The development of the pediatric stroke neuroimaging platform (PEDSNIP).

Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, resulting in a focal lesion. Our understanding of mechanisms of injury and repair associated with focal injury in the developing brain remains rudimentary. Neuroimaging can reveal important insights into these mechanisms. In adult stroke population, multi-center neuroimaging studies are common and have accelerated the translation process leading to improvements in treatment and outcome. These studies are centered on the growing evidence that neuroimaging measures and other biomarkers (e.g., from blood and cerebrospinal fluid) can enhance our understanding of mechanisms of risk and injury and be used as complementary outcome markers. These factors have yet to be studied in pediatric stroke because most neuroimaging studies in this population have been conducted in single-centred, small cohorts. By pooling neuroimaging data across multiple sites, larger cohorts of patients can significantly boost study feasibility and power in elucidating mechanisms of brain injury, repair and outcomes. These aims are particularly relevant in pediatric stroke because of the decreased incidence rates and the lack of mechanism-targeted trials. Toward these aims, we developed the Pediatric Stroke Neuroimaging Platform (PEDSNIP) in 2015, funded by The Brain Canada Platform Support Grant, to focus on three identified neuroimaging priorities. These were: developing and harmonizing multisite clinical protocols, creating the infrastructure and methods to import, store and organize the large clinical neuroimaging dataset from multiple sites through the International Pediatric Stroke Study (IPSS), and enabling central searchability. To do this, developed a two-pronged approach that included building 1) A Clinical-MRI Data Repository (standard of care imaging) linked to clinical data and longitudinal outcomes and 2) A Research-MRI neuroimaging data set acquired through our extensive collaborative, multi-center, multidisciplinary network. This dataset was collected prospectively in eight North American centers to test the feasibility and implementation of harmonized advanced Research-MRI, with the addition of clinical information, genetic and proteomic studies, in a cohort of children presenting with acute ischemic stroke. Here we describe the process that enabled the development of PEDSNIP built to provide the infrastructure to support neuroimaging research priorities in pediatric stroke. Having built this Platform, we are now able to utilize the largest neuroimaging and clinical data pool on pediatric stroke data worldwide to conduct hypothesis-driven research. We are actively working on a bioinformatics approach to develop predictive models of risk, injury and repair and accelerate breakthrough discoveries leading to mechanism-targeted treatments that improve outcomes and minimize the burden following childhood stroke. This unique transformational resource for scientists and researchers has the potential to result in a paradigm shift in the management, outcomes and quality of life in children with stroke and their families, with far-reaching benefits for other brain conditions of people across the lifespan.

Neuroimaging in Pediatric Stroke.

Pediatric stroke is unfortunately not a rare condition. It is associated with severe disability and mortality because of the complexity of potential clinical manifestations, and the resulting delay in seeking care and in diagnosis. Neuroimaging plays an important role in the multidisciplinary response for pediatric stroke patients. The rapid development of adult endovascular thrombectomy has created a new momentum in health professionals caring for pediatric stroke patients. Neuroimaging is critical to make decisions of identifying appropriate candidates for thrombectomy. This review article will review current neuroimaging techniques, imaging work-up strategies and special considerations in pediatric stroke. For resources limited areas, recommendation of substitute imaging approaches will be provided. Finally, promising new techniques and hypothesis-driven research protocols will be discussed.

Wallerian Degeneration of the Cerebral Peduncle and Association with Motor Outcome in Childhood Stroke.

BACKGROUND: To evaluate the presence of Wallerian degeneration and its relationship with sensorimotor deficits following childhood-onset arterial ischemic stroke (AIS). METHODS: Children surviving unilateral AIS older than one month of age were assessed for severity of sensorimotor neurological deficit with the Pediatric Stroke Outcome Measure at least one year post stroke (mean follow-up = 2.9 years, S.D. = ±1.6). The area (mm3) of each cerebral peduncle was measured on T2-weighted magnetic resonance images to calculate an Asymmetry Index (AI). The AI between patients with childhood stroke (cases) and controls (children with normal MRI) was compared. In the stroke group, the AI between patients with good and poor motor outcome, and the correlation between the AI and motor outcome was calculated. RESULTS: Asymmetry was compared in 52 children with stroke (cases) and 20 controls (normal brain MRIs). The AI was greater in patients with stroke (mean = 6.8%, S.D. = ±5.9) compared with controls (mean = 3.4%, S.D. = ±3.5, P < 0.02). Patients with poor outcome had an AI of 10% or greater compared with patients with good outcome (mean 10.4 versus 4, P < 0.001), and the AI was moderately correlated with motor deficit severity (r = 0.582, P = 0.001). CONCLUSIONS: Asymmetry of the cerebral peduncle is a feasible method of assessing Wallerian degeneration in children with unilateral AIS. The degree of asymmetry in the cerebral peduncles was moderately correlated with neurological outcome severity and reflects the degree of motor deficit in children following stroke.

The Potential for Advanced Magnetic Resonance Neuroimaging Techniques in Pediatric Stroke Research.

BACKGROUND: This article was written to provide clinicians and researchers with an overview of a number of advanced neuroimaging techniques in an effort to promote increased utility and the design of future studies using advanced neuroimaging in childhood stroke. The current capabilities of advanced magnetic resonance imaging techniques provide the opportunity to build on our knowledge of the consequences of stroke on the developing brain. These capabilities include providing information about the physiology, metabolism, structure, and function of the brain that are not routinely evaluated in the clinical setting. METHODS: During the Proceedings of the Stroke Imaging Laboratory for Children Workshop in Toronto in June 2015, a subgroup of clinicians and imaging researchers discussed how the application of advanced neuroimaging techniques could further our understanding of the mechanisms of stroke injury and repair in the pediatric population. This subgroup was established based on their interest and commitment to design collaborative, advanced neuroimaging studies in the pediatric stroke population. RESULTS: In working toward this goal, we first sought to describe here the magnetic resonance imaging techniques that are currently available for use, and how they have been applied in other stroke populations (e.g., adult and perinatal stroke). CONCLUSIONS: With the continued improvement in advanced neuroimaging techniques, including shorter acquisition times, there is an opportunity to apply these techniques to their full potential in the research setting and learn more about the effects of stroke in the developing brain.

The pediatric stroke outcome measure: a validation and reliability study.

BACKGROUND AND PURPOSE: The Pediatric Stroke Outcome Measure (PSOM) is an objective, disease-specific outcome measure containing 115 test items suitable for newborn to adult ages. The PSOM measures neurological deficit and function across 5 subscales: right sensorimotor, left sensorimotor, language production, language comprehension, and cognitive/behavior yielding a final 10-point deficit score. The goal of this study was to examine PSOM construct validity in measuring neurological outcome in pediatric stroke survivors and interrater reliability (IRR) for both prospective and retrospective scoring. METHODS: For construct validity, PSOM subscale scores were correlated with scores on standardized neuropsychological measures matched by functional domain. We assessed IRR by comparing same-day "live" PSOM scores from 2 independent raters in 10 children (prospective IRR) and by comparing PSOM scores estimated from medical dictations across 5 raters in another 10 children (retrospective IRR). RESULTS: We analyzed PSOM scores from 203 children with ischemic stroke. PSOM subscales show good construct validity (ρ=0.2-0.4; P<0.05). PSOM subscale scores of normal/abnormal demonstrate strong agreement for domain-matched neuropsychology scores (alternative chance-corrected statistic=0.4-0.8). IRR was excellent with the 2 prospective raters' scores in almost perfect agreement (intraclass correlation coefficient, 0.93; 95% CI, 0.76-0.98). Retrospective IRR demonstrated strong agreement with an intraclass correlation coefficient of 0.77 (95% CI, 0.56-0.92). CONCLUSIONS: The PSOM is a valid and reliable outcome measure for pediatric stroke. It is useful for retrospective scoring from health records and prospective serial longitudinal outcome assessments and is ideally suited for prospective clinical trials in pediatric stroke.

Corticospinal tract pre-wallerian degeneration: a novel outcome predictor for pediatric stroke on acute MRI.

BACKGROUND AND PURPOSE: In neonatal arterial ischemic stroke, pre-Wallerian degeneration in descending corticospinal tracts (DCST) on diffusion MRI (DWI) predicts poor outcome. This signal has not been studied in older children. METHODS: A consecutive arterial ischemic stroke cohort (1 month to 18 years) with acute DWI and >12 months of follow-up were enrolled (SickKids Children's Stroke Program). DCST-DWI variables were quantified with a validated software technique and correlations to the Pediatric Stroke Outcome Measure were sought. RESULTS: Abnormal DCST-DWI signal was detected in 20 of 29 children (69%), with 85% having motor deficits on Pediatric Stroke Outcome Measure. DCST variables correlated with hemiparesis included: (1) any abnormal signal within the course of the DCST; (2) midbrain location; (3) percentage of peduncle; (4) vertical length; and (5) relative volume affected (all P<0.003). Unexpectedly, abnormal DWI signal was detected in the contralesional DCST in 7 children, all with severe hemiparesis. DCST signal abnormality increased over time, outlasted infarct DWI changes, and was difficult to appreciate on visual inspection. CONCLUSIONS: DCST-DWI signal is an acute predictor of motor outcome in childhood stroke and can help guide management. Previously unrecognized contralesional DCST signal predicts severe hemiparesis.

Frequency, predictors, and neurologic outcomes of vaso-occlusive strokes associated with cardiac surgery in children.

OBJECTIVE: Our aim was to define the frequency, predictors, and outcomes of stroke associated with cardiac surgery in children with congenital heart disease. METHODS: We performed a case-control study of children (term birth to 18 years) with congenital heart disease who underwent cardiac surgery at the Hospital for Sick Children between January 1, 1992, and March 1, 2001. Case subjects experienced stroke within 72 hours after cardiac surgery, and control subjects (2 for each case subjects) had cardiac surgery and no stroke. The frequency of arterial ischemic stroke/cerebral sinovenous thrombosis was calculated among children who underwent cardiac surgery during the study period. Predictors for stroke, including age, gender, simple versus complex procedure, reoperation, bypass duration, circulatory arrest, postoperative hematocrit level, and intraoperative activated clotting time, were tested. The presence of clinical and radiologically defined stroke was the main outcome. Neurologic outcomes were assessed in case subjects with the Pediatric Stroke Outcome Measure. RESULTS: During the study period, 30 children with stroke (28 with arterial ischemic stroke and 2 with cerebral sinovenous thrombosis) were identified among 5526 children undergoing cardiac surgery. This yielded a risk for arterial ischemic stroke/cerebral sinovenous thrombosis of 5.4 strokes per 1000 children undergoing a cardiac operation. Univariate analysis revealed that older age at the time of the procedure, longer duration of cardiopulmonary bypass, number of days in the hospital postoperatively, and reoperation were associated with stroke. In multivariate analyses, only reoperation was associated with stroke. CONCLUSIONS: The frequency of vaso-occlusive stroke in children with congenital heart disease undergoing cardiac surgery was 5.4 cases per 1000 children. Age, duration of bypass, and reoperation may be associated with stroke risk.

Craniocervical arterial dissection in children: clinical and radiographic presentation and outcome.

Craniocervical arterial dissection is a recognized cause of arterial ischemic stroke in children. Whether children with craniocervical arterial dissection have dissection characteristics different from those of adults is unclear. A retrospective review of children, 1 month to 18 years of age, with dissection from two Canadian pediatric ischemic stroke registry centers was conducted. From 213 patients with arterial ischemic stroke, 16 (7.5%) were identified with dissection, 37.5% had warning symptoms, and 50% had a history of head or neck trauma. The clinical presentation included headache (44%), altered consciousness (25%), seizures (12.5%), and focal deficits (87.5%). Dissection involved extracranial vessels in 75% and anterior circulation in 56%. Follow-up included complete recovery in 43%, mild to moderate deficits in 44%, and severe deficits in 13%. Fourteen (87.5%) children received antithrombotic treatment. Follow-up angiography showed resolution of abnormalities in 60% of vessels. Total occlusion had the worst outcome for recanalization. In conclusion, the etiology of arterial dissection in the majority of children appears to be either trauma or idiopathic. Long-term angiography shows variable outcomes, depending on the initial findings. The relationship of angiographic outcomes with recurrent strokes requires further study in pediatric dissection. (J Child Neurol 2006;21:8-16).

Post-varicella arteriopathy of childhood: natural history of vascular stenosis.

OBJECTIVE: To determine the course of vascular changes in childhood post-varicella arteriopathy (PVA) and its relationship to recurrent arterial ischemic stroke or TIA (AIS/TIA). METHODS: Subjects were children with AIS/TIA occurring <1 year after varicella, ischemic localization consistent with unilateral disease affecting the supraclinoid internal carotid artery or proximal anterior or middle cerebral arteries, and no identified AIS/TIA etiology other than PVA. Charts, brain MRI, and sequential cerebral vessel imaging (selective cerebral angiography or MR angiography [SCA/MRA]) were retrospectively reviewed. RESULTS: Twenty-three children had varicella at age 1.0 to 10.4 years and had single or multiple AIS/TIAs 4 to 47 weeks later. Initial SCA/MRA was performed within 1 month of presentation, and each child had one to five repeat SCA/MRAs during a 4- to 87-month period. There was vascular stenosis in 19 children, maximal on initial studies in 15 of these. Subsequent stenosis regression occurred in 17 children. In 11 of these, one or two additional SCA/MRAs showed further regression as long as 48 months after presentation; there was no restenosis. Eight of 23 children had recurrent AIS/TIA with antithrombotic therapy within 33 weeks of presentation, including 1 of 17 children with documented stenosis regression. CONCLUSION: Vascular stenosis of childhood post-varicella arteriopathy takes a monophasic course, generally with subsequent stenosis regression and only occasional stenosis progression after arterial ischemic stroke/TIA. Arterial ischemic stroke/TIA rarely recurs with antithrombotic prophylaxis after stenosis regression occurs.

Independent walking after neonatal arterial ischemic stroke and sinovenous thrombosis.

Few studies have examined walking after neonatal arterial ischemic stroke and sinovenous thrombosis. We looked at the development of walking in a retrospective and consecutive cohort study of 88 term and near-term neonates. We used Kaplan-Meier survival curves and Cox proportional hazards models to assess (1) sex, (2) stroke type (arterial ischemic stroke or sinovenous thrombosis), (3) number of cerebral hemispheres with infarction, and (4) presence of neonatal comorbidity as predictors of the probability over time of starting to walk independently. These variables were assessed as predictors of parent-reported gait normality using the chi-square test on 2 x 2 contingency tables. Seventy-five of 83 survivors (90.4%, 95% confidence interval = 81.9-95.7) walked with a median time of first steps at 13 months of age (95% confidence interval = 12-14). Only bilateral strokes were associated with a lower probability over time of initiating independent walking (hazard ratio = 0.41, P = .04). Parents reported normal gait for 58 of 75 walkers (77.3%, 95% confidence interval = 67.8-86.8). No variables predicted parent-reported gait normality. Our findings suggest that most survivors of neonatal arterial ischemic stroke and sinovenous thrombosis walk with a gait that appears normal to parents, but bilateral infarctions decrease the probability over time of starting to walk independently.