV Number of procedures: 5 to 7. If incomplete recovery, may continue with treatment at the discretion of the treating physician. *If reactions to FFP, consider solvent detergent-treated human plasma preparations.	Removal of circulating immunoglobulins and inflammatory mediators from plasma.	Common: hypersensitivity reactions or anaphylaxis, citrate toxicity (hypocalcemia, hypomagnesemia, metabolic alkalosis). Rare: hypovolemia, thrombosis or bleeding from removal of clotting factors, transmission of blood-borne pathogens, vascular access complications (infection, thrombosis, bleeding, vascular damage), increased risk of infection from removal of endogenous immunoglobulins, lack of drug effect because of drug removal.	Pre-post procedure: CBC, differential, ionized calcium, magnesium, potassium, phosphate, TCO, bicarbonate, albumin, coagulation screening.
Maintenance (in selected cases)
Prednisone Variable length oral taper, starting at 1 to 2 mg/kg/day – maximum 60 mg/day AND/OR Monthly intravenous methylprednisolone pulses (20 to 40 mg/kg/day – maximum 1 g/day, for 1 to 3 days).	Multiple (as above)	Common: gastrointestinal symptoms, hot flashes, Cushingoid facies, diabetes, hirsutism, hypertension, acne, weight gain, mood disturbances, insomnia, striae. Rare: palpitations, cardiac arrhythmias, electrolyte abnormalities, psychosis, myopathy, avascular necrosis. Long term: osteoporosis or osteopenia, cataracts.	Monitor CBC, differential, renal function tests, glycemia, blood pressure, heart rhythm, weight, bone density. Strongly consider vitamin D and calcium supplementation. Consider proton pump inhibitors for gastric protection.
IVIg Tailor to the lowest dose that maintains clinical efficacy, typically, 1 to 2 g/kg divided over 1 to 5 days. Frequency: variable, every 3 to 8 weeks.	As above	As above	As above
Maintenance: Immunosuppressive agents (in selected cases)
T- and B-cell targeted agents
Cyclophosphamide, 500 to 1000 mg/m2 pulses	Alkylating agent, impairs DNA synthesis and induces apoptosis in lymphocytes and other actively proliferating cells.	Common: gastrointestinal symptoms, hair thinning or alopecia, nausea, vomiting. Rare: infusion reactions or anaphylaxis, diarrhea, stomatitis, urinary tract and renal toxicity, opportunistic infections, hepatotoxicity, hyponatremia, myelosuppression, risk of malignancy, infertility.	Exclude or correct any urinary tract obstructions prior to treatment; monitor CBC, renal and liver functions, electrolytes, urinalysis periodically. Monitor for signs or symptoms of malignancy and infection, cardiac function, and respiratory function. Several drug interactions.
Mycophenolate mofetil, target dose 800 to 1200 mg/m2 divided in two doses per day OR Mycophenolic acid, target dose 500 to 800 mg/m2 divided in two doses per day.	Reversibly inhibits inosine monophosphate dehydrogenase with reduction of de novo synthesis of guanosine nucleotides and cytostatic effect on T and B lymphocytes; inhibition of adhesion molecule expression and lymphocyte recruitment into sites of inflammation; induction of apoptosis of activated T-lymphocytes.	Common: nausea and diarrhea, mild neutropenia, anemia. Rare: renal and liver toxicity, metabolic dysfunction, hypertension. Extremely rare: serious infections (including opportunistic infections and progressive multifocal leukoencephalopathy), increased risk of malignancies (lymphoma, skin cancer).	Monitor CBC, renal and liver function, electrolytes, cholesterol periodically. Monitor for signs or symptoms of malignancy and infection. Several drug interactions.
Azathioprine 2 to 3 mg/kg/day	Purine analogue, blocks the de novo purine synthesis pathway, cytotoxic to stimulated lymphocytes.	Common: gastrointestinal symptoms, dose-related cytopenias, hepatotoxicity. Rare: serious infections (including opportunistic infections and progressive multifocal leukoencephalopathy) and malignancy risk (increasing with treatment duration and cumulative dose).	Monitor periodically CBC, renal and liver function, bilirubin, and electrolytes. Increased risk of myelotoxicity in patients with reduced TPMT activity; consider TPMT testing in patients with cytopenias unresponsive to dose reduction. Monitor for signs or symptoms of malignancy and infection. Several drug interactions.
Selective depletion of B-cells
Rituximab, eg, 500 mg/m2 for two doses, 2 weeks apart	Chimeric monoclonal antibody against CD20.	Common: hypersensitivity reactions or anaphylaxis and other infusion-related reactions (throat irritation, nausea, gastrointestinal symptoms, hypo- or hypertension, fever, chills, headache, insomnia). Rare: prolonged hypogammaglobulinemia, anaphylaxis, renal and liver toxicity, cytopenias, increased risk of infections. Extremely rare: progressive multifocal leukoencephalopathy.	Premedication with antihistamines, acetaminophen, and intravenous steroids; management of infusion reactions. Monitoring: CBC, renal and liver functions, lymphocyte immunophenotyping at 2 weeks, 4 months, and then monthly from induction; re-treatment at B cell reconstitution in selected cases.

No randomized controlled trials focusing specifically on CNS vasculitis are available for the pediatric population, but targeted therapies in some monogenic disorders have been evaluated or are currently under investigation with clinical trials. Decision to treat and choice of plan is based on physician judgment of best care, but the need for careful assessment of possible genetic etiologies and specific targets is paramount in clinical decision making. Most of the above-mentioned treatments may entail embryo-fetal toxicity. Women of reproductive potential must be counseled regarding pregnancy prevention and planning. Live attenuated vaccines should be avoided during use; other vaccinations may be less effective during therapy.

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

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E Ann Yeh MD MA FRCPC

Dr. Yeh of the University of Toronto has received a research grant from Biogen and honorariums from Alexion, Biogen, Hoffman/LaRoche, and Novartis for scientific advisory service.
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Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Diagnosis of childhood immune-mediated CNS vasculitides

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Diagnosis of childhood immune-mediated CNS vasculitides …

Diagnosis of childhood immune-mediated CNS vasculitides

Introduction

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Historical note and terminology

Clinical manifestations

Vasculitis syndromes

Table 1. List of Most Common Systemic Rheumatologic Diseases That May Be Associated with CNS Vasculitis and Systemic Vasculitides with Possible CNS Involvement

Prognosis and complications

Biological basis

Differential diagnosis

Confusing conditions

Table 2. Differential Diagnosis of CNS Vasculitis

Diagnostic workup

Table 3. Laboratory Investigations

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Outcomes

Table 4. Common Treatments for Childhood CNS Vasculitis

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Hepatic encephalopathy

Cervical spondylotic myelopathy

Bowel dysfunction in neurologic disorders

Diagnosis of childhood immune-mediated CNS vasculitides

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Vasculitis syndromes

Table 1. List of Most Common Systemic Rheumatologic Diseases That May Be Associated with CNS Vasculitis and Systemic Vasculitides with Possible CNS Involvement

Prognosis and complications

Biological basis

Differential diagnosis

Confusing conditions

Table 2. Differential Diagnosis of CNS Vasculitis

Diagnostic workup

Table 3. Laboratory Investigations

Management

Outcomes

Table 4. Common Treatments for Childhood CNS Vasculitis

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

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Hepatic encephalopathy

Cervical spondylotic myelopathy

Bowel dysfunction in neurologic disorders

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