Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study

Discussion

The diagnosis of childhood arteriopathy is complex, and pediatric stroke experts have developed their diagnostic acumen across the years through the cumulative exposure to many cases. However, because these diseases are rare, pediatric patients with childhood arteriopathy are often seen by health care professionals who have not developed this expertise. The VIPS study presented a unique opportunity to help nonexperts in not only accurately diagnosing pediatric patients with childhood arteriopathy but also distinguishing among specific types based on objectively defined clinical and imaging parameters. The VIPS study previously demonstrated that arteriopathies can be more accurately classified when clinical data are used than when imaging findings are used alone, and when follow-up vascular imaging is performed.¹¹ The current analysis adds to our prior publication by defining the prevalence and predictive value of the individual characteristics that a pediatric stroke expert uses to diagnose childhood arteriopathy. In addition, it allows identification of patterns (ie, combinations of characteristics that distinguish certain arteriopathies) and assessment of the relative importance of each of these characteristics. This analysis assumes the availability of complete and accurate clinical and imaging data at the time of the arteriopathy classification; in real clinical situations, arteriopathy classification should be revisited as new data become available with time.

As a first step in the approach to vascular imaging abnormalities in a child with arterial ischemic stroke, radiologists and clinicians should consider whether the abnormality represents inherent arterial disease (ie, arteriopathy) versus thrombus from a proximal source (cardioembolism or artery-to-artery embolism). Underlying cardiac disease strongly favors cardioembolism; however, 4 children with congenital heart disease had an arteriopathic stroke (1 with a dissection, 3 with Moyamoya disease), indicating that arteriopathic stroke should be considered even in patients with cardiac disease.

Arterial stenosis or irregularity reduces the odds of cardioembolism but can be seen with a recanalizing thrombus. Complete arterial occlusion appeared to reduce the odds of cardioembolism in our model but only because it is a common feature of arteriopathies like Moyamoya disease and dissection; it was still the most common vascular imaging finding in cardioembolism. Distinguishing arteriopathy from thrombus remains challenging; our expert team could not make the distinction in 34 cases (designated possible arteriopathy, Fig 1), highlighting the need for an echocardiogram as part of the work-up of pediatric patients suspected of having childhood arteriopathy.

The most common childhood arteriopathies in our cohort of children presenting with acute arterial ischemic stroke were Moyamoya disease, arterial dissection (intracranial and extracranial), and FCA-i. This distribution would likely be different in a cohort including all children with cerebral or cervical arteriopathy; primary small-vessel CNS vasculitis, for example, typically presents with only headache or cognitive decline and no focal signs or symptoms. Although atherosclerosis may begin in childhood, it was not seen as a cause of stroke in VIPS, consistent with findings in prior reports.^3,24

Age was the one demographic characteristic that helped distinguish among arteriopathy subtypes. FCA-i tended to affect older school-aged children, while Moyamoya disease affected younger children; dissection had no age predilection. Sex and race did not correlate with arteriopathy subtype (after accounting for sickle cell disease). Although primary Moyamoya disease occurs more commonly in Korean and Japanese populations,²⁵ we had no enrolling sites in those countries and saw a broad distribution of ethnicities among our subjects with Moyamoya disease.

A diagnosis of dissection is suggested by the involvement of cervical arteries. On the basis of current definitions, FCA-i does not include arteriopathies affecting the posterior circulation. Moyamoya disease predominantly affects the anterior circulation; posterior circulation involvement, when present, is rarely symptomatic. Hence, dissection is high on the differential in a previously healthy child presenting with a posterior circulation arterial ischemic stroke. In addition, FCA-i, Moyamoya disease, and secondary vasculitis are intracranial arteriopathies; involvement of the cervical arteries is strongly suggestive of dissection.

Distinguishing the etiologies of FCA—focal stenosis or irregularity of the distal ICA or proximal MCA—remains a challenge even to pediatric stroke experts. The differential diagnosis includes FCA-i, FCA-d (intracranial dissection of the anterior circulation), and early, unilateral Moyamoya disease. All typically present with hemiparesis, but headache at the stroke ictus is common in FCA-i and FCA-d, but not in Moyamoya disease. Banding was considered a pathognomonic feature for FCA-i but was present in less than one-quarter of cases (being more conspicuous on conventional angiograms compared with CTAs and MRAs); hence, it was useful when present but not a sensitive feature of FCA-i. Infarct location in the lenticulostriate territory and smaller infarct size correlated with FCA-i and were more prevalent biomarkers. However, FCA-i and FCA-d are, in general, difficult to distinguish from each other as shown in postmortem cases.²⁶

An infarct in the superficial middle cerebral artery territories (ie, cerebral convexities) was more suggestive of Moyamoya disease. Chronic deep borderzone infarcts, also common in Moyamoya disease, do not result in focal deficits; because this is a cohort of children with acute arterial ischemic stroke, such infarcts were not included in this analysis. A history of head trauma and/or coincident cervical artery abnormalities suggests dissection. Improved neuroimaging techniques, including vessel wall imaging,²⁷ are needed to distinguish forms of FCA with greater certainty, though vessel wall imaging may not be 100% specific and there may be some overlap, with FCA-d showing minimal enhancement on vessel wall imaging and FCA-i typically presenting with marked enhancement on vessel wall imaging. The distinction between FCA-d and FCA-i is particularly important because their management strategies differ. FCA-i and FCA-d are currently treated with antiplatelet therapy. In addition, life-long restriction of activities (eg, no contact sports) is often recommended after an arterial dissection,²⁸ and clinical trials of corticosteroids for the treatment of FCA-i are under development.

In this article, the definition of FCA-i was restricted to focal disease of the distal ICA and its proximal branches, including but not limited to TCA.^14,23 However, we anticipate that increased use of vessel wall imaging,²⁷ allowing the delineation of enhancing arterial segments, will necessitate a broader definition of FCA. For example, we observed cases of focal stenosis of the petrous carotid or posterior circulation arteries that we diagnosed as having a definite arteriopathy that could not be further classified. If such cases had vessel wall imaging demonstrating enhancement of the affected vessel, it may be reasonable to expand the definition of FCA-i to include these cases. In addition, we identified 1 case of FCA-i that demonstrated arteriopathy progression after 6 months, contrary to the traditional definition of TCA; this highlights the fact that while FCA-i includes TCA, not all cases FCA-i are TCA.

The main limitation of our study is that there is notrue criterion standard for the diagnosis of childhood arteriopathies. Our expert review team was uncertain about the classification in 52 cases: 34 with possible arteriopathy and 18 with a definite arteriopathy that could not be further classified (Fig 1). Even among the arteriopathies that the review team classified with high certainty, there was likely some misclassification that cannot be measured. Because all imaging was performed on a clinical basis, there was variability in both the type and timing of imaging performed. As noted in our prior study, follow-up vascular imaging was helpful for classification, yet it was available in only a minority of patients.¹⁴ The circularity of some analyses—biomarkers used to classify a subtype and then evaluated as predictors of that subtype—must be emphasized; head trauma, for example, was an anticipated predictor of arterial dissection because it was used in the classification process. In such cases, the value of the analysis is in the prevalence of the predictor, such as noting that a minority of dissection cases had trauma, so an absence of trauma does not rule out this diagnosis.

Last, analyses of arteriopathy subtypes were underpowered (as reflected by large confidence intervals of coefficients in the multivariable models), so they should be interpreted with caution. However, advantages of our study include a prospectively collected cohort, a large sample size relative to most pediatric stroke studies, and rigorous classification methods based on independent, central expert reviews and adjudication. Our study allows the quantification of the prevalence of the predictors, the strength of their correlations with specific diagnoses, and patterns of multiple predictors. These results should provide a guide for clinicians and neuroradiologists to generate a reasonable differential for an arteriopathic stroke in a child and to prioritize diagnoses on that list. The application of these findings will depend, however, on the accurate characterization of the imaging biomarkers by the interpreting neuroradiologist.