Acute infections have been associated with arterial ischemic stroke (AIS) in adults, and recent data suggest a similar association in children. Although infection may cause AIS by inducing a systemic pro-thrombotic state, it may also cause a cerebral arteriopathy through either (1) direct invasion by infectious agents into arterial walls, or (2) endothelial injury mediated by local inflammatory cytokines. Children are the ideal subject population to study the vascular effects of infection because of the absence of age-related atherosclerotic risk factors. Furthermore, recent data suggest that, in children with AIS, arteriopathy strongly predicts recurrence. While this arteriopathy includes established entities, such as arterial dissection and moya moya, most children have an isolated unilateral focal stenosis of intracranial vessels. The etiology of this remains unclear, although several infectious agents, including herpes viruses, have been implicated. We propose a multicenter study of childhood stroke to test the hypotheses that infection can lead to AIS by causing vascular injury, and the resultant arteriopathy predisposes children to recurrent stroke. Our primary aims are: (1) to measure the cross-sectional prevalence and characteristics of both recent infections and arteriopathy in an international cohort of children with AIS;(2) to determine whether recent infection is associated with arteriopathy among children with AIS, and to further elucidate associations with infection site, time frame, infectious burden, and recent herpes virus infections;(3) to prospectively determine if arteriopathy and inflammatory markers predict stroke recurrence, and whether these associations vary by type arteriopathy. Methods: Over 3 years, we will prospectively enroll 480 children (aged 1 month to through18 years) with AIS at 25 centers (14 U.S., 6 Canadian, and 5 non-North American) and collect (1) extensive infectious histories (through parental interview), (2) blood samples (and CSF, when available), and (3) clinically obtained but standardized brain and cerebrovascular imaging studies. Imaging studies will be centrally reviewed and adjudicated. Centralized laboratory assays will include serologies and molecular assays for herpes viruses, and levels of inflammatory markers. Subjects will be followed prospectively for recurrent ischemic events. We will bank biological specimens (including DNA) for future studies of specific infectious agents and mediators of inflammation relevant to thrombosis and vascular injury. Significance/Future Directions: The data obtained from this study will shed light on the role of infection in childhood stroke. Because arteriopathy is likely the major predictor of recurrent stroke in children, a better understanding of the vascular injury pathway is critical for the development of rational strategies for secondary stroke prevention in children. The long-term goal is to identify inflammatory mediators causing arteriopathy that may serve as targets for therapeutic intervention.

Public Health Relevance

Ischemic stroke (blockage of blood vessels to the brain) affects approximately 4,000 U.S. children per year, and recurs in 1 out of 5 cases, causing lifelong disabilities in affected individuals and great costs to society. The proposed study will improve our understanding of this disease by determining whether infections injure blood vessels and thereby predispose children to stroke. It will also determine causes of recurrence, a crucial step towards developing ways to prevent repeated strokes in children.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Hirtz, Deborah G
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Wintermark, M; Hills, N K; DeVeber, G A et al. (2017) Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study. AJNR Am J Neuroradiol 38:2172-2179
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