The approach to diagnostic evaluation of childhood-onset AIS is challenging. Although multiple anatomic and thrombotic risk factors in childhood-onset AIS have been clearly delineated, their significance on outcome and treatment selection is still poorly understood. Hence, the approach to diagnostic evaluation of childhood-onset AIS remains controversial and diverse. It is crucial to identify anatomic causes of clot formation through imaging modalities, although weighing the risks and benefits of each approach to testing is a challenging task with little supporting data. As an example, conventional angiography provides gold standard vascular imaging of the head and neck, but carries a small chance of transient global amnesia, secondary vascular injury and/or stroke (up to 1.4% in one series of 137 patient aged 5–24) [42
]. Similarly, computed tomography with angiography (CTA) exposes the child to increased radiation burden, but contains less artifact than magnetic resonance angiography (MRA). At a minimum, children with AIS should have cerebral imaging, vascular imaging of the head and neck, as well as echocardiography, with consideration of bubble study to detect a patent foramen ovale. American Heart Association (AHA) pediatric stroke guidelines suggest that “the least invasive study that will provide an adequate assessment is usually the test to perform, but whether to do a test and the order in which a study is performed will vary with the clinical situation” [43
MRA, CTA and conventional angiography are the most commonly used imaging modalities employed to visualize vascular anomalies in childhood onset AIS. Local expertise, degree of suspicion for a vascular abnormality and age of the patient all inform the study choice. As arteriopathies can sometimes present after the acute onset of stroke (<3 months post stroke) and often change over time [19
], repeat vascular imaging is usually performed. Although MRA is the least invasive procedure (no radiation or stroke risk), according to the AHA recommendations “some conditions, including extracranial arterial dissections, particularly involving the posterior circulation, and small-vessel vasculitis, are difficult to exclude on MRA.” [43
] Detection of extracranial dissection is improved with fat-saturated T1 imaging.
At our center, MRA of the head and neck (with T1 fat saturated images of the neck) is the first line modality for vascular imaging in acute childhood-onset AIS. We have recently added contrast to our studies to reduce false positives. CTA is considered in patients with large vessel anomalies that are uncertain on MRA. Conventional angiography is considered in cases of clinically suspected dissection, moyamoya, or possible vasculitis. Repeat imaging at 3–12 months is essential, as 19% of unilateral vascular anomalies will transiently worsen, 6% can progress, and only 23% of non-progressive disease will completely normalize [19
].Although some studies suggest that PFO and right to left shunt in cryptogenic stroke are detected more often with transesophageal echocardiography (TEE) and transcranial Doppler ultrasonography (TCD), than in patients with transthoracic echocardiography (TTE); [44
] the implications of a PFO in childhood-onset AIS remain unknown. AHA pediatric stroke guideline suggest, “in some series, the prevalence of a patent foramen ovale (PFO) is greater in young adults with unexplained ischemic stroke than in normal individuals, and the significance of a PFO in a child with stroke is even less certain. Optimal treatment of paradoxical embolism associated with PFO is not known” [43
Although multiple types of genetic and acquired thrombophilia are established as independent risk factors for incident AIS, data supporting significant prognostic impact upon recurrence risk are limited to a few individual traits such as elevated lipoprotein (a), protein C deficiency, and the presence of multiple risk factors [14
]. AHA pediatric stroke guidelines suggest, “although the risk of stroke from most prothrombotic states is relatively low, the risk tends to increase when prothrombotic disorder occurs in children with other risk factors. Thus, it is reasonable to evaluate for the more common prothrombotic states even when another stroke risk factor has been identified.” [43
] Given the lack of adequately powered studies to detect the impact of thombophilia on recurrence risk in childhood-onset AIS, our approach is to comprehensively evaluate for both genetic and acquired thrombophilias. One approach, outlined by the Subcommittee for Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (ISTH), suggests an initial evaluation of: complete blood count, antithrombin, protein C activity, free and total protein S antigen, FVL and/or functional activated protein C resistance assay, prothrombin G20210A, homocysteine level +/− MTHFR, lipoprotein (a), lupus anticoagulant, anticardiolipin antibodies, and hemoglobin electrophoresis (for sickle cell disease screening) [46
]. Typically, abnormal potentially-acquired thrombophilia findings should be retested at about 12 weeks from initial testing.
In addition to consideration of anatomic and thrombotic risk factors, diagnostic evaluation for alternative etiologies also needs to be considered, including pharmacological causes (such as cocaine), rheumatologic disease (such as lupus), metabolic disease (such as Fabry Disease), mitochondrial disease (such as MELAS), and other genetic conditions (such as CADASIL).