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Editorials
thrombotic markers with recurrence. Second, recruiting patients by collaboration of investigators from three coun- tries and including multiple sites supports the generaliz- ability of the results. As the study sites were large tertiary or quaternary centers, another key element of the design was the exclusion of referrals from outside the catchment area, which minimizes referral bias. One study showed that there is a higher rate of AIS recurrence among refer- rals, providing evidence of differences in the populations of patients which would affect generalizability of the results.3 Furthermore, prothrombotic marker testing was performed at each site, which demonstrates the ability to determine these markers in different clinical laboratories. Finally, there was a clear clinical and radiologically com- bined definition of initial AIS and recurrent stroke events.
There are a few limitations to the study. The first is combining all three clinical entities for determination of association of prothrombotic markers with recurrence risk. While this could be considered a strength, as the results are generalizable to the pediatric population with AIS, there is a missed opportunity to determine markers specific to each clinical population. As the mechanisms for AIS and AIS recurrence likely differ based on the underlying disorder, it is reasonable to predict that the markers will vary by diagnosis. Another important limita- tion is the extended study period from 1990 to 2016. While this allowed the enrollment of a large number of patients with incident AIS, over time there are variations in clinical practice including index case diagnosis and interventions. These factors could influence patients’ out- comes as well as characterization of the study popula- tions, which affects the generalizability of the study results. However, even with the limitations, the results of the study are valid and are a valuable contribution to this area of research.
In pediatric AIS studies international collaboration is essential to assemble adequately powered cohorts for deter- mination of predictive markers for AIS recurrence. In futures studies, with recent publications in the area includ- ing the current paper, there are now avenues for determin-
ing predictive models which include clinical variables and biomarkers. For example, the Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE) clas- sification is a consensus-based standardized tool for classi- fying arteriopathic and non-arteriopathic AIS. Patients with arteriopathy classified as CASCADE 2 (unilateral focal cere- bral arteriopathy) and 3 (bilateral cerebral arteriopathy) have an increased risk of AIS recurrence as do those classi- fied as CASCADE 5 (patients with cardio-embolism).6 A recent publication by Fullerton et al. identified inflammato- ry markers associated with risk of recurrence in arteriopath- ic patients.7 Therefore, a model could be based on a combi- nation of clinical variables and both thrombophilia and inflammatory markers. The current publication by deVeber et al. will help to shape future studies determining predic- tive models. These predictive models will allow secondary prophylaxis interventions to be targeted to only those chil- dren at risk of recurrence, ultimately improving the care of children who have had an AIS.
References
1. Strater R, Becker S, von EA, et al. Prospective assessment of risk fac- tors for recurrent stroke during childhood--a 5-year follow-up study. Lancet. 2002;360(9345):1540-1545.
2. Ganesan V, Prengler M, Wade A, Kirkham FJ. Clinical and radiologi- cal recurrence after childhood arterial ischemic stroke. Circulation. 2006;114(20):2170-2177.
3. Stacey A, Toolis C, Ganesan V. Rates and risk fctors for arterial ischemic stroke recurrence in children. Stroke. 2018;49(4):842-847.
4. Kenet G, Lutkhoff LK, Albisetti M, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121(16):1838-1847.
5. deVeberG,KirkhamF,ShannonK,etal.Recurrentstroke:theroleof thrombophilia in a large international pediatric stroke population. Haematologica. 2019;104(8):1676-1681.
6. Bohmer M, Niederstadt T, Heindel W, et al. Impact of childhood arterial ischemic stroke standardized classification and diagnostic evaluation classification on further course of arteriopathy and recur- rence of childhood stroke. Stroke. 2018 Dec 7. [Epub ahead of print]
7. Fullerton HJ, deVeber GA, Hills NK, et al. Inflammatory biomarkers in childhood arterial ischemic stroke: correlates of stroke cause and recurrence. Stroke. 2016;47(9):2221-2228.
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