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• W2765365871 abstract "Cerebral infarcts (overt and silent strokes) are a major cause of morbidity in children with sickle cell anaemia (SCA) (DeBaun & Kirkham, 2016). Silent cerebral infarcts (SCIs), defined as infarct-like lesions on brain magnetic resonance imaging (MRI) without corresponding focal neurological deficits (DeBaun et al, 2014), are the most common form of neurological disease in children with SCA (DeBaun et al, 2012), occurring in 39% by 18 years of age (Bernaudin et al, 2015). Intracranial vasculopathy, defined as >50% stenosis of major intracranial vessels on magnetic resonance angiography (MRA) (Hulbert et al, 2011; Thangarajh et al, 2012), is associated with overt strokes and SCIs in children with SCA (Abboud et al, 2004; Hulbert et al, 2011; Thangarajh et al, 2012; Bernaudin et al, 2015). However, no prospective study has shown that baseline intracranial vasculopathy is predictive of infarct recurrence in children with SCA, SCIs and normal transcranial Doppler (TCD) velocities (<200 cm/s by non-imaging and <185 cm/s by imaging technique) (Adams et al, 1998). The Silent Cerebral Infarct Transfusion (SIT) Trial includes the largest group of children with SCA, SCIs and normal TCD velocities who have undergone MRI and MRA of the brain with central adjudication of cerebral infarcts and intracranial vasculopathy (DeBaun et al, 2014). In a secondary analysis of the SIT Trial, we aimed to test the hypothesis that in children with SCA, SCIs and normal TCD velocities, the presence of baseline MRA-defined intracranial vasculopathy is associated with cerebral infarct recurrence. The SIT trial [registered at http://www.clinicaltrials.gov (NCT00072761) and http://www.ISRCTN.org (ISRCTN52713285)] was a randomized, single-blind and prospective clinical trial conducted at 29 clinical centres across North America and Europe between 2003 and 2013, and approved by the Institutional Review Boards at all participating institutions. The study design and methods were previously published (DeBaun et al, 2014). Secondary analysis was performed on participants from the SIT trial who were randomly allocated to the observation or blood transfusion groups and underwent MRA of the brain at least once. Participants included children aged 5–15 years with confirmed diagnosis of SCA (haemoglobin SS or haemoglobin Sβ0 thalassemia), normal TCD velocity (time-averaged maximum mean velocity <200 cm/s by non-imaging technique, or time-averaged maximum velocity <185 cm/s by imaging technique), and no prior history of overt strokes or seizures (DeBaun et al, 2014). Informed consent and assent were obtained prior to enrolment. Primary outcome in the study was defined as cerebral infarct recurrence (overt stroke, new or enlarging SCI, or both). The paediatric definition of SCI is an infarct-like lesion on brain MRI measuring ≥3 mm along the greatest linear dimension and visible in at least two planes of fluid-attenuated inversion recovery (FLAIR) T2-weighted images (axial and coronal), without corresponding neurological deficits (DeBaun et al, 2014). We defined intracranial vasculopathy on MRA as >50% stenosis (moderate or severe disease) in any of the internal carotid, middle, anterior and posterior cerebral arteries, excluding cervical MRA (Hulbert et al, 2011; Thangarajh et al, 2012). Presence or absence of infarct-like lesions and intracranial vasculopathy was determined by a committee of neuroradiologists, and SCIs and overt strokes were independently determined by a committee of paediatric neurologists (DeBaun et al, 2014). We evaluated differences in the distributions of demographic and clinical features among SIT trial randomized participants with and without a baseline MRA, using IBM SPSS Statistics (Version 24, Armonk, NY: IBM Corp.) to perform all analyses. A total of 196 children in the SIT trial were randomized to either observation or transfusion groups, with baseline MRAs of the brain performed electively at each participating site in 56% (110 of 196). Table 1 summarizes the demographics and clinical features of the randomized study population who did and did not receive baseline MRAs; white blood cell count was the only difference in clinical characteristics. In the subgroup of randomly allocated children from the SIT trial who had baseline MRAs of the brain (N = 110), median age was 9·4 years (range 5–15 years), 58% (64 of 110) were male, mean TCD velocity was 146·3 cm/s and MRA-defined intracranial vasculopathy was present in 1·8% (2 of 110) at baseline (Table 1). The characteristics of the study participants with baseline MRA-defined intracranial vasculopathy are outlined in Table 2. Infarct recurrence occurred in 14% (15 of 110) of participants with a baseline MRA of the brain. In the group with infarct recurrence, 7% (1 of 15) had baseline intracranial vasculopathy. Among participants with baseline intracranial vasculopathy, 50% (1 of 2) had infarct recurrence, compared to 13% (14 of 108) of those without baseline intracranial vasculopathy. In children with SCA, SCIs are associated with increased risk of new infarcts (overt strokes and SCIs) (Miller et al, 2001; Pegelow et al, 2002), and MRA-defined intracranial vasculopathy is associated with increased risk for SCIs (Thangarajh et al, 2012; Bernaudin et al, 2015). In children with SCA and prior overt strokes or abnormal TCD velocities, intracranial vasculopathy has shown to be predictive of cerebral infarct recurrence (Abboud et al, 2004; Hulbert et al, 2011). In our study in children with SCA, SCIs and normal TCD velocities, we demonstrate that MRA-defined intracranial vasculopathy is rare (2%; 2 of 110) and not likely to be a major risk factor for future cerebral infarcts. The conclusions of this study are limited to children with SCA, SCIs and normal TCD velocities. SCIs affect approximately 39% of all children with SCA (Bernaudin et al, 2015), compared to 10% with abnormal TCD velocities (Adams et al, 1998). Given that the presence of SCIs and abnormal TCD velocities are independent events, children with SCIs and normal TCD velocities are a substantial portion of the paediatric population with SCA. We have demonstrated for the first time that in children with SCA, SCIs and normal TCD velocities, the prevalence of baseline MRA-defined intracranial vasculopathy is rare (2%). Further prospective studies are needed to validate the potentially marginal clinical utility of MRA-defined intracranial vasculopathy for the detection of cerebral infarct recurrence in this subset of children with SCA. This work was supported by Vanderbilt Medical Scholars Program at Vanderbilt University (N.A.C.). The SIT Trial is supported by the National Institute of Neurological Disorders and Stroke (NINDS), Rockville, Maryland (ClinicalTrials.gov identifier: U01 NS042804) and Burroughs Wellcome Foundation (M.R.D.). We would like to thank Dr. Mathula Thangarajh for interpretation of MRA imaging data, and the members of the DeBaun laboratory and Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease for their critical review of the manuscript. The authors declare no competing financial interests. All authors participated in critical revision and finalization of the manuscript. N.A.C. performed data analysis and interpretation and wrote the manuscript. M.R.D. designed the study and contributed to writing the manuscript. M.R.P., S.P., and R.C.M. participated in interpretation and analysis of imaging data. L.C.J. performed data analysis. M.R. performed statistical analysis." @default.
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• W2765365871 date "2017-10-26" @default.
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• W2765365871 title "Intracranial vasculopathy and infarct recurrence in children with sickle cell anaemia, silent cerebral infarcts and normal transcranial Doppler velocities" @default.
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