Association studies of childhood ischemic stroke have largely been limited to hematologic studies of genetic pro-thrombotic conditions; summarized in a recent meta-analysis, these conditions are modest stroke risk factors.34
A small case-control study suggested an association between varicella zoster infection and childhood AIS.30
Population-based cohort studies, limited by either few incident cases or reliance on administrative data, have shown that male gender and black race modestly increase risk of childhood stroke, while sickle cell disease has a strong effect, but have not assessed other risk factors.32, 35, 36
In this case-control study nested within a population-based cohort, we confirmed the importance of diseases traditionally considered risk factors for childhood AIS: autoimmune, hematologic, and cardiac diseases. In addition, we found that environmental exposures—documented medical encounters for head/neck trauma, and acute infections—were the most common independent risk factors.
Although traumatic cervical or cerebral arterial dissection has long been recognized as a cause of childhood AIS,37
recent exposure to trauma has never been formally evaluated as a risk factor. In our cohort, a head/neck trauma in the prior 12 weeks was both prevalent (present in 12% of cases) and strongly associated with AIS (OR= 9.0 in adjusted analysis). Because we could only measure trauma that resulted in a medical encounter, the true prevalence of preceding trauma among children with AIS is likely higher. (The true prevalence of trauma would also be higher among control children, which could impact the estimate of relative risk.) The time between trauma exposure and AIS ictus was short (median of 0.5 days); when we narrowed the time window for the trauma exposure to 1 week, the adjusted OR increased to 36. Loss of consciousness and admission for trauma were particularly associated with childhood AIS, suggesting that more severe head/neck trauma might indicate a subgroup of trauma victims at particularly high risk.
Published estimates of the association between trauma and adult AIS are, to our knowledge, lacking; however, there is a large body of literature on “blunt cerebrovascular injury (BCVI)” referring to non-penetrating traumatic injury of cervical or cerebral vessels (namely arterial dissection). Among patients presenting to trauma centers, approximately 1.5% have evidence of BCVI on vascular imaging,38–41
and 12% of those with BCVI will go on to have a stroke.42
A variety of screening paradigms for BCVI have been published; patients meeting certain clinical or radiologic criteria are screened with cerebrovascular imaging, most often CT angiography (CTA).38–41
Although the efficacy of antithrombotic therapy for stroke prevention in this setting has yet to be established, trauma patients found to have BCVI are typically treated prophylactically with aspirin or heparin.22–26
A better understanding of the association between trauma and AIS in children—specifically, what trauma characteristics confer a higher risk of AIS—is needed to develop strategies for primary stroke prevention in pediatric trauma victims.
Major infections, like bacterial meningitis and sepsis, have long been considered etiologies of childhood AIS: meningitis can cause a vasculitis of the circle of Willis,43
and sepsis can lead to embolic strokes due to systemic thrombosis or endocarditis.44, 45
Fortunately, vaccines against Haemophilus influenzae
, type B, Neisseria meningitidis
, and Streptococcus pneumonia
are now widely available, and we observed only four AIS cases with preceding bacterial meningitis. Minor infections, however, remain common among children, and have been linked to AIS in adults.5, 7–12
In our cohort, a medical encounter for a minor acute infection was the most frequently observed childhood AIS risk factor, present in a 33% of cases. Because our definition of recent infection required a documented medical encounter, the true prevalence of this risk factor is higher, as many minor infections do not result in a medical visit. However, hospital series and an international prospective registry study have reported preceding minor infections (by parental report) in 24 to 34% of cases.3, 4, 46
The strength of the association between recent infection and AIS observed in our study (adjusted OR 3.9) was similar to that reported in the adult studies, ranging from 2.9 (95% CI 1.6,5.3) for an infection in the prior 2 months,12
to 4.5 (95% CI 2.1,9.7) for an infection in the prior week.5
As in adults, the association between recent infection and AIS does not appear to be specific to any particular type of infection; a variety of infectious illnesses were observed in our cases, with none predominating. We did not observe a clear seasonal predilection to stroke associated with either infection or trauma in our cohort; however, the relatively temperate climate in Northern California may minimize seasonal variation in infection. We saw no association between chicken pox and AIS; however, we likely under-detected this exposure because clinics discourage parents from bringing children with suspected chicken pox to clinic and exposing other patients.
Minor infections could predispose to AIS by promoting thrombosis through systemic inflammation, or by causing endothelial injury to a cervical or cerebral artery.47, 48
Supporting the latter mechanism, in an international prospective registry of childhood AIS, recent minor infection was significantly associated with cerebral arteriopathy.49
Among previously healthy children presenting with a first AIS, a cerebral arteriopathy is found in the majority,3
and is the strongest predictor of recurrent childhood AIS.28, 50
Hence, a better understanding of the role of infection, the focus of the on-going NIH-funded Vascular effects of Infection in Pediatric Stroke (VIPS) study,51
is crucial for stroke prevention in children. The influenza vaccine has been shown to decrease stroke risk in adults;13, 14
influenza vaccination programs may similarly act as primary stroke prevention in children.
The retrospective nature of our study was a limitation. Missing data led to potential misclassification of exposure variables. However, because we abstracted exposure variables only if that exposure was documented prior to the stroke diagnosis, or the index date in the paired controls, misclassification likely would be non-differential and should therefore bias our results towards the null hypothesis. Hereditary thrombophilias have been shown to be risk factors for childhood AIS,34
yet could not be evaluated in this study, and we were underpowered to examine interactions between risk factors. Underrepresentation of socioeconomic extremes reduces the generalizability of our findings. Strengths of the study, however, included the availability of unbiased controls and longitudinal clinical data in a population-based setting; this allowed for novel observations regarding environmental exposures as risk factors for childhood AIS.