The study also found that even children who were asymptomatic upon infections with the SARS-CoV-2 virus were still at risk of developing strokes.
It should be noted that stroke manifestations or symptoms in children are slightly different from that seen in adults, hence making initial diagnosis difficult at times.
The study findings were published in the peer reviewed journal: Pediatric Neurology.
https://www.pedneur.com/article/S0887-8994(22)00210-7/fulltext
Our study found a correlation between an increase in pediatric ischemic strokes and a peak in pediatric COVID-19 cases that was distinct from timing of MIS-C cases. We found an increased number in pediatric strokes at PCH from March 2020 to June 2021, with a peak in incidence of cases in February 2021.
This peak had a temporal relationship with the pediatric COVID-19 case rate in Utah, which peaked in December 2020. Our data suggest that prior COVID-19 infection, but not acute infection, may be related to the development of stroke in the pediatric population.
Viral infection has been described as a potential trigger of pediatric ischemic stroke.18
LVO strokes of the middle cerebral artery territories were the most common stroke type in both our pandemic and historical cohorts, which differs from other recent studies on pediatric stroke and COVID-19 infection, wherein focal cerebral arteriopathy was more implicated.10
However, acute intervention in the form of tPA and/or thrombectomy was only performed in one-quarter of patients in the pandemic cohort, with the majority of patients presenting with delayed diagnoses of stroke in both the pandemic and historical cohorts. These data have important clinical and public health implications and could broaden our understanding of long-term health consequences of COVID-19 infection in pediatrics and potentially provide guidance for stroke prevention moving forward.
MIS-C and hyperinflammatory syndrome following COVID-19 infection, and its distinction from acute COVID-19 infection in children, is increasingly understood.20 In a few patients of the pandemic cohort (n = 3), there was temporal overlap between MIS-C and diagnosis of stroke.
The same number of patients (n = 3) had prior mild or asymptomatic COVID-19 infection, did not develop MIS-C, but did present with stroke. In terms of timing, there was a one- to two-month lag in MIS-C cases, but a two- to three-month time lag of stroke cases at PCH, following the peak pediatric COVID-19 rates in Utah in December 2020.
We did not see a relationship between acute COVID-19 infection (PCR positivity) and stroke in our pandemic cohort, as the patients who were PCR positive at time of admission were also found to be COVID-19 antibody positive, suggesting that stroke could be a delayed complication of COVID-19 infection, similar to, and perhaps related to, the hyperinflammatory state that has been described two to six weeks following acute infection.21
Likewise, hypercoagulability has been broadly recognized in the setting of COVID-19,22 to the extent that many pediatric inpatients meet NIH COVID-19 Treatment Guidelines criteria for therapeutic anticoagulation.23 A proposed mechanism for this hyperinflammatory and prothrombotic state is from viral activation of the clotting cascade and simultaneous endothelial disruption.24
Despite our setting at a major pediatric referral center, with a large pediatric catchment (>1.7 million), and with essentially near-complete ascertainment as all pediatric stroke patients are referred or transferred to PCH in this region, pediatric stroke remains relatively rare, and thus sample size was a limitation of our study.
Within our pandemic cohort, the specific timing of COVID-19 infection in relation to stroke onset was difficult to delineate because many of our patients were asymptomatic and subsequently found to be antibody positive at the time of admission.
Furthermore, antibody testing for COVID-19 was not performed in a third of our stroke cohort, so it is unknown whether they had prior COVID-19 infection. As such, our assumption about timing to stroke is based on population data in our region. Follow-up to this study could be bolstered by continued review for pediatric strokes with new surges in COVID-19 infection rates associated with the Delta and Omicron variants.
We did note higher rates of black or Asian children who had stroke in our cohort, relative to population prevalence of these racial/ethnicity groups.17 However, we do not have data on relative rates of COVID-19 infection in different racial/ethnic groups of pediatric populations in Utah, so we cannot determine whether the higher stroke incidence reflects a higher risk of stroke, or reflects a higher incidence of COVID-19 infections.
There is mounting evidence that COVID-19 infection can lead to a delayed hyperinflammatory response, and our study suggests that stroke, particularly LVO stroke, with or without co-occurring diagnosis of MIS-C, could be a presentation of this prothrombotic state. Based on epidemiologic data, we hypothesize that there is likely a delay of at least one month from the timing of initial COVID-19 infection to the development of stroke.
We did find a correlation of increased risk of stroke after COVID-19 infection in children; this is in contrast to initial reports of no increased risk, but which only had data on the first three months of the pandemic.10 Furthermore, our finding is matched by a more recent multicenter study reporting an increased stroke risk.25
Our study also highlights the delay in pediatric stroke diagnosis, as the majority of patients in our study presented outside of the window for acute intervention; this underscores the need for greater education surrounding early stroke detection in children. Stroke in the pediatric population is often diagnosed late or misdiagnosed altogether, likely because it is relatively rare and often presents with vague symptoms.
Understanding stroke risk factors and association with other disease states such as COVID-19 is imperative in guiding early diagnosis and potential prevention strategies of stroke in children.
