INTRODUCTION — Childhood primary angiitis of the central nervous system (cPACNS), or simply primary central nervous system (CNS) vasculitis, is the most common inflammatory brain disease affecting children. It typically presents with neurologic deficits, a stroke-like event, new onset of seizures, and/or psychiatric symptoms.
It is critical to first define the disease subtype, namely angiography positive or angiography negative, in order to best determine the diagnostic evaluation, including the distinct differential diagnoses of each subtype. The diagnostic evaluation focuses on ruling out other forms of primary and secondary inflammatory brain diseases and noninflammatory vasculopathies in addition to performing confirmatory studies, such as blood and cerebrospinal fluid (CSF) inflammatory markers, brain magnetic resonance imaging (MRI) and angiography, and, when angiography-negative disease is suspected, brain biopsies.
Treatment for cPACNS includes immunosuppression and anticoagulation to prevent disease progression and complications, in addition to symptomatic treatments such as anticonvulsive medications.
A general overview of childhood vasculitis is discussed in detail separately, as is PACNS in adults. (See "Vasculitis in children: Incidence and classification" and "Vasculitis in children: Evaluation overview" and "Vasculitis in children: Management overview" and "Primary angiitis of the central nervous system in adults".)
DEFINITION — cPACNS criteria are based upon the modified Calabrese criteria for adult PACNS and include [1-3]:
●Newly acquired, otherwise unexplained focal or diffuse neurologic deficits or psychiatric symptom in a patient less than 18 years of age
●Angiographic and/or histopathologic features of central nervous system angiitis
●Absence of an underlying or associated systemic disease
EPIDEMIOLOGY — Inflammation is an increasingly recognized cause of neurologic deficits in children [1-4]. The term "childhood primary angiitis of the central nervous system" (cPACNS) or "central nervous system" (CNS) vasculitis is used if the target of inflammation is the cerebral vasculature [1]. However, overlapping terminologies such as transient cerebral arteriopathy, post-varicella arteriopathy/angiopathy, and focal cerebral arteriopathy make epidemiologic evaluations challenging. Exact prevalence and incidence are not available for PACNS in adults or children.
Angiography-positive cPACNS corresponding to overall arterial ischemic stroke affects males more commonly than females [5]. CNS vasculitis is the most important etiology in the differential for previously healthy children presenting with ischemic stroke outside the neonatal period. Angiography-negative cPACNS shows a female predominance [2,6].
All cases described in the literature before 2000 were based upon autopsy reports, demonstrating the high mortality of the disease if not recognized and treated. Since then, earlier consideration of CNS vasculitis in the diagnostic evaluation of new-onset neurologic deficits and unexplained seizures has resulted in dramatically improved survival. At many tertiary care centers, cPACNS is the most frequently diagnosed inflammatory brain disease in children.
PATHOGENESIS — cPACNS is an inflammatory disease, based upon blood and cerebrospinal fluid (CSF) analysis, cerebrovascular imaging, and biopsy findings; the exact pathogenesis remains to be determined.
Autopsy cases, which are rare in angiography-positive cPACNS, typically reveal intramural inflammation with predominantly T cell infiltrates. In children in whom a triggering viral infection/reactivation of viruses from the trigeminal nerve root ganglion is documented, these viruses are typically found in the smooth muscle layer of the inflamed vessel, suggesting an adaptive immune response driving angiography-positive central nervous system (CNS) vasculitis. Vessel wall inflammation results in intraluminal stenoses and increased adherence of platelets to the vessel wall causing thrombus formation and artery-to-artery embolisms in the vascular territory in particular at the time of highly active inflammation and high degree of stenosis.
It remains unclear why the majority of children have a monophasic, unilateral inflammatory process affecting the proximal vasculature, the so-called nonprogressive cPACNS subtype, while others have proximal and distal vessel involvement that progress into new vascular territories.
Characteristic histologic findings of angiography-negative CNS vasculitis include perivascular and intramural T lymphocytic infiltrates with reactive endothelial cell changes and an absence of marked nonangiocentric parenchymal inflammation. In contrast with adult brain biopsies, necrosis and beta-amyloid depositions are absent in children with CNS vasculitis (picture 1) [7-9]. Associated findings include proliferation of reactive astrocytes, microglia, and oligodendrocytes (gliosis) and perivascular demyelination [7].
Granulomas are rarely seen in cPACNS and rather suggest an associated evolving systemic vasculitis such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis or a CNS infection. Hemorrhagic vascular changes are equally uncommon. More likely causes are genetic diseases resulting in vascular fragility such as deficiency of adenosine deaminase 2 (DADA2), collagen-vascular diseases such as a pathologic variant in the COL4A1 gene encoding procollagen type IV alpha 1, or infections such as Epstein-Barr virus and cytomegalovirus.
CLINICAL FEATURES — Subtypes of cPACNS are delineated based upon the size of the cerebral vessel involved and the disease course [1]. Three major subtypes, angiography-positive, nonprogressive large-medium-vessel cPACNS (NP-cPACNS), angiography-positive, progressive large-medium-vessel cPACNS (P-cPACNS), and angiography-negative small-vessel cPACNS (SV-cPACNS), can be distinguished on the basis of characteristic clinical presentations and laboratory and imaging features [1,2].
Stroke and headache are the most common clinical presentation in children with angiography-positive, large-medium-vessel central nervous system (CNS) vasculitis. A variable extent of focal sensorimotor deficits can be seen. The most commonly affected area of the brain are the basal ganglia due to the unique vascular blood supply through the so-called perforator arteries branching from the commonly affected proximal middle cerebral artery in a 90-degree angle. Acute stroke features in cPACNS most commonly result from decreased or fluctuating blood supply in the affected vascular territories due to vessel wall inflammation causing critical vessel stenosis.
Children with angiography-positive cPACNS most commonly present with unilateral sensorimotor deficits, hemiparesis, or aphasia. This presentation is distinctly different from embolic stroke symptoms, which can wax and wane in the acute phase. Headaches in older children and behavior changes in younger children due to pain are frequently seen. Not uncommonly, stroke features resolve and recur in the acute phase, which makes disease recognition very challenging. However, it is critical to recognize childhood strokes due to CNS vasculitis early on since intermittent deficits are frequently reversible.
In contrast, symptoms are static in the subacute phase of both NP-cPACNS and P-cPACNS due to the development of artery-to-artery embolisms, and they resemble adult ischemic stroke. Reversibility is often limited. Symptoms arising from the anterior circulation are more commonly seen. Bilateral deficits and systemic features of inflammation such as fever are highly suspicious for progressive CNS vasculitis.
Subtypes are helpful for guiding treatment plans and explaining disease course to patients and caregivers, though they are not absolute, and features of the different subtypes may overlap in individual patients. (See 'Diagnosis' below.)
Angiography-positive, nonprogressive cPACNS — NP-cPACNS is a monophasic condition characterized by unilateral clinical symptoms and corresponding unilateral vessel wall inflammation that typically results in inflammatory stenosis of the distal internal carotid artery (ICA), proximal middle cerebral artery (MCA), and/or proximal anterior cerebral artery (ACA) [10-12]. Other terms used to describe what is probably the same condition are transient cerebral arteriopathy (TCA), focal cerebral arteriopathy (CA), and post-varicella arteriopathy/angiopathy (PVA) [5,13,14]. By definition, PVA develops after exposure to varicella-zoster virus (VZV) and is associated with a reactivation of VZV in the trigeminal ganglia, retro-axonal transport of virus, and a characteristic pattern of vessel wall inflammation of the cerebral arteries [14]. Beyond VZV, studies have demonstrated that a variety of infectious triggers are associated with the development of this characteristic vasculitis subtype [15].
Children with NP-cPACNS present with sudden-onset, strictly unilateral, focal neurologic deficits and are commonly diagnosed with arterial ischemic stroke [1]. Presenting signs may include motor deficits, such as hemiparesis, hemifacial weakness, and loss of fine motor skills, as well as unilateral sensory loss [1]. Only 10 percent of children present with additional diffuse neurologic deficits, such as decreased cognition or change in behavior; some of these deficits are related to pain. Headaches are common at presentation of NP-cPACNS [1]. Systemic features of inflammation are typically absent in this subtype; however, a remote history of infectious symptoms lasting several weeks may be present.
In NP-cPACNS, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are commonly normal due to the focal nature of vessel wall inflammation [1]. Less than 50 percent of children have any detectable inflammatory markers, such as a mildly raised protein level or pleocytosis on cerebrospinal fluid (CSF) analysis. Opening pressure is sometimes elevated, but the clinical relevance of this finding remains uncertain. Raised von Willebrand factor (vWF) antigen is seen in two-thirds of patients, reflecting an acute endothelial irritation that results in a detectable vWF antigen release into the circulation [16].
Parenchymal brain MRI studies in children with NP-cPACNS show unilateral ischemic lesions in large-vessel distributions with characteristic changes in the stroke sequences depending on the timing of the images in relation to the events [10]. The basal ganglia are most commonly affected. Vasculitis is best confirmed by magnetic resonance angiography (MRA), which typically demonstrates irregular unilateral stenosis and/or dilatation of the distal ICA and proximal segments of the ACA and/or MCA (image 1) [1,11]. Similar to extracranial large-vessel vasculitis, designated gadolinium-enhanced vessel wall studies are required and can show vessel wall thickening and contrast wall enhancement due to intramural inflammation [17,18].
NP-cPACNS is an active inflammatory disease that can extend in the affected vascular territory, in particular over the first weeks of illness. In addition, artery-to-artery embolisms can develop and result in worsening parenchymal disease. However, by definition, NP-cPACNS does not extend into previously unaffected vascular territory and remains strictly unilateral. If the involvement of new vascular territories is demonstrated on repeat neuroimaging, the disease should be reclassified as progressive cPACNS.
Angiography-positive, progressive cPACNS — P-cPACNS tends to be more extensive than NP-cPACNS, proximal and distal vessel segments are commonly inflamed, and ischemic and inflammatory processes beyond the characteristic NP-cPACNS pattern are seen [1,10].
Headaches are the leading clinical feature in P-cPACNS, and they have been reported in up to 95 percent of affected children [1]. In addition, children with progressive large-vessel disease most commonly have both focal and diffuse neurologic deficits on presentation [1], although it is often the focal deficits such as hemisensory loss or fine motor skill deficits that are first noted and lead to the diagnosis. The diffuse deficits that are also present in these patients include difficulty in concentration, cognitive dysfunction, and mood and personality changes. Development of diffuse deficits is often insidious and can occur days to weeks before the diagnosis is made.
Inflammatory markers may be mildly to moderately raised in children with progressive disease, although normal CSF and/or acute-phase reactants do not exclude a progressive central nervous system (CNS) vasculitis [1].
The parenchymal lesions seen on MRI are commonly present in more than one vascular territory [10]. One in five children has bilateral lesions that are typically asymmetric and often involve both proximal and distal segments of the cerebral arteries (image 2) [1,10-12]. The anterior circulation is more commonly affected than the posterior circulation.
Angiography-negative, brain biopsy-positive, small-vessel cPACNS — Children with SV-cPACNS frequently present with severe encephalopathy, extensive focal deficits, and/or status epilepticus. The potential for rapid progression necessitates an expeditious and extensive evaluation, with a brain biopsy often required to confirm the diagnosis [2,6,19]. Systemic features, such as fever and fatigue, are frequently present in SV-cPACNS [2]. The majority of children with SV-cPACNS have seizures, and all seizure types are seen [2,6].
The mode of onset differs significantly from child to child. Some children present with a meningitis-like illness and have rapidly progressive disease course. In contrast, other children develop cognitive deficits over weeks to months, complain of headaches, or are diagnosed with focal seizures [6]. The diagnosis can be delayed in children with an underlying learning disability or autism because inflammation-associated cognitive decline can be more difficult to detect in these children.
Inflammatory markers are frequently abnormal in SV-cPACNS, although the degree of abnormality can range widely. One study reported at least one abnormal inflammatory serum marker at diagnosis in three out of four children with SV-cPACNS [6]. Over 90 percent of children in this study had an abnormal CSF analysis including increased CSF protein and/or cell count.
MRI abnormalities are present in the majority of patients with SV-cPACNS [10]. However, a normal MRI does not exclude the diagnosis. Ischemic lesions are uncommon in SV-cPACNS. Gadolinium enhancement of lesions and meninges are seen in almost 50 percent of children with active disease. Although the MRI findings in SV-cPACNS may be quite diverse, inflammatory lesions are most commonly seen in the subcortical white matter and cortical gray matter (image 3) [10]. Autopsies have established the generalized character of SV-cPACNS, in contrast with the sometimes-focal appearance on MRI. Nonetheless, the small caliber of vessels involved means that, by definition, all children with SV-cPACNS will have a normal MRA and conventional angiogram. Thus, brain biopsy is often necessary in order to make a definitive diagnosis.
DIAGNOSIS — A high level of suspicion and a rapid diagnostic evaluation of children suspected to have central nervous system (CNS) vasculitis are critical. The diagnostic evaluation for suspected cPACNS is a stepwise process that includes assessment for other forms of childhood inflammatory brain disease and disorders that mimic these diseases in addition to studies to confirm the presence of CNS vasculitis (algorithm 1) [20]. Patients should also be evaluated for potential prothrombotic abnormalities that may contribute to the disease process. (See 'Differential diagnosis' below.)
The first steps in the diagnostic evaluation in children with clinical features suggestive of cPACNS include:
●A general assessment for underlying disease processes (eg, infections, malignancies, other underlying systemic diseases). (See 'Differential diagnosis' below.)
●Neuropsychiatric testing as indicated by the clinical presentation (this testing may not be available urgently or in the inpatient setting).
●Laboratory studies to evaluate for inflammatory disease. Initial studies typically include an erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP), complete blood count (CBC) with differential, and testing for autoantibodies including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), extractable nuclear antigens (ENA), anti-double-stranded deoxyribonucleic acid (anti-dsDNA), complement components 3 and 4 (C3 and C4), and von Willebrand factor (vWF) antigen.
●Lumbar puncture for analysis of cerebral spinal fluid (CSF), including oligoclonal bands, neuronal antibodies, antibody synthesis, and tests for infections (culture and polymerase chain reaction [PCR]) and malignancies (cytologic analysis).
●A brain MRI and magnetic resonance angiography (MRA). The MRI should include the following sequences: T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) for parenchymal lesions [10,21]. Serial studies may be necessary to diagnose small-vessel cPACNS (SV-cPACNS) and are best viewed on T2/FLAIR sequences [10]. Notably, meningeal enhancement is not present in other primary inflammatory brain diseases, such as demyelinating diseases, and can help to distinguish SV-cPACNS [22]. The brain MRA should be performed with post-gadolinium-induced vessel wall enhancement, if possible. Conventional angiography (CA) is more sensitive but is also more invasive. Thus, it is usually only performed when the MRA is negative (particularly in small children or if posterior circulation involvement is suspected), when there is a question of vascular dissection [1,10,11], or when precise delineation of involved vessels is needed in children with large-medium-vessel cPACNS [1,10,11]. (See 'Differential diagnosis' below and 'Angiography-positive, nonprogressive cPACNS' above.)
Magnetic resonance vessel imaging with designated vessel wall contrast sequenced is usually sufficient to confirm the diagnosis of angiography-positive cPACNS. In children with suspected angiography-negative CNS vasculitis, also often called small-vessel CNS vasculitis, brain biopsies are routinely performed to establish the diagnosis and exclude other inflammatory brain diseases or, most importantly, mimics such as malignancies and infections [2].
●In children with suspected small-vessel disease in whom another disease process has not been identified, an elective brain biopsy is necessary to establish the final diagnosis of SV-cPACNS [2,7,23]. Ideally, the biopsy should be performed before treatment or within seven days of starting treatment. If biopsy is not possible, the clinician needs to decide if treatment should be started without having a definitive diagnosis.
The following studies illustrate the utility of brain biopsy and factors that may influence the diagnostic yield:
●In a study evaluating the diagnostic yield of elective brain biopsy performed between 1988 and 2003 in children with progressive neurologic decline, the overall diagnostic yield was 48.5 percent [24]. The diagnostic yield improved over time, increasing to 68.8 percent when only the biopsies performed in the last eight years of the study were included. The most frequent diagnosis made was SV-cPACNS.
●The diagnostic yield is dependent upon the quality of the brain biopsy, and the best results are obtained if all three layers are available for evaluation [7,24]. Lesional biopsies are preferred to nonlesional biopsies, although the diagnostic yield of nonlesional biopsies was identical to lesional biopsies in one small series [7]. The inflammation in cPACNS is influenced by immunosuppressive treatment. Depending on the therapy being used, there are up to seven days to perform a biopsy after immunosuppressive therapy is initiated. The inflammation might have decreased significantly and the intramural infiltrate might have resolved if a biopsy is performed after this time, leading to an inconclusive biopsy report.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis in a child that presents with neurologic deficits, particularly a stroke-like event, and/or psychiatric symptoms is broad and includes more common conditions, such as infections, strokes, metabolic disorders, and malignancies (eg, central nervous system [CNS] lymphoma). A broad array of infections should be considered in the differential diagnosis, including infection with viruses (eg, cytomegalovirus [CMV], Epstein-Barr virus [EBV], and human immunodeficiency virus [HIV]), bacteria (eg, Mycobacterium tuberculosis, Mycoplasma pneumonia, streptococcal pneumonia), fungi (eg, Candida albicans, Aspergillus, or Actinomyces), or other micro-organisms (eg, spirochete, such as Borrelia burgdorferi [Lyme disease]). These infections are discussed in separate topic reviews. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Viral meningitis in children: Clinical features and diagnosis" and "Emergency department approach to acute-onset psychosis in children" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Overview of common presenting signs and symptoms of childhood cancer" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" and "Inborn errors of metabolism: Identifying the specific disorder".)
The differential diagnosis narrows once the presence of CNS vasculitis is confirmed and differs greatly for large-medium-vessel cPACNS (nonprogressive [NP]-cPACNS and progressive [P]-cPACNS) and small-vessel cPACNS (SV-cPACNS) (table 1 and table 2) [20].
The differential diagnosis of large-medium-vessel disease includes noninflammatory vasculopathies (most common), cerebral vasospasm conditions, and several syndromes associated with cerebral vasculopathies (table 3) [25,26]. Clinically, the presentation is usually a stroke-like event for both large-medium-vessel cPACNS and for these other entities. However, additional characteristics of a possible underling cause of noninflammatory vasculopathies or genetic or syndromic disorder may be apparent on clinical examination (eg, café-au-lait lesions in neurofibromatosis 1) and help lead to the correct diagnosis. It is possible to differentiate between noninflammatory vasculopathies and inflammatory large-vessel cPACNS with gadolinium vessel wall enhancement [17,18].
The differential diagnosis for SV-cPACNS includes demyelinating diseases, neuronal antibody-mediated diseases, and other, less common conditions, such as Rasmussen encephalitis and neurosarcoidosis. Infection should also be excluded in children with meningeal enhancement on brain MRI (table 3) [10]. Although the nonvasculitic inflammatory brain diseases (IBrainD) have specific characteristics, these characteristics overlap [22]. Thus, an elective brain biopsy is mandatory to establish a diagnosis and initiate the appropriate therapy if an IBrainD is suspected, but no conclusive diagnosis can be established with clinical, laboratory, and neuroimaging features (table 4).
The differential diagnosis of cPACNS also includes secondary CNS vasculitis, which can affect both or either large or small cerebral vessels. The causes of secondary CNS vasculitis include infections, systemic rheumatic diseases, other systemic inflammatory diseases, and other systemic processes (table 4). The neurologic clinical and radiographic patterns of large-vessel CNS vasculitis are similar to angiography-positive, secondary CNS vasculitis (table 5). Causes of secondary CNS vasculitis are differentiated from cPACNS by the presence of additional clinical findings and identification of an underlying disease process.
TREATMENT
Treatment approaches — Suggested treatment protocols for the three different types of cPACNS are based upon limited observational data and the clinical experience of experts as well as data extrapolated from the adult literature and therapeutic strategies for other forms of vasculitis.
Immunosuppressive therapy is the mainstay of treatment for children with PACNS. We suggest intravenous induction therapy followed by oral maintenance therapy, which is tapered over several months. Steroid-sparing agents, such as cyclophosphamide and mycophenolate mofetil (MMF), are used in addition to glucocorticoids for progressive large-vessel cPACNS and small-vessel cPACNS since longer courses of anti-inflammatory agents are required for these types of cPACNS [6,23,27,28]. Other diagnoses for which treatment is contraindicated (eg, glucocorticoids in the setting of infection or malignancy) should be excluded prior to starting anti-inflammatory therapies. (See 'Differential diagnosis' above.)
For patients with medium- or large-vessel vasculopathy on cerebral angiography and in patients who present with ischemic stroke, we additionally suggest anticoagulation acutely followed by maintenance antiplatelet therapy. Antithrombotic therapy for stroke prevention is reviewed in detail separately. (See "Ischemic stroke in children: Management and prognosis".)
Treatment is started when the diagnosis is confirmed radiographically in medium- or large-vessel disease (eg, evidence of active vessel wall inflammation is seen) or in suspected small-vessel disease pending biopsy results if suspicion is high once other diagnoses have been excluded. (See 'Differential diagnosis' above.)
Our overall specific approach for the three types of cPACNS includes:
●For angiographically positive, nonprogressive cPACNS:
•Methylprednisolone 30 mg/kg (maximum 1 g) daily for 3 to 5 days, followed by oral prednisone 2 mg/kg (maximum 100 mg) daily, tapering over 3 months
•Unfractionated heparin or weight-based low molecular weight heparin followed by aspirin 3 to 5 mg/kg (maximum 300 mg) daily for long-term therapy (see "Ischemic stroke in children: Management and prognosis", section on 'Early antithrombotic therapy')
●For angiographically positive, progressive cPACNS or angiographically negative (brain biopsy-positive) cPACNS:
•Methylprednisolone 30 mg/kg (maximum 1 g) daily for 3 to 5 days, followed by prednisone 2 mg/kg (maximum 100 mg) daily, tapering over 12 months
•Cyclophosphamide 500 to 750 mg/m2 monthly intravenous infusions for 6 months, followed by mycophenolate mofetil 100 to 1200 mg/m2 daily dose for months 7 to 24
•Unfractionated heparin or low molecular weight heparin (typically 3 to 5 days) followed by aspirin 3 to 5 mg/kg (maximum 300 mg) daily for long-term therapy (for children with cPACNS that is either angiographically positive or associated with ischemic stroke)
Dosing regimens for various agents and monitoring are discussed separately. (See "Determinants of glucocorticoid dosing" and "Heparin and LMW heparin: Dosing and adverse effects" and "General principles of the use of cyclophosphamide in rheumatic diseases" and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
In the absence of trial data, treatment strategies for cPACNS are based upon observational data without control groups and expert opinion. The available evidence is summarized in a 2019 review [29]. (See "Primary angiitis of the central nervous system in adults" and "Overview of the management of vasculitis in adults".)
Additional medications are used in specific circumstances:
●Antiseizure medications are reserved for patients with seizures. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
●Acyclovir is given if there is a suspicion of varicella-zoster virus (chickenpox) exposure or reactivation (shingles). (See "Treatment of varicella (chickenpox) infection" and "Post-exposure prophylaxis against varicella-zoster virus infection" and "Treatment of herpes zoster in the immunocompetent host".)
●Calcium (1000 mg/day) and vitamin D (1000 international units/day) supplements are given during systemic glucocorticoid treatment.
●Trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis pneumonia (PCP) is given to patients on cyclophosphamide. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Trimethoprim-sulfamethoxazole'.)
Duration of therapy — Treatment is discontinued once the protocol has been completed, assuming the treatment was successful and the patient has not had any new disease activity during the treatment taper.
Refractory disease — There are limited options for refractory disease. One patient with multiple relapses was successfully treated with a tumor necrosis factor alpha (TNF-alpha)-blocking agent, infliximab [30].
MONITORING — Patients' interval histories should be assessed regularly as subtle changes in a child's functioning or well-being may be the first hint of active disease. These should be accompanied by careful physical examinations, particularly focusing on neurologic and neuromuscular functioning. The pediatric stroke outcome measure (PSOM) [31] can be used to assess a patient's neurologic function during serial visits, combined with an overall disease activity score such as a clinician visual activity score.
Diminished health-related quality of life was reported in children with inflammatory brain diseases, specifically in children presenting with seizures and cognitive dysfunction [32]. Cognitive outcomes and quality-of-life assessments should be incorporated into the monitoring of children with CNS vasculitis.
Laboratory tests, such as acute-phase reactants or von Willebrand factor (vWF) antigen [16], may also be useful in monitoring disease activity. Serial MRIs are used to assess disease activity/progression and are performed at diagnosis, 3 months, 6 months, 12 months, and then on a yearly basis. Monitoring in children with vasculitis is discussed in detail separately. (See "Vasculitis in children: Management overview", section on 'Patient monitoring'.)
COMPLICATIONS — The most common complications of cPACNS are strokes, seizures, and psychosis/behavioral changes. In addition, patients may have therapy-related complications. Long-term systemic glucocorticoid use can lead to numerous side effects. Immunosuppressive treatment can lead to increased risk of infections. These potential complications are reviewed in detail separately. (See "Major side effects of systemic glucocorticoids".)
Strokes — Strokes are often the presenting manifestation of large-vessel central nervous system (CNS) vasculitis. Treatment should focus on both the underlying vasculitis and also the effects and consequences of the stroke itself. Treatment with anticoagulation should be initiated immediately. In addition, these patients benefit from physical therapy and occupational therapy. Early intervention and initiation of therapies are associated with a better long-term neurologic outcome. (See "Initial assessment and management of acute stroke".)
Seizures — CNS vasculitis patients frequently present with seizures, particularly in patients with small-vessel disease. Antiseizure medication therapy should be initiated according to the epilepsy guidelines. Most patients require one or more antiseizure medications to control the seizure activity. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
Psychosis and behavioral complications — Many patients suffer from behavioral complications as a result of the disease or the disease process. Psychosis is seen less often in patients with CNS vasculitis than in those with neuronal antibody-mediated inflammatory brain diseases. Evaluation and management by a psychologist or psychiatrist is preferable if one of these specialists is available. Antipsychotic medications should be weaned over a longer period than usual and under close supervision. In a retrospective study, children with primary CNS vasculitis displayed diminished cognitive outcomes with relative deficits in working memory and processing speed, whereas lower intellectual functioning was more common in the small-vessel disease subtype [33]. (See "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation".)
PROGNOSIS — The mortality and morbidity have decreased significantly compared with historic controls in the literature due to earlier clinical recognition, an increase in early elective brain biopsies, and more aggressive treatment regimens, although exact numbers are not available, due to the rarity of the disease and likelihood that some cases are still missed. The long-term impact on cognitive function, especially in the small-vessel disease subtype, is still not well understood.
RESOURCES — BrainWorks is a large multinational database and network of researchers studying children with inflammatory brain diseases, including children with cPACNS. The website includes information on the diagnosis and management of cPACNS and resources for caregivers and families.
SUMMARY AND RECOMMENDATIONS
●Definition and terminology – Childhood primary angiitis of the central nervous system (cPACNS) is a form of childhood central nervous system (CNS) vasculitis or inflammatory brain disease. The different subtypes of cPACNS are classified based upon the size of the cerebral vessel involved and the disease course. These include:
•Nonprogressive large-medium-vessel cPACNS (NP-cPACNS)
•Progressive large-medium-vessel cPACNS (P-cPACNS)
•Small-vessel cPACNS (SV-cPACNS)
Each subtype is associated with distinct presenting symptoms and laboratory and neuroimaging findings. (See 'Definition' above.)
●Diagnosis – The diagnostic evaluation for suspected cPACNS includes assessment for other forms of childhood CNS vasculitis or inflammatory brain disease or disorders that mimic these diseases. Testing typically includes laboratory testing for inflammatory markers, brain MRI and angiography, and cerebrospinal fluid analysis (algorithm 1). A brain biopsy is required to confirm the diagnosis of SV-cPACNS. Patients should also be evaluated for potential prothrombotic abnormalities that may contribute to the disease process. (See 'Diagnosis' above.)
●Differential diagnosis
•Clinical differential – The differential diagnosis for a child that presents with neurologic deficits, particularly a stroke-like event, and/or psychiatric symptoms is broad and includes more common conditions, such as infections, strokes, metabolic disorders, and malignancies (table 2). (See 'Differential diagnosis' above.)
•Radiologic differential – The differential diagnosis for a symptomatic child with radiologic evidence of vasculopathy varies based on the size of impacted cerebral vessels. For patients with medium-to-large vessel involvement, the differential diagnosis includes noninflammatory vasculopathies, cerebral vasospastic conditions, and several syndromes associated with cerebral vasculopathies (table 3). For patients with small-vessel involvement, the differential includes demyelinating diseases, neuronal antibody-mediated diseases, and infection (table 4). (See 'Differential diagnosis' above.)
●Treatment approaches – Treatment for most patients with cPACNS includes immunosuppressive therapy and antithrombotic therapy. Our preferred approach for most patients includes the following (see 'Treatment approaches' above):
•We suggest immunosuppressive therapy with intravenous induction therapy followed by oral maintenance therapy for children with PACNS (Grade 2C). The specific regimen varies by subtype of cPACNS:
-For patients with angiographically positive, nonprogressive cPACNS, we use methylprednisolone 30 mg/kg (maximum 1 g) daily for 3 to 5 days, followed by oral prednisone 2 mg/kg (maximum 100 mg) daily, tapering over 3 months.
-For patients with angiographically positive, progressive cPACNS or angiographically negative (brain biopsy-positive) cPACNS, we use methylprednisolone 30 mg/kg (maximum 1 g) daily for 3 to 5 days, followed by oral prednisone 2 mg/kg (maximum 100 mg) daily, tapering over 12 months. In addition, we add cyclophosphamide 500 to 750 mg/m2 monthly intravenous infusions for 6 months, followed by mycophenolate mofetil 100 to 1200 mg/m2 daily dose for months 7 to 24.
•We also suggest anticoagulation acutely followed by maintenance antiplatelet therapy for patients with medium- or large-vessel vasculopathy on cerebral angiography or who present with ischemic stroke (Grade 2C). This typically includes unfractionated heparin or low molecular weight heparin acutely (typically 3 to 5 days) followed by aspirin 3 to 5 mg/kg (maximum 300 mg) daily for long-term therapy.
●Follow-up monitoring – In addition to regular histories, physical examinations, and monitoring of laboratory tests, serial MRIs may be useful to assess disease activity/progression. (See 'Monitoring' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Marinka Twilt, MD, PhD, and Susanne Benseler, MD, PhD, who contributed to earlier versions of this topic review.
