Focal Cerebral Arteriopathy Steroid Trial

FCA is an acute, monophasic, presumed inflammatory disease that causes unilateral stenosis of the intracranial anterior circulation. In the medical literature, it has also been called transient cerebral arteriopathy (TCA) and post-varicella arteriopathy when it occurs after chicken pox. Although rare (1 to 3 cases seen per year at a typical academic children's hospital in the US), it is one of the most common causes of arterial ischemic stroke in a previously healthy child. Pediatric stroke investigators identified an FCA treatment trial as the #1 priority of the field (Steinlin M, Dev Med Child Neurol 2017) because of its aggressive natural history: it often progresses dramatically over days to weeks with recurrent or expanding infarcts. A 2017 European retrospective cohort study suggested that corticosteroid treatment may improve outcomes for FCA (Steinlin M, Stroke 2017).

Europeans have begun the PASTA (Paediatric Arteriopathy STeroid Aspirin) trial (PI Steinlin): a "gold-standard" RCT to test the efficacy of corticosteroids for FCA. A 2018 survey of pediatric stroke investigators (participating in the NIH-funded Vascular effects of Infection in Pediatric Stroke, VIPS II, cohort study) revealed discomfort with randomization to "no steroids" as the majority now treat FCA with corticosteroids. However, despite attitudes favoring their use, corticosteroids were given to only 36% of 55 children with suspected FCA in the VIPS II cohort and (when given) were started a median of 3 days post-stroke (IQR 1.5, 6) (unpublished preliminary data). This incongruity reflects diagnostic uncertainty at stroke baseline: the characteristic arteriopathy evolution is needed for definitive diagnosis of FCA, and ≈1 in 5 children with suspected FCA at baseline have an alternate diagnosis. Hence, the pressing clinical question is: Should we treat all children with suspected FCA immediately or wait and treat only the subset that demonstrate disease progression?

Early treatment has the potential advantage of preventing FCA progression, but the disadvantage of over treatment of those with alternate diagnoses. With a comparative effectiveness approach, the FOCAS trial will compare these two treatment approaches. FOCAS will also collect the steroid treatment safety data needed to guide clinical decisions.

Inclusion criteria

• Age 1 year through 18 years at stroke/TIA ictus (ineligible as of 19th birthday).
• Acute arterial ischemic stroke (AIS) or transient ischemic attack (TIA) in prior 4 days (96 hours).

• AIS definition: neurological deficit with acute onset (including seizures) and acute infarct(s) corresponding to arterial territory(ies) on brain imaging.
• TIA definition: neurological deficit with acute onset (not including seizures) consistent with ischemia of an arterial territory(ies) but without acute infarction on brain imaging.
• Imaging inclusion criteria:

a. Baseline imaging findings consistent with FCA: i. unilateral focal irregularity, banding, stenosis, wall thickening/enhancement, or occlusion of the distal internal carotid artery (ICA) and/or its proximal branches (A1, M1, posterior communicating artery, proximal PCA), OR ii. unilateral infarction in the territory of the lenticulostriate arteries with normal MRA.

b. Ability to return at 1-month (±7 days) post-stroke for an MRI/MRA (non-contrast) on a scanner of the same magnet strength as baseline MRI/MRA.*

• Consent to study procedures.

• A repeat baseline MRI/MRA can be performed as a research scan within 24 hours of enrollment if needed to meet this requirement.

Exclusion criteria

• Prior stroke.
• Another identified cause of stroke/TIA, other than FCA. (Intracranial dissection is considered a subtype of FCA and will be included if the patient is not predisposed to dissection for the reasons listed below.)
• Presence of childhood stroke risk factors (known to be present at the time of enrollment):

• Risk factors for arterial dissection: connective tissue disorder (e.g., Ehlers-Danlos type IV, Marfan syndrome, osteogenesis imperfect); severe head or neck trauma in the two weeks preceding AIS/TIA (defined as skull or cervical fracture, or an ICU admission for trauma).
• Risk factors for moyamoya: genetic disorder or syndrome that predisposes to moyamoya (e.g., trisomy 21, neurofibromatosis type 1, tuberous sclerosis, sickle cell anemia, MOPD type II, PHACE syndrome); prior cranial radiation therapy.
• Risk factors for secondary vasculitis or vasospasm: acute meningitis, systemic lupus erythematosus or other autoimmune disorder that can cause vasculitis, recent cocaine/amphetamine use (prior 7 days), recent subarachnoid hemorrhage (prior 14 days).
• Risk factors for cardioembolism: complex congenital heart disease; recent cardiac surgery or catheterization (prior week); endocarditis or other cardiac valve disease with vegetations; right-to-left cardiac shunting lesion with deep vein thrombosis (DVT) or a known thrombophilia.
• Imaging exclusion criteria:

• Baseline parenchymal imaging demonstrating remote or bilateral infarcts
• Vascular imaging demonstrating bilateral arteriopathy or moyamoya collaterals
• Contraindication to corticosteroid therapy (e.g., baseline immunosuppression, significant infection, etc.) as determined by the treating physicians.
• Current or recent (within prior week) treatment with corticosteroids.
• Pregnant, post-partum (within 6 months of childbirth), or nursing.