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Underlying pathologies in pediatric stroke
In children, stroke recurrence is common and associated with significant morbidity and mortality. Five-year recur- rence rates are estimated to be between 6-20%, with rates as high as 66% in certain subgroups.15-20 Several studies have identified vasculopathy, in particular moyamoya, as an important factor in predicting recurrent stroke.8,15,20 There are some early data to suggest that prothrombotic states may also enhance the risk of recurrence, but many of these studies are limited by size and scope.7,11,15,16,21 We therefore conducted an international cohort study to inves- tigate the relevance of prothrombotic risk factors, as well as underlying stroke subtypes, to a second stroke in pedi- atric patients.
Methods
Study population, design, and endpoints
The present study is a multicenter cohort study to assess the rate of symptomatic stroke recurrence per 100 person-years fol- lowing a first AIS. The core protocol was developed by the German collaborative group and was adopted by centers in Toronto and the UK; data were pooled across these sites to deter- mine whether the data were generalizable and to increase the sta- tistical power for analysis of the secondary study objective, i.e. the time to recurrence. From January 1990 to January 2016, con- secutively admitted in- and out-patients from each study site, i.e. Canada (Toronto: single-center registry), Germany (Kiel- Lübeck/Münster: multicenter national registry: patients newly enrolled after 2002), and the UK (London/Southampton: two-cen- ter registry) were enrolled and pooled in the pediatric stroke data- base located in Germany. Consecutive patients with a first symp- tomatic AIS were recruited whether or not prothrombotic risk factors were present and recurrence was ascertained during fol- low up in survivors. Patients referred from other tertiary centers were excluded. Neonates <1 month of age and children with sick- le cell anemia were not enrolled in the present dataset, as recur- rence rates and risk factors differ markedly in these subjects from those in other subtypes of childhood AIS. After enrollment, chil- dren with moyamoya, and those with congenital homozygous protein C or antithrombin deficiency were excluded, since recur- rence risk and therapy differ substantially from those in the remaining study cohort. In addition, we excluded children in whom thrombophilia screening was not performed and those lost to follow up.
The first AIS was confirmed by standard imaging methods, i.e. magnetic resonance imaging and computed tomography.15,16 AIS was defined as an acute-onset neurological deficit with an acute focal infarct in a corresponding arterial vascular territory.
Recurrence was defined as clinically symptomatic AIS events which presented as acute focal neurological deficits with infarc- tion in a vascular distribution on neuroimaging and which began more than 24 h following the onset of the first stroke. The fixed study end date for the last follow up was January 1, 2017. The number of patients with recurrence, and type of antithrombotic (antiplatelet or anticoagulant) therapy administered prior to recur- rence were recorded. The proportion of deaths following stroke recurrence was also recorded. Following discontinuation of antithrombotic treatment, asymptomatic pediatric patients were followed up every few months for the first year and at more pro- longed intervals thereafter (at least yearly). All patients were seen at least once for a follow-up evaluation by a pediatric neurologist. Transient ischemic attacks, defined as acute-onset neurological deficits lasting <24 h and with no associated infarct on repeat neu- roimaging, were excluded from the study endpoint, as were
‘silent’ recurrent strokes noted on follow-up imaging without clin- ical manifestations.
Ethics
This study was performed in accordance with the ethical stan- dards laid down in the updated version of the 1964 Declaration of Helsinki and was either approved or the requirement for approval was waived, by Research Ethics Boards at the Hospital for Sick Children, Toronto, the Great Ormond Street Hospital, (and UK National Health Service), and the University of Münster.
Details of the stroke subtypes,11,22 treatment modalities,21-25 lab- oratory work-up26-28 and statistical methods applied29,30 are summa- rized in the Online Supplement.
Results
From January 1990 to January 2016, a total of 990 in- and out-patients consecutively reviewed at the study sites from Canada (n=308), Germany (n=461), and the UK (n=221), aged >1 month and without sickle cell anemia were enrolled and pooled in the pediatric stroke database located in Germany. After enrollment, we excluded 54 children with moyamoya, two patients with either con- genital homozygous protein C or homozygous antithrom-
haematologica | 2019; 104(8)
Figure 1. Flow chart of patients’ distribution through the study. AIS: arterial ischemic stroke.
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