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G. deVeber et al.
pediatric stroke patients > 1 month of age, a second AIS event was diagnosed in 17.9% of patients within a median period of 3.1 months after the first stroke. In this interna- tional cohort of children who had had a stroke we found that the presence of more than one prothrombotic risk fac- tor was associated with AIS recurrence. Specifically, as demonstrated recently in children with recurrent deep venous thrombosis and thromboembolic stroke, heterozy- gous antithrombin deficiency is a major risk factor for sec- ond AIS events.31 In addition, data presented here confirm an increased risk for recurrent stroke events in the subgroup of patients with an underlying vasculopathy.15,22,32-35
The rates of recurrent cerebral thrombo-embolic events vary widely across published studies. Differences are likely related to: (i) the variable inclusion of neonates, known to have a very low rate of recurrence; (ii) the ethnicity of the patients enrolled and other variables in the patient popula- tions; (iii) the definitions of recurrence; and (iv) the duration of follow up. Some studies mix transient ischemic attacks and recurrent stroke in reporting the recurrence risk.14-20 Adverse outcomes resulting from recurrent AIS are certainly more ominous than those for a transient ischemic attack alone, with a mortality rate after second AIS of 9.4% in our patients. Keeping in mind differences in patient populations, underlying diseases as well as treatment modalities applied, and assuming that inclusion of transient ischemic attacks would approximately double the recurrence risk,16 the recur- rence rate reported by us for AIS alone is within the lower rate of approximately 20% reported by other authors.14-20 It is possible that our lower rate of recurrence reflects the use of standardized treatment protocols and institutional pedi- atric stroke programs in our centers. Specialized stroke care is likely to lower the rate of recurrence through experienced selection of patients for antiplatelet/anticoagulant treatment and more consistent use of any preventative treatment.
With respect to the inherited prothrombotic risk factors investigated, multivariable analysis provided evidence that the presence of vasculopathy, heterozygous antithrombin deficiency, increased Lp(a) and more than one cause of thrombophilia are risk factors for recurrent ischemic stroke in pediatric patients.14,36-38 The numbers needed to screen to detect one patient each with elevated Lp(a) or combined thrombophilic abnormalities in the present cohort were 10 and 20, respectively. The benefit of recognizing an underly- ing thrombophilic condition, as well as the numbers need to screen to detect a carrier at risk, should be balanced against clinical impact, cost and potential insurance implications. In contrast to the literature on recurrent venous thromboem- bolism in a similar population of children, as well as an asso- ciation with first AIS onset,11,38 the presence of isolated muta- tions in factor 5 at rs6025, factor 2 at rs1799963, protein C- and protein S were not individually significantly associated with recurrent AIS in this multicenter cohort. Despite the recurrence rate of 17.9% (160/894 patients), our study may have been underpowered to find these associations. Alternatively, these factors may have been more aggressive- ly treated with antithrombotic treatment, reducing the risk of recurrence in affected patients. Importantly, combinations of prothrombotic risk factors, including the factor 5 muta- tion at rs6025, in 26% of cases were associated with recur- rence, emphasizing the importance of comprehensive inves- tigation and appropriate management.
Our study has several limitations. First, the long duration of the study means that many children were enrolled more than a decade ago, when the selection of treatments may
Figure 3. Arterial ischemic stroke-free survival in children with elevated lipopro- tein (a) compared with that in the remaining children with normal lipoprotein (a) levels (P=0.039).
have been different from that currently recommended. While this long duration provided us with the opportunity to monitor children for longer-term recurrent AIS, our inclu- sion of some children with only a brief follow-up duration, as short as 1 month, could also have resulted in our under- estimating recurrence risk, and our rate of recurrence should therefore be viewed as a minimum estimate. Secondly, the proportions of children with vascular, cardiac or cryptogenic stroke varied across countries, likely representing either dif- ferences in assignment of patients to categories (e.g. inclu- sion or exclusion of occlusion alone as ‘vasculopathy’) or dif- ferent referral patterns to the centers (Toronto, London/Southampton and Kiel-Lübeck/Münster) in the three countries. Thirdly, we were unable to include pediatric stroke drug therapy as a main focus of this study since rec- ommendations on antithrombotic and antiplatelet agents for children with stroke are derived from non-randomized pedi- atric trials and small case series with a low level of evidence, without adjustment for treatable prothrombotic risk factors such as heterozygous antithrombin deficiency21-25 or routine drug monitoring to detect resistance to acetylsalicylic acid or non-drug compliance. Finally, the thrombophilia testing was done over time and in three different laboratory settings. However, since laboratory parameters were investigated with standard laboratory techniques and assays and were only classified as abnormal when (i) abnormal on a repeat test and (ii) confirmed by family studies or the identification of an underlying gene mutation,26-28 it is likely that our results are reliable.
In summary, recurrent AIS is relatively frequent, and is associated with significant mortality. Risk is enhanced in children who have vasculopathy, even when moyamoya is excluded, and in those with certain isolated thrombophilic risk factors or more than one prothrombotic disorder. The results of this study emphasize the value of pooling individ- ual patients’ data across geographic regions. Future studies should seek to validate our findings in additional cohorts of children with a first AIS with stroke subtypes clearly defined according to new pediatric stroke classifications, such as CASCADE.39,40 Of note, our finding that recurrence of child- hood AIS is comparable across European and North American centers supports the feasibility of multinational recruitment strategies to provide sufficient power to ran-
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haematologica | 2019; 104(8)