Childhood primary angiitis of the central nervous system: Angiography-negative 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 typically presents with a stroke phenotype. (See "Childhood primary angiitis of the central nervous system: Angiography-positive subtype".)

●Angiography-negative cPACNS – AN-cPACNS affects small vessels and typically presents with an encephalitis phenotype. A diagnosis of AN-cPACNS is characterized by the presence of inflammatory changes in serum and cerebrospinal fluid (CSF), as well as inflammatory lesions on neuroimaging with normal vasculature on magnetic resonance angiography (MRA), when infection and autoimmune encephalitis have been excluded. Confirmation of the diagnosis of AN-cPACNS requires a brain biopsy demonstrating perivascular lymphocytic infiltrates affecting the small arteries in the parenchyma.

The clinical presentation of cPACNS overlaps with many other disorders including infections, autoimmune disease, malignancy, demyelinating disease, 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 AN-cPACNS. The clinical aspects of AP-cPACNS are discussed separately. (See "Childhood primary angiitis of the central nervous system: Angiography-positive subtype".)

EPIDEMIOLOGY — AN-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]. AN-cPACNS has been reported to have a female predominance [6,7].

PATHOPHYSIOLOGY — Blood and cerebrospinal fluid (CSF) markers, neuroimaging findings, and brain biopsy features point to cPACNS as an inflammatory disorder, with inflammation of the vessel wall being the hallmark feature [8]. However, the exact pathogenesis is unknown.

Perivascular and intramural T cell infiltrates of the small muscular arteries, arterioles, capillaries, and venules characterize AN-cPACNS (picture 1) [9]. Proliferation of astrocytes, microglia, and oligodendrocytes, as well as perivascular demyelination, have also been reported [9]. If granulomas are seen on tissue examination, other processes are more likely, including a systemic vasculitis or central nervous system (CNS) infection [8].

CLINICAL PRESENTATION — Patients with AN-cPACNS most commonly present with acute or subacute onset of at least two neuropsychiatric symptoms other than headache, for example, seizures, cognitive dysfunction, behavior changes, ataxia, and/or visual dysfunction [1,2]. Multifocal neurologic deficits are seen, and psychiatric symptoms, including mood abnormalities, are also common. The encephalitis phenotype is often accompanied by headache and systemic inflammatory symptoms, such as fever and fatigue [6-8].

In a small study of 45 patients, the most common neuropsychiatric symptoms present in patients with AN-cPACNS were seizures (85 percent), cognitive dysfunction (62 percent), headaches (62 percent), and behavior changes (42 percent) [2]. Motor deficits, vision abnormalities, and fever were also identified in 35 to 40 percent of patients with this subtype [2]. Symptom onset is highly variable in the encephalitis phenotype with some children presenting with rapid onset and progression, while others have a more insidious course with weeks to months of progressive symptoms.

Children with cPACNS who present with acute stroke symptoms are typically found on diagnostic testing to have angiography positive (AP)-cPACNS. (See "Childhood primary angiitis of the central nervous system: Angiography-positive subtype".)

DIAGNOSIS — The diagnosis of AN-cPACNS should be suspected in children who present with encephalitis of uncertain etiology. 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.

●Histologic confirmation – The angiography-negative (AN) subtype of cPACNS is confirmed by pathologic assessment of tissue obtained by brain biopsy. (See 'Referral and additional testing' below.)

DIFFERENTIAL DIAGNOSIS — The relatively nonspecific presenting features of encephalitis as well as the variable onset and temporal course of the encephalitis phenotype results in a lengthy differential diagnosis of conditions that may present with acute to subacute or progressive neuropsychiatric symptoms [7]. These conditions include (table 1):

●Demyelinating conditions (see "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis")

●Neurosarcoidosis (see "Neurologic sarcoidosis")

●Viral and other infections (see "Acute viral encephalitis in children: Clinical manifestations and diagnosis")

●Autoimmune encephalitis (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis")

●Hashimoto encephalitis (see "Hashimoto encephalopathy")

●Systemic vasculitides (see "Vasculitis in children: Incidence and classification", section on 'Major primary vasculitides' and "Vasculitis in children: Incidence and classification", section on 'Secondary vasculitis')

●Metabolic diseases (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, polymerase gamma syndromes) (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS' and "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Severe encephalomyopathy of infancy or childhood')

●Malignancy (see "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis")

DIAGNOSTIC EVALUATION — Diagnostic testing in patients with clinically suspected AN-cPACNS is performed to identify findings consistent with the diagnosis and exclude common alternative diagnostic possibilities (algorithm 1). Initial testing includes laboratory testing, imaging, and cerebrospinal fluid (CSF) analysis. Additional follow-up testing, including biopsy, is 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 encephalitis 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, such as neurofibromatosis type 1 or Down syndrome, also have associated findings that are readily identified on history and physical examination.

Initial testing

Laboratory testing — Initial testing for a child with suspected AN-cPACNS should include screening laboratory testing including:

●Complete blood count with differential

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

●Electrolytes (basic metabolic profile)

●Liver function tests and albumin

●Lactate

●Vitamin B12 level

Serum (and CSF) testing for antineuronal autoantibodies (panel to assess for pediatric autoimmune encephalitis) should be performed in patients with no systemic complaints other than fever. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis", section on 'Autoimmune and postinfectious causes'.)

Most children with AN-cPACNS have evidence of inflammation on serum and CSF testing. In one report, 75 percent of children with AN-cPACNS had at least one abnormal serum inflammatory marker, and over 90 percent had increased CSF protein and/or cell count [7]. Leukocytosis with lymphocytic predominance was the most common finding. Children with AN-cPACNS have higher mean ESR and CRP levels at diagnosis compared with those with angiography positive (AP)-cPACNS [2].

The presence of electrolyte abnormalities, altered kidney function, transaminitis, elevated bilirubin, low albumin, or low vitamin B12 levels should prompt consideration of diagnoses other than AN-cPACNS. Microbiologic investigations must be negative. Any positive finding excludes the diagnosis of AN-cPACNS.

Additional testing may be performed as indicated by the clinical assessment [11]. For instance, the presence of accompanying systemic complaints, recent travel, or specific animal exposures may warrant additional infectious testing. Urine testing for toxicology may be performed if there is a history suggestive of exposure. (See 'Referral and additional testing' below.)

Neuroimaging — Neuroimaging is required for all patients with unexplained neuropsychiatric symptoms. Magnetic resonance imaging (MRI) of the brain including T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and T1-post contrast sequences is the preferred modality for AN-cPACNS to assess for inflammatory and/or ischemic lesions, leptomeningeal enhancement, and structural changes, such as tumors. Head computed tomography (CT) 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.

Findings consistent with AN-cPACNS include T2 hyperintensities as well as parenchymal contrast enhancement.

Magnetic resonance angiography (MRA) is not typically performed as part of the initial workup for AN-cPACNS because the vessels implicated in this subtype are too small to be seen on imaging studies.

CSF analysis — CSF analysis should include routine studies (ie, cell count, protein, glucose), cultures, oligoclonal bands, antineuronal autoantibodies, and lactate levels [11]. Additional specific testing for infections varies by geographic epidemiology, season, travel, and other exposures [12]. CSF studies can be helpful in distinguishing AN-cPACNS from infectious and autoimmune disorders.

Referral and additional testing — Confirmatory testing is performed for patients with clinical features and initial diagnostic testing suggestive of AN-cPACNS. Referral to clinicians and centers experienced with the diagnosis and management of cPACNS may help guide appropriate additional testing and treatment.

●Testing for autoantibodies for all patients – All children presenting with encephalitis who have no systemic complaints (except fever) should have serum and CSF testing for antineuronal autoantibodies, when preliminary investigations are not suggestive of infection, if not performed during the initial diagnostic evaluation.

Additional autoantibody testing for patients with systemic features of an autoimmune rheumatic disease or a personal or family history of autoimmunity or immune deficiency includes thyroid autoantibodies, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), double-stranded deoxyribonucleic acid (DNA) antibodies, and quantitative immunoglobulins.

●Brain biopsy for definitive diagnosis – While the initial diagnostic evaluation may lead to a strong suspicion for AN-cPACNS, definitive diagnosis of this condition requires brain biopsy showing signs of small-vessel vasculitis with perivascular lymphocytic infiltrates (picture 1) [7,9,13]. Brain biopsy is typically delayed until the results of antineuronal autoantibody and infectious testing are available since positive results would confirm alternate diagnoses [14].

Ideally, brain biopsy is performed prior to or within seven days of starting treatment, as the inflammation can decrease significantly and the intramural infiltrate can resolve if the biopsy is performed after this time, thereby leading to an inconclusive result [9]. The yield of brain biopsy is also dependent on the quality of the biopsy, with the best results seen if all three layers (ie, leptomeninges, gray matter, and white matter) are obtained [9]. Moreover, lesional biopsies are preferred over nonlesional biopsies [9]. In one study evaluating the diagnostic yield of brain biopsy in children over a 15-year period (1988 to 2003), the overall diagnostic yield was 48.5 percent, and the most frequent diagnosis made was small-vessel cPACNS [15]. The yield improved over time to 68.8 percent when only the last eight years of the study were included [15].

The brain biopsy is not repeated if it is negative. Alternative diagnoses should be considered. (See 'Differential diagnosis' above.)

●Electroencephalogram – An electroencephalogram (EEG) is indicated in any patient presenting with seizures to assess for ongoing nonconvulsive seizures and features suggestive of specific diagnoses, for example, extreme delta brush in N-methyl-D-aspartate (NMDA) receptor encephalitis.

●Cerebral angiography not indicated – While cerebral digital subtraction angiography may be performed to help confirm the diagnosis of AP-cPACNS, the small-vessel inflammation that is the hallmark of AN-cPACNS cannot be seen even on catheter-based invasive angiography [9,16].

MANAGEMENT AND OUTCOMES

Initial treatment for AN-cPACNS — All children with AN-cPACNS require early initiation of antiinflammatory therapy. Supportive therapies also help to promote recovery. Treatment recommendations for AN-cPACNS are based upon limited, low-quality, observational data and clinical experience [2,7,13,17]. Multidisciplinary management is recommended for children and adolescents with AN-cPACNS, drawing on the expertise of pediatric subspecialists, including neurologists, rheumatologists, psychiatrists, and rehabilitation therapists.

Antiinflammatory therapy — We suggest treatment with initial glucocorticoids plus a glucocorticoid-sparing agent for patients with AN-cPACNS. The usual regimen includes glucocorticoids for initial immunosuppression as well as a second immunosuppressive agent at diagnosis to address the underlying immune dysregulation, prevent recurrence, and reduce the need for ongoing glucocorticoids. A typical regimen consists of:

●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 (maximum 60 mg) with a taper over 6 to 12 months.

●Induction course of cyclophosphamide infusions (500 to 750 mg/m² monthly) for six months followed by 18 months of maintenance immunosuppression using oral mycophenolate mofetil (800 to 1200 mg/m²/day divided twice daily) or mycophenolic acid (500 to 800 mg/m²/day divided twice daily) [13]. Further immunosuppressive therapy is generally not needed unless there is clinical or imaging evidence of relapse. (See 'Treatment of relapses' below.)

Mycophenolate for both induction and maintenance therapy is an alternative option for children and adolescents with mild to moderate disease [18]. Several small observational studies suggest that maintenance treatment with mycophenolate is superior to azathioprine with fewer relapses [2,6,7,18,19].

For patients treated with cyclophosphamide, prophylaxis against Pneumocystis jirovecii using trimethoprim is advised [20]. Common gastrointestinal side effects of systemic glucocorticoids may be prevented by coadministration of proton pump inhibitors, while supplementation with vitamin D and calcium (if insufficient dietary intake) is often used to reduce osteopenia.

Supportive management — Interdisciplinary care involving physical therapists, occupational therapists, and speech language pathologists is essential to help determine the full extent and 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 be able to help characterize cognitive dysfunction to provide specific school recommendations based on their assessments.

Additional medications may be used to address symptoms of AN-cPACNS that profoundly impact daily functioning:

●Patients who have seizures typically require antiseizure medications in addition to immunosuppressive therapies. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)

●Mood dysfunction, hallucinations, and other psychiatric symptoms may benefit from selective serotonin reuptake inhibitors, second generation antipsychotics, or tricyclic antidepressants, as advised by pediatric psychiatrists. (See "Overview of prevention and treatment for pediatric depression".)

●Many children and adolescents with AN-cPACNS report disrupted sleep patterns that may benefit from melatonin or trazodone. (See "Pharmacotherapy for insomnia in children and adolescents: A rational approach".)

Ongoing monitoring for AN-cPACNS — Children and adolescents with AN-cPACNS should be monitored clinically, typically every three to six months for the first year and then yearly to track recovery and to assess for recurrence of inflammation and an indication for a repeat course of antiinflammatory therapy.

Monitoring should consist of careful clinical assessments accompanied by standardized outcome measures, including neurocognitive assessment tools and quality-of-life metrics, such as the PedsQL Quality-of-Life Inventory [21]. If inflammatory markers and/or von Willebrand factor (vWF) antigen are elevated at diagnosis, following these levels may be helpful as markers of active inflammation [22]. Serial MRIs are not routinely recommended in patients with AN-cPACNS, although repeat imaging is suggested if there are ongoing or recurrent neuropsychiatric symptoms.

Treatment of relapses — For patients with recurrent symptoms and evidence of new inflammation on imaging, additional antiinflammatory therapy is warranted. For patients who improved with initial course of antiinflammatory therapy, further treatment may include a repeat course of cyclophosphamide and mycophenolate mofetil. Other immunosuppressive agents may be warranted for patients who relapse during initial antiinflammatory therapy. Specific options vary according to the clinical scenario. As examples, severe relapse symptoms during maintenance therapy may warrant repeat initial induction treatment followed by dose adjustment or an alternative agent for maintenance therapy, whereas milder relapse symptoms may not warrant repeat initial induction before modifying maintenance therapy.

Prognosis and outcomes in AN-cPACNS — Early recognition is critical to optimize outcomes in children with AN-cPACNS [2,7,13,17]. Delayed diagnosis is associated with ongoing neuropsychiatric symptoms and poorer outcomes. Reduction in disease activity is slower in patients with AN-cPACNS compared with those with angiography positive (AP)-cPACNS, and they are more likely to have continuing deficits in cognitive function [2].

Studies report good resolution of symptoms and return to normal functioning in up to 70 percent of children with AN-cPACNS, but ongoing cognitive dysfunction is common and more prominent than in children with AP-cPACNS [2,7]. Specific deficits in working memory and processing speed, compared with verbal comprehension and perceptual reasoning, were noted in children with all types of cPACNS in one study [23]. However, lower full-scale IQ (intelligence quotient) scores and increased frequency of intellectual disability were seen in children with AN-cPACNS compared with those with AP-cPACNS. In addition, relapses are more common in patients with AN-cPACNS, occurring in approximately 40 percent, compared with those with AP-cPACNS [7].

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. (See "Childhood primary angiitis of the central nervous system: Angiography-positive subtype".)

•AN-cPACNS affects small vessels and typically presents with an encephalitis phenotype.

●Clinical features – Patients with AN-cPACNS most commonly present with acute or subacute onset of at least two neuropsychiatric symptoms, for example, seizures, cognitive dysfunction, behavior changes, ataxia, and/or visual dysfunction. Multifocal neurologic deficits are seen, and psychiatric symptoms, including mood abnormalities, are also common. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of AN-cPACNS is made in patients whose symptoms fulfill diagnostic criteria after diagnostic evaluation to exclude alternative possibilities (algorithm 1). Pathologic assessment of tissue obtained by brain biopsy is used to confirm the diagnosis of AN-cPACNS. (See 'Diagnosis' above.)

●Diagnostic evaluation – Diagnostic testing in patients with clinically suspected AN-cPACNS is performed to identify findings consistent with the diagnosis and exclude common alternative diagnostic possibilities (table 1). Initial testing includes laboratory testing, brain MRI with contrast, and cerebrospinal fluid (CSF) analysis. (See 'Initial testing' above.)

Additional follow-up testing, including biopsy, is performed to confirm the diagnosis. 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 – For patients with AN-cPACNS, we suggest treatment with initial glucocorticoids plus a glucocorticoid-sparing agent (Grade 2C). A typical regimen consists of (see 'Management and outcomes' 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 (maximum 60 mg) with a taper over 6 to 12 months.

•Induction course of cyclophosphamide infusions (500 to 750 mg/m² monthly) for six months followed by 18 months of maintenance immunosuppression using oral mycophenolate mofetil (800 to 1200 mg/m²/day divided twice daily) or mycophenolic acid (500 to 800 mg/m²/day divided twice daily).

Children and adolescents with AN-cPACNS should be monitored to track recovery and assess for recurrence of inflammation and an indication for a repeat course of antiinflammatory therapy.

●Prognosis – Resolution of symptoms and return to normal functioning occur in up to 70 percent of children with AN-cPACNS, but ongoing cognitive dysfunction is common. (See 'Prognosis and outcomes in AN-cPACNS' above.)