PIs: Heather J. Fullerton, Max Wintermark and Nicholas Stence
STATUS: Data Analysis
FUNDING: Marc and Lynne Benioff Pediatric Stroke Research Fund
Focal cerebral arteriopathy of childhood (FCA), also known as “transient cerebral arteriopathy” (TCA), is an acute, monophasic disease causing unilateral stenosis of the intracranial anterior circulation. FCA is one of the most common causes of arterial ischemic stroke (AIS) in a previously healthy child, and has also been described in young adults(ref). It confers a high risk of recurrent stroke (up to 25% within 1-year), compounding post-stroke lifelong disability. Mounting evidence suggests that most cases of FCA are inflammatory diseases, and possibly para/post-infectious. Vessel wall imaging (VWI) studies demonstrate enhancement of affected arterial segments. In its early phase, FCA can demonstrate rapid progression over days to weeks. Children with progressive arteriopathies seem to have a higher risk of recurrent ischemia, and a single study suggests a link between elevated inflammatory biomarkers (hsCRP and serum amyloid A), arteriopathy progression, and stroke recurrence. Varicella zoster virus is a long-established cause of FCA, yet other pathogens, including other herpes viruses, likely play a role as FCA continues to occur in VZV-vaccinated children.
Steroid treatment in FCA is increasingly utilized for prevention of recurrent stroke, although in the absence of clinical trial data. Equipoise remains: steroids might suppress the presumed focal inflammatory process of the vessel wall, but might also worsen the underlying infectious pathogenesis. A European and Australian Delphi consensus identified this issue as the highest priority for a clinical trial in the field of childhood stroke. A European/Australian Phase 3 randomized trial protocol, the Paediatric Arteriopathy Steroid Aspirin (PASTA) project, has received pilot funding in France. North American investigators, meanwhile, are drafting a Phase 2 trial protocol, the Focal Cerebral Arteriopathy Steroids (FOCAS) trial. FOCAS and PASTA investigators have realized the need for a quantitative measure of FCA severity to serve as a clinical trial endpoint that measures progression and regression of the arteriopathy over time. Our goal was to develop and validate the FCA Severity Score (FCASS) in the subcohort of children with FCA enrolled in the “Vascular effects of Infection in Pediatric Stroke” (VIPS) study.
The VIPS study was a prospective cohort study that enrolled 355 children (29 days to 18 years of age) with AIS at 37 international centers; its methods have been previously published [REF]. We performed central review of clinical data and cerebral and vascular imaging to confirm the AIS diagnosis and classify cervical and cerebral arteriopathies. We defined FCA as “unifocal and unilateral stenosis/irregularity of the large intracranial arteries of the anterior circulation (distal internal carotid artery [ICA] and/or its proximal branches).” FCA was further subclassified as FCA-inflammation type (FCA-i), FCA-dissection type (FCA-d), and FCA-undetermined (FCA-u).
Development of the FCASS: As the first step, two neuro-radiologists (M.W., N.S.) independently reviewed the vascular imaging for all FCA cases in VIPS and assigned a numeric score to each intracranial arterial segment: 0=no involvement; 1=irregularity or banding with no stenosis; 2= stenosis, <50% reduction in diameter; 3= stenosis, >50% reduction in diameter; 4=occlusion. The initial review included nine unilateral arterial segments, each scored separately: cervical, petrous, cavernous, and supraclinoid segments of the ICA; M1 and M2 segments of the middle cerebral artery (MCA); A1 and A2 segments of the anterior cerebral artery (ACA); and the posterior cerebral artery (PCA; either P1 or P2). The scores for the individual segments were summed to provide an initial total score. One neuro-radiologist (M.W.) scored all imaging twice in two separate sessions.
In an iterative process, we refined the scoring system with an a priori goal of maximizing (1) simplicity, (2) intra-rater and inter-rater reliability, and (3) correlation with clinical outcome measures. With the goal of developing a “user-friendly” too, we maximized simplicity by eliminating the scoring of arterial segments that were uncommonly involved or otherwise did not differentiate between cases. Clinical outcome measures included 1-year cumulative stroke recurrence rates and 1-year PSOM scores, as defined in prior VIPS publications.