Childhood primary angiitis of the central nervous system: Angiography-positive subtype

INTRODUCTION AND CLASSIFICATION — Childhood primary angiitis of the central nervous system (cPACNS), also called primary central nervous system (CNS) vasculitis, is an inflammatory disorder of the CNS that affects children and adolescents and presents with the acute or subacute onset of neurologic and/or psychiatric symptoms. Patients with cPACNS typically present with either arterial ischemic stroke or encephalitis.

There are two subtypes of cPACNS that correspond to these distinct clinical presentations, angiography-positive (AP) and angiography-negative (AN) [1,2].

●Angiography-positive cPACNS – AP-cPACNS affects medium and large vessels and usually presents with a stroke phenotype. A diagnosis of AP-cPACNS is characterized by the presence of unilateral vessel stenosis and/or dilatation, as well as vessel wall thickening and contrast enhancement, with a unilateral ischemic lesion in the vascular territory of the affected vessel. Exclusion of underlying infection, hypercoagulability, and other causes of visualized vascular abnormalities is required.

AP-cPACNS is further subdivided into:

•Nonprogressive AP-cPACNS – Typically monophasic and unilateral.

•Progressive AP-cPACNS – Characterized by new findings of active vasculitis three or more months after diagnosis and initiation of treatment. (See 'Progressive AP-cPACNS' below.)

●Angiography-negative cPACNS – AN-cPACNS affects small vessels and usually presents with an encephalitis phenotype. (See "Childhood primary angiitis of the central nervous system: Angiography-negative subtype".)

The clinical presentation of cPACNS overlaps with many other disorders including infections, autoimmune disease, malignancy, demyelinating disease, noninflammatory vasculopathies, and metabolic disease [3,4]. This clinical overlap demands a high index of suspicion and thorough diagnostic investigation that may require noninvasive imaging, catheter angiography, and/or brain biopsy to identify cPACNS and rule out alternative etiologies [3,4]. Recognizing the distinct cPACNS phenotypes is critical as this has significant implications for diagnostic evaluation and subsequent treatment with anticoagulation, immune suppression, and supportive therapies.

This topic will review the clinical features, diagnosis, and management of AP-cPACNS. The clinical aspects of AN-cPACNS are discussed separately. (See "Childhood primary angiitis of the central nervous system: Angiography-negative subtype".)

EPIDEMIOLOGY — AP-cPACNS is rare, but the actual incidence and prevalence is unknown. Estimates of the incidence of pediatric cerebral vasculitis are highly variable and dependent upon the study population and search strategy employed [5]. The presence of similar and overlapping entities described by different names, such as transient or focal cerebral arteriopathy, also makes determining the incidence and prevalence of cPACNS challenging [5]. AP-cPACNS has been reported to affect males more often than females [6].

PATHOPHYSIOLOGY — Blood and cerebrospinal fluid markers, neuroimaging findings, and brain biopsy features point to cPACNS as an inflammatory disorder, with inflammation of the vessel wall being the hallmark feature [7]. However, the exact pathogenesis is unknown.

In AP-cPACNS, vessel wall inflammation is thought to cause narrowing of the vessel lumen (image 1) and increased adherence of platelets to the vessel wall [7]. This, in turn, can lead to thrombus formation, artery-to-artery embolization, and decreased perfusion in the affected vascular territory [7]. In most patients with AP-cPACNS, this inflammation is monophasic and unilateral. However, in a subset, there is progression and worsening of the arteriopathy beyond three months of disease (image 2) [7]. (See 'Progressive AP-cPACNS' below.)

CLINICAL PRESENTATION — Patients with AP-cPACNS most commonly present with acute arterial ischemic stroke. The arterial ischemic stroke phenotype is characterized by the acute onset of focal motor and/or sensory deficits such as asymmetric facial weakness, hemiparesis, and/or a unilateral sensory deficit [1,2,8]. A small study of 45 patients demonstrated that the most common symptoms in patients with AP-cPACNS were motor deficits (84 percent), headaches (63 percent), and speech deficits (53 percent) [2]. The clinical presentation of ischemic stroke in children is discussed in greater detail separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Clinical presentation'.)

A history of chronic or recurrent headaches may be elicited in many patients who present with acute ischemic stroke. Patients who present with chronic neurologic symptoms and evidence of prior infarction and bilateral vessel involvement may have progressive disease [8,9]. (See 'Progressive AP-cPACNS' below.)

Children with cPACNS who present with subacute and/or progressive neuropsychiatric symptoms are more typically found to have AN-cPACNS. (See "Childhood primary angiitis of the central nervous system: Angiography-negative subtype".)

DIAGNOSIS — The diagnosis of AP-cPACNS should be suspected in children who present with ischemic stroke and have evidence of unexplained vasculopathy on imaging. The diagnosis is made in patients whose symptoms fulfill diagnostic criteria after diagnostic evaluation to exclude alternative possibilities. (See 'Diagnostic evaluation' below.)

●Diagnostic criteria — The diagnosis of cPACNS is based on the following modification of the Calabrese criteria for adult primary angiitis of the central nervous system (PACNS) and requires [3,4]:

•An acquired and otherwise unexplained neurologic or psychiatric deficit

•Angiographic and/or histopathologic evidence of central nervous system (CNS) angiitis

•Absence of an underlying or associated systemic disease to explain criteria 1 and 2

In adults, PACNS is considered definite if there is confirmation of vasculitis on tissue biopsy and probable in the absence of histopathologic evidence but with supportive findings on neuroimaging and cerebrospinal fluid (CSF) analysis [10]. Of note, CNS angiitis is considered secondary if it occurs because of a systemic illness, for example, an infectious process, systemic vasculitis, or metabolic disorder.

●Angiographic confirmation – The angiography-positive (AP) subtype of cPACNS may be diagnosed or suspected by noninvasive neuroimaging (eg, magnetic resonance angiography) and can be confirmed by digital subtraction angiography, although this may not be necessary in all cases. (See 'Referral and additional testing' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for patients with AP-cPACNS broadly includes the other conditions that may present with acute stroke associated with intracranial vasculopathy, including the following (table 1):

●Noninflammatory vasculopathies (eg, arterial dissection, moyamoya disease) (see "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis")

●Reversible cerebral vasoconstriction syndrome (see "Reversible cerebral vasoconstriction syndrome")

●Infectious arteriopathies (eg, postvaricella vasculitis) (see "Varicella zoster virus vasculopathy")

●Secondary central nervous system (CNS) vasculitis due to underlying infection, systemic autoimmune rheumatic disease, or malignancy (see "Vasculitis in children: Incidence and classification", section on 'Secondary vasculitis')

●Postcranial radiation vasculopathy (see "Delayed complications of cranial irradiation", section on 'Vasculopathy and ischemic stroke')

●Cogan syndrome (see "Cogan syndrome")

●Genetic disorders associated with vasculopathy (ie, neurofibromatosis type 1, Down syndrome, sickle cell disease, PHACE [posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies] syndrome, Fabry disease) (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Down syndrome: Clinical features and diagnosis" and "Overview of the clinical manifestations of sickle cell disease" and "PHACE syndrome" and "Fabry disease: Clinical features and diagnosis")

DIAGNOSTIC EVALUATION — Diagnostic testing is performed in patients with clinically suspected AP-cPACNS to identify findings consistent with the diagnosis and exclude common alternative diagnostic possibilities (algorithm 1). Initial testing includes brain and vascular imaging and laboratory testing. Additional follow-up testing, including digital subtraction angiography (DSA), may be performed to confirm the diagnosis.

Clinical examination — A detailed history and physical examination, including a thorough neurologic assessment, are critical in the initial evaluation of any child or adolescent presenting with the stroke phenotype. These will guide further testing as well as identify potential alternative etiologies. For example, accompanying fever, infectious symptoms, and high-risk exposures, such as contact with animals or recent travel, may point toward an underlying infection. Additional systemic features, such as fever, fatigue, skin rashes, and musculoskeletal pain or swelling, may raise suspicion for a systemic autoimmune rheumatic disease, while fever, night sweats, and unexplained weight loss are concerning for an underlying malignancy. Genetic syndromes associated with vasculopathy, such as neurofibromatosis type 1 or Down syndrome, also have associated findings that are readily identified on history and physical examination.

Initial testing

Neuroimaging — Neuroimaging of the brain and intracranial vessels is performed for all patients with stroke symptoms. Imaging can provide a wealth of information for patients with AP-cPACNS. Thus, the initial step in the diagnostic evaluation of a child presenting with an acute onset focal neurologic deficit is to obtain neuroimaging.

Magnetic resonance imaging (MRI) of the brain with contrast and magnetic resonance angiography (MRA) of the head are the preferred diagnostic imaging modalities for cPACNS; head computed tomography (CT) and computed tomographic angiography (CTA) of the head may be performed for patients with a contraindication to MRI (eg, metallic implant/foreign body). However, CT-based imaging is less sensitive than MRI and exposes patients to radiation.

●Brain MRI with contrast – Brain MRI should include the following sequences: T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), and T1-post contrast sequences [11]. DWI and ADC allow for the identification of acute infarction, while T2 and FLAIR sequences enable the identification of subacute to chronic infarcts and help to differentiate the ischemic lesions seen in cPACNS from other types of intracranial pathology. While not universally included in standard MRI protocols, susceptibility-weighted imaging or gradient-recalled echo sequences can best reveal intracranial hemorrhage. Brain MRI is typically performed without contrast for patients with acute stroke but should be performed with contrast when cPACNS is a diagnostic possibility or may be repeated as a limited study to obtain postcontrast sequences.

All patients with AP-cPACNS will have an abnormal brain MRI (image 1).

•Typical findings – Typical initial MRI findings are unilateral acute or subacute ischemic lesions in the vascular territory of the affected vessel(s) [9]. Narrowing of the proximal middle cerebral artery (MCA) makes the lenticulostriate arteries that branch off the MCA to supply the basal ganglia vulnerable to decreased perfusion through the area of critical vessel stenosis. As such, the basal ganglia are most often affected in AP-cPACNS [9].

Contrast administration can reveal vessel wall enhancement [12], indicative of an inflammatory vasculopathy. Meningeal or parenchymal contrast enhancement can also be used to help distinguish other causes of an acute-onset focal neurologic deficit, for example, tumor, demyelination, or central nervous system (CNS) infection.

•Children with evidence of prior infarction – Evidence of acute and chronic ischemic stroke on initial brain MRI and/or stroke in more than one vascular territory may indicate the progressive form of AP-cPACNS [7,9]. (See 'Progressive AP-cPACNS' below.)

●Brain MRA – MRA is an essential component of initial diagnostic imaging for patients presenting with suspected AP-cPACNS. MRI and MRA may be done simultaneously or sequentially depending upon the suspicion for underlying vascular pathology, the need for sedation for younger children, and the accessibility of imaging in different centers.

MRA is also typically abnormal in children with AP-cPACNS [9,13]. Findings suggestive of AP-cPACNS include:

•Focal narrowing or irregularity at the site of vessel wall inflammation (image 1)

•Multifocal areas of narrowing or irregularity

•Abnormal/dilated collateral vessels

•Vessel wall thickening and contrast enhancement

In patients with severe arterial narrowing, there may be an absence of flow distal to the area of stenosis, mimicking a large-vessel occlusion. The presence of abnormal collateral vessels on MRA may suggest an underlying chronic disease process.

Normal neuroimaging excludes this diagnosis, and clinicians should consider alternative diagnoses within the differential. However, MRA may be less sensitive than invasive angiography, especially in infants and for mild abnormalities in the posterior cerebral circulation [13-15].

The most commonly affected vessels include the distal internal carotid artery (ICA), the proximal MCA, and/or the proximal anterior cerebral artery (ACA) [8]. The anterior circulation is more commonly affected than the posterior circulation [7]. Patients with progressive disease may have more than one vascular territory affected and may have bilateral involvement. However, the presence of bilateral, diffuse multifocal abnormalities in the presence of multiple collateral vessels should prompt consideration of other etiologies within the differential diagnosis, particularly a more longstanding noninflammatory vasculopathy such as moyamoya or fibromuscular dysplasia.

●Digital subtraction angiography – DSA may be performed to confirm AP-cPACNS and to exclude alternative diagnostic entities when MRA is nondiagnostic. (See 'Referral and additional testing' below.)

Laboratory testing — Laboratory testing for a child or adolescent with stroke and suspected cPACNS is performed to screen for alternative inflammatory or thrombophilic causes of stroke. Initial testing includes:

●Complete blood count (CBC) with differential

●Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

●Partial thromboplastin time (PTT) and International normalized ratio (INR)

●Fibrinogen

●D-dimer

Evidence of systemic inflammation in AP-cPACNS is typically absent or mild and nonspecific [7]. Inflammatory markers are usually normal given the focal nature of the vascular pathology. Fewer than half of affected children have pleocytosis or elevated protein levels on CSF analysis, if it is performed [8]. In addition, two-thirds of patients may have an elevated vWF antigen, reflecting endothelial disruption [16]. von Willebrand factor (vWF) antigen has been reported as a possible marker of disease activity for cPACNS [16]. (See 'Ongoing monitoring for AP-cPACNS' below.)

Referral and additional testing — Additional testing is performed for patients with suspected AP-cPACNS to confirm the diagnosis, including for those with atypical clinical features or nondiagnostic MRA [17]. Referral to clinicians and centers experienced with the diagnosis and management of cPACNS may help guide appropriate additional testing and treatment.

●Cerebral angiography – Angiographic evidence of CNS vasculitis is required for diagnosis of AP-cPACNS. DSA, also referred to as catheter angiography or conventional angiography, is the gold standard for cerebrovascular imaging for the diagnosis of AP-cPACNS. DSA can help identify evidence of vasculitis and exclude alternative vascular entities. As an example, in certain cases, dissection may be difficult to distinguish from cPACNS on noninvasive imaging. Similarly, inflammation that causes such severe arterial narrowing that forward flow is severely limited or nonexistent may mimic a large-vessel occlusion and, in some cases, this may be difficult to distinguish on noninvasive imaging.

●Testing for autoantibodies – Thrombophilia testing should be performed in children with ischemic stroke to exclude a prothrombotic disposition. Testing should include antiphospholipid antibodies (anticardiolipin antibodies, anti-beta-2 glycoprotein antibodies, and lupus anticoagulant).

Testing for other autoantibodies is generally reserved for patients who have initial clinical or laboratory features that raise suspicion for a systemic inflammatory disease. Autoantibody testing in patients where secondary CNS vasculitis is suspected may include: antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), extractable nuclear antigens (ENA), and anti-double-stranded deoxyribonucleic acid (anti-dsDNA).

Of note, secondary CNS vasculitis is more likely than cPACNS in patients who have additional systemic symptoms. (See "Vasculitis in children: Evaluation overview".)

●Cerebrospinal fluid (CSF) testing – Lumbar puncture is not required for patients with suspected AP-cPACNS and would only be considered if there is accompanying fever or other symptoms that raise suspicion for an underlying infection. Positive microbiologic investigations in CSF or serum would exclude a diagnosis of AP-cPACNS.

●Genetic testing – Genetic testing for conditions associated with vasculopathy may be performed for selected patients based on family history as well as clinical and imaging findings (table 1). Genetic testing may also help to distinguish cPACNS from the genetic disorders emerging as important causes of CNS vasculopathy.

●Brain biopsy – Brain and/or meningeal biopsy is not required to confirm a diagnosis of AP-cPACNS in children. The presence of ischemic lesions and vessel wall inflammation on neuroimaging and the exclusion of other causes of CNS vasculitis is sufficient.

MANAGEMENT AND OUTCOMES

Initial treatment of AP-cPACNS — All children with AP-cPACNS require early initiation of antiinflammatory and antithrombotic therapy. Supportive therapies also help to promote recovery. Treatment recommendations for AP-cPACNS are based upon data from case reports/case series and clinical experience rather than trial-based data [17,18]. Multidisciplinary management is recommended for children and adolescents with AP-cPACNS, drawing on the unique expertise of various pediatric subspecialists, including neurologists, hematologists, and rheumatologists.

Antiinflammatory therapy — For patients with AP-cPACNS, we suggest treatment with systemic glucocorticoids. The typical regimen involves intravenous (IV) methylprednisolone at a dose of 30 mg/kg/day up to a maximum dose of 1000 mg for three to five days. This is followed by oral prednisolone 2 mg/kg/day up to a maximum dose of 60 mg with a taper over three months. Further immunosuppressive therapy is generally not needed unless there is clinical or imaging evidence of progressive disease. (See 'Progressive AP-cPACNS' below.)

Patients treated with glucocorticoids are often given additional therapies to prevent common adverse effects, including coadministration of proton pump inhibitors to reduce gastrointestinal irritation and supplementation with vitamin D plus calcium as needed to promote bone health.

In a small observational study of patients with AP-cPACNS, the addition of immunosuppressive therapy to antithrombotic therapy was associated with better neurologic outcomes and fewer relapses than treatment with antithrombotic therapy alone [8,19].

Antithrombotic therapy — For patients with AP-cPACNS, we also suggest antithrombotic therapy. Evidence of efficacy is based on antithrombotic therapy for other causes of ischemic stroke as there are no data on efficacy of antithrombotic treatment for AP-cPACNS.

The regimen varies across centers and is often extrapolated from general pediatric stroke guidelines [5,17,18]. Many centers use low molecular weight heparin or unfractionated heparin in the acute phase with dosing as recommended by a hematologist or thrombosis team [17,18]. This is followed most often by aspirin (3 to 5 mg/kg/day) as long-term maintenance therapy [17,18]. The duration of treatment with aspirin varies widely but is typically a minimum of two years [17]. Aspirin may be discontinued if vessels return to normal. Vessels may normalize within the first two years if there is mild disease but rarely return to normal with more severe disease.

Supportive management — Interdisciplinary care involving physical therapists, occupational therapists, and speech language pathologists is essential to promote recovery of neurologic deficits, including paresis and speech and language disorders. These allied health providers may also perform a home assessment to arrange for any necessary equipment to maintain safety after hospital discharge. In addition, neuropsychologists, psychologists, and occupational therapists may provide specific school recommendations based upon their assessments.

Ongoing monitoring for AP-cPACNS — Children and adolescents with AP-cPACNS should be monitored clinically and with surveillance imaging to track recovery and assess for recurrence of inflammation, which can occur in a subset of children and indicates development of progressive AP-cPACNS. Additional treatment is required for patients with progressive AP-cPACNS.

Monitoring includes:

●Careful clinical assessments typically at 3, 6, and 12 months after diagnosis and then yearly for two to three years, unless the patient develops new symptoms. Clinical evaluation should be accompanied by standardized outcome measures, such as the Pediatric Stroke Outcome Measure (PSOM) [20] and Pediatric Stroke Quality of Life Measure (PSQLM) [21].

●Serial brain MRI and magnetic resonance angiography (MRA) at 3, 6 and 12 months after diagnosis and then yearly for at least two to three years. Patients may be followed clinically if imaging has remained stable through three-year follow-up.

von Willebrand factor (vWF) antigen is a possible marker of disease activity if the initial level is increased. One study found an association between highly elevated levels of vWF antigen at diagnosis and lower measures of disease activity after 12 months of treatment [16].

Progressive AP-cPACNS

Identification — Progressive AP-cPACNS is identified by recurrent stroke or by new vessel abnormalities on MRI/MRA, with or without new areas of infarction, occurring three or more months after diagnosis. Imaging changes may not be accompanied by recurrence of or new clinical features. Progressive disease may occur even with timely diagnosis and optimal treatment of AP-cPACNS. Nonprogressive AP-cPACNS appears more common than the progressive subtype. In a study of 62 children with AP-cPACNS, progressive disease was identified in 32 percent [8].

On initial presentation — It is often difficult to distinguish between the nonprogressive and progressive forms of AP-cPACNS at the time of initial presentation, especially in the case of progressive AP-cPACNS presenting early with unilateral clinical and imaging findings. Early clues suggestive of a progressive form of AP-cPACNS include:

●Clinical features – In children with the progressive form of AP-cPACNS, careful history may reveal days to weeks of headaches prior to onset of stroke. Additional clinical features, including cognitive dysfunction and changes in mood and personality, may be superimposed on the typical stroke phenotype and may precede the onset of the focal neurologic deficit that brings the child to medical attention [8].

●Initial neuroimaging findings – Subtle imaging findings may help to distinguish patients with progressive versus nonprogressive AP-cPACNS at diagnosis. In progressive AP-cPACNS, ischemic parenchymal MRI lesions are commonly present in more than one vascular territory and may be bilateral and asymmetric [7,9]. Over time, additional areas of vascular abnormality develop in children and adolescents with progressive AP-cPACNS and both proximal and distal vessel segments in multiple vascular beds may be affected [9,13].

Careful follow-up clinical and imaging monitoring is warranted to confirm progressive AP-cPACNS and guide subsequent therapy.

By surveillance monitoring — New ischemic stroke following initial treatment may indicate progressive AP-cPACNS. In addition, new vessel wall enhancement on surveillance follow-up MRI may serve as a potential marker of active inflammation in children and adolescents [22]. Over time, additional areas of vascular abnormality develop in children and adolescents with progressive AP-cPACNS, and both proximal and distal vessel segments in multiple vascular beds may be affected (image 2) [9,13].

Treatment — Patients with progressive AP-cPACNS are typically given additional antiinflammatory treatment because of the potential for ongoing inflammation leading to infarction and further neurologic deficits. Treatment recommendations are based upon limited, low-quality, observational data and clinical experience [17,18,23].

●For patients with progressive AP-cPACNS and new areas of infarction on MRI or vessel abnormalities on MRA, we suggest immunosuppressive therapy to address the underlying immune dysregulation and prevent further recurrence. This includes:

•For all patients, oral prednisolone 2 mg/kg/day up to a maximum dose of 60 mg with a taper over six months.

•For patients with severe symptoms and/or imaging findings (eg, bilateral, multivessel involvement and large areas of ischemia), a six-month induction course of cyclophosphamide (500 to 750 mg/m² monthly) followed by 18 months of maintenance immunosuppression using mycophenolate mofetil (800 to 1200 mg/m²/day divided twice daily) or mycophenolic acid (500 to 800 mg/m²/day divided twice daily) [17,18]. For patients treated with cyclophosphamide, prophylaxis against Pneumocystis jirovecii using trimethoprim is advised [22].

•For patients with mild to moderate symptoms and/or findings, induction and maintenance therapy using mycophenolate for 24 months (without a preceding cyclophosphamide course) [23].

The use of azathioprine for induction and/or maintenance is controversial. Although there are case reports supporting its use [24,25], there is also concern for more disease flares compared with mycophenolate [2,26,27], similar to central nervous system (CNS) lupus and lupus nephritis [28,29].

Prognosis and outcomes in AP-cPACNS — Earlier recognition has improved outcomes in children with cPACNS. Most patients with AP-cPACNS respond well to initial therapy. They tend to experience a more rapid decrease in disease activity compared with those with angiography-negative (AN)-cPACNS at one and two years after diagnosis [2]. Approximately 40 percent of patients experience complete neurologic recovery, while the remaining 60 percent have neurologic deficits that range from mild to severe and often include dystonia [8,30]. Recurrence of stroke following initial treatment in patients with progressive AP-cPACNS is rare [31]. Persistent vascular abnormalities are common in patients with cPACNS, and there are reports of discordant progression of vascular abnormalities without accompanying clinical signs of active inflammatory disease [30,31].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis".)

SUMMARY AND RECOMMENDATIONS

●Definition and subtypes – cPACNS is a central nervous system (CNS) inflammatory disorder that affects children and adolescents and presents with the acute or subacute onset of neurologic and/or psychiatric symptoms. Patients with cPACNS typically present with either arterial ischemic stroke (AIS) or encephalitis. (See 'Introduction and classification' above.)

There are two subtypes of cPACNS that correspond to these distinct clinical presentations, angiography-positive (AP) and angiography-negative (AN).

•AP-cPACNS affects medium and large vessels and typically presents with a stroke phenotype.

•AN-cPACNS affects small vessels and typically presents with an encephalitis phenotype. (See "Childhood primary angiitis of the central nervous system: Angiography-negative subtype".)

●Clinical features – Patients with AP-cPACNS most commonly present with acute arterial ischemic stroke. The arterial ischemic stroke phenotype is characterized by the acute onset of focal motor and/or sensory deficits such as asymmetric facial weakness, hemiparesis, and/or a unilateral sensory deficit. A history of chronic or recurrent headaches may be elicited in many patients who present with acute ischemic stroke. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis is made in patients whose symptoms fulfill diagnostic criteria after diagnostic evaluation to exclude alternative possibilities (algorithm 1). The characteristic vasculopathy of AP-cPACNS may be identified by noninvasive neuroimaging (eg, magnetic resonance angiography [MRA]) and can be confirmed by digital subtraction angiography (DSA). (See 'Diagnosis' above.)

●Diagnostic evaluation – Diagnostic testing is performed in patients with clinically suspected AP-cPACNS to identify findings consistent with the diagnosis and exclude common alternative diagnostic possibilities (table 1). Initial testing includes neuroimaging with brain MRI and MRA and laboratory testing. (See 'Initial testing' above.)

Additional testing, including DSA, is performed to confirm the diagnosis of AP-cPACNS. Referral to clinicians and centers experienced with the diagnosis and management of cPACNS may help guide appropriate additional testing and treatment. (See 'Referral and additional testing' above.)

●Management

•Initial treatment for all patients – For patients with AP-cPACNS, we suggest initial treatment with systemic glucocorticoids plus antithrombotic therapy (Grade 2C). A typical regimen consists of (see 'Initial treatment of AP-cPACNS' above):

-Intravenous (IV) methylprednisolone at a dose of 30 mg/kg/day up to a maximum dose of 1000 mg for three to five days followed by oral prednisolone 2 mg/kg/day up to a maximum dose of 60 mg with a taper over three months.

-Weight-based low molecular weight heparin or unfractionated heparin in the acute phase followed by aspirin (3 to 5 mg/kg/day) as long-term maintenance therapy.

•Surveillance – Children and adolescents with AP-cPACNS should be monitored clinically and with surveillance imaging to track recovery and assess for recurrence of inflammation, which can occur in a subset of children and indicates development of progressive AP-cPACNS. Progressive AP-cPACNS is identified by new ischemic stroke or by new vessel abnormalities on MRI/MRA, with or without new areas of infarction, occurring three or more months after diagnosis. (See 'Ongoing monitoring for AP-cPACNS' above.)

•Additional treatment for progressive AP-cPACNS – For patients with progressive AP-cPACNS, we suggest further antiinflammatory therapy (Grade 2C). (See 'Progressive AP-cPACNS' above.)

-For all patients, oral prednisolone 2 mg/kg/day up to a maximum dose of 60 mg with a taper over six months.

-For patients with severe symptoms and/or imaging findings (eg, bilateral, multivessel involvement and large areas of ischemia), a six-month induction course of cyclophosphamide (500 to 750 mg/m² monthly) followed by 18 months of maintenance immunosuppression using mycophenolate mofetil (800 to 1200 mg/m²/day divided twice daily) or mycophenolic acid (500 to 800 mg/m²/day divided twice daily).

-For patients with mild to moderate symptoms and/or findings, induction and maintenance therapy using mycophenolate for 24 months (without a preceding cyclophosphamide course)

●Prognosis – Approximately 40 percent of patients with AP-cPACNS recover completely, while the remaining 60 percent have persisting neurologic deficits that range from mild to severe and often include dystonia. Recurrence of stroke is rare and tends to occur in patients with progressive AP-cPACNS. (See 'Prognosis and outcomes in AP-cPACNS' above.)