Primary angiitis of the central nervous system in children, which encompasses a spectrum of progressive and nonprogressive large- and small-vessel inflammatory brain diseases, has been linked in recent years to a range of neurologic conditions, such as refractory status epilepticus, movement disorders, severe cognitive dysfunction, optic neuritis, and psychiatric symptoms in previously healthy children, according to Dr. Susanne Benseler, director of the Childhood CNS Vasculitis Program at the Hospital for Sick Children in Toronto.

Although an accurate, timely diagnosis is essential for optimizing neurologic outcomes in this reversible disease, overlapping clinical features with noninflammatory brain conditions – such as vasoconstrictive disorders and neuronal antibody–associated conditions – can complicate the diagnosis and lead to treatment delays, as well as potentially devastating consequences, Dr. Benseler said at the joint annual meeting of the Canadian Rheumatology Association and the Mexican Congress of Rheumatology.

In this column, Dr. Benseler answers questions about the management of primary angiitis of the central nervous system in children (cPACNS) and offers a diagnostic algorithm that allows for rapid evaluation and initiation of targeted therapy.

QUESTION: What is the incidence of cPACNS in the general population?

Dr. Benseler: Primary central nervous system vasculitis in children includes progressive and nonprogressive, angiography-positive, large-vessel vasculitis, small-vessel vasculitis, and most recently, primary CNS venulitis. Because it has only recently been described in case reports and case series, the true incidence of cPACNS remains unknown, but as recognition of the condition increases, so does the number of cases that are diagnosed and treated appropriately. For example, we currently have no idea how many kids presenting with status epilepticus have CNS vasculitis. We can assume that the number is large, however, because once we began looking for vasculitis in these children, we have been diagnosing it in case after case.

QUESTION: What are some of the risk factors for the development of the disease?

Dr. Benseler: Primary childhood CNS vasculitis develops in heretofore perfectly healthy children. Preceding viral illness may play a role. However, no true risk factors have been identified so far. It does not run in families, and it does not reflect any "weakness" of the immune system. It is the exact opposite.

QUESTION: How is cPACNS diagnosed, and what are some of the more pressing diagnostic challenges?

Dr. Benseler: The diagnosis is based on an algorithm of clinical features, including the presence of newly acquired neurologic deficits and/or psychiatric symptoms; such serum inflammatory markers as C-reactive protein, erythrocyte sedimentation rate, and von Willebrand’s factor antigen; the absence of neuronal autoantibodies in the cerebrospinal fluid; evidence of ischemic or inflammatory parenchymal disease on MRI; and evidence of CNS vascular disease on angiography or brain biopsy (Curr. Opin. Rheumatol. 2010;22: 590-7). At the same time, causes of secondary vasculitis, noninflammatory vasculopathies, and nonvasculitic inflammatory brain diseases have to be excluded.

QUESTION: Should elective brain biopsies be done routinely in patients with suspected cPACNS, or is there a specific subgroup of children in whom the procedure is most appropriate?

Dr. Benseler: Following the diagnostic algorithm, brain biopsies should be considered in children in whom the treating physician has a strong clinical suspicion of an inflammatory brain disease in the absence of vasculitis on angiography.

QUESTION: You have noted that the spectrum of the disease in children comprises progressive and nonprogressive forms. Are there differences that are apparent at diagnosis that might help clinicians distinguish between the two forms, and how would this affect management?

Dr. Benseler: We have reported the clinical, laboratory, and imaging characteristics of both subtypes. Children with nonprogressive disease present with strokes in the absence of significant inflammatory markers. The vascular wall of the distal internal carotid artery and/or proximal middle cerebral artery and/or anterior cerebral artery are inflamed and thickened on gadolinium-enhanced MRI angiography. The lumen is narrowed, causing ischemic strokes in the vascular territory, which typically includes the basal ganglia. These kids are started on antithrombotic therapy in addition to a 3-month course of high-dose corticosteroids.

In contrast, children with progressive CNS vasculitis present with additional diffuse deficits, and have evidence of inflammatory markers and angiographic abnormalities affecting multiple vessel segments, including the distal vessels. Children are diagnosed based on their angiographic appearance and are treated with the same protocol that we have reported for small-vessel vasculitis, which includes 6 months of cyclophosphamide, monthly pulses plus high-dose steroids, followed by 18 months of mycophenolate maintenance therapy with tapering doses of steroids (Lancet Neurol. 2010;9:1078-84).

QUESTION: What are some of the key management considerations for cPACNS?

Dr. Benseler: The management of CNS vasculitis has multiple components, including drug theory for inflammation; symptom therapy, such as antiseizure medications, selective serotonin reuptake inhibitors, and other drugs; supportive medications, such as vitamin D and pneumocystis jiroveci pneumonia prophylaxis; rehabilitation; family support; and school-adjustment counseling.

This column, "Ask the Expert," regularly appears in Rheumatology News, an Elsevier publication. Dr. Benseler is also associate professor of pediatrics in the division of rheumatology and an associate scientist in Child Health Evaluative Sciences in the Research Institute at the University of Toronto. She has no conflicts of interest to disclose.

Primary CNS Vasculitis in Children