Association of Acute Infarct Topography With Development of Cerebral Palsy and Neurologic Impairment in Neonates With Stroke.

BACKGROUND AND OBJECTIVES: Research investigating neonatal arterial ischemic stroke (NAIS) outcomes have shown that combined cortical and basal ganglia infarction or involvement of the corticospinal tract predict cerebral palsy (CP). The research question was whether voxel-based lesion-symptom mapping (VLSM) on acute MRI can identify brain regions associated with CP and neurodevelopmental impairments in NAIS. METHODS: Newborns were recruited from prospective Australian and Swiss pediatric stroke registries. CP diagnosis was based on clinical examination. Language and cognitive-behavioral impairments were assessed using the Pediatric Stroke Outcome Measure, dichotomized to good (0-0.5) or poor (≥1), at ≥18 months of age. Infarcts were manually segmented using diffusion-weighted imaging, registered to a neonatal-specific brain template. VLSM was conducted using MATLAB SPM12 toolbox. A general linear model was used to correlate lesion masks with motor, language, and cognitive-behavioral outcomes. Voxel-wise t-statistics were calculated, correcting for multiple comparisons using family-wise error (FWE) rate. RESULTS: Eighty-five newborns met the inclusion criteria. Infarct lateralization was left hemisphere (62%), right (8%), and bilateral (30%). At a median age of 2.1 years (interquartile range 1.9-2.6), 33% developed CP and 42% had neurologic impairments. Fifty-four grey and white matter regions correlated with CP (t > 4.33; FWE < 0.05), including primary motor pathway regions, such as the precentral gyrus, and cerebral peduncle, and regions functionally connected to the primary motor pathway, such as the pallidum, and corpus callosum motor segment. No significant correlations were found for language or cognitive-behavioral outcomes. DISCUSSION: CP after NAIS correlates with infarct regions directly involved in motor control and in functionally connected regions. Areas associated with language or cognitive-behavioral impairment are less clear.

The incidence of pediatric ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Despite its importance in being among the top 10 causes of childhood death, there is limited data on the incidence of stroke in children and whether this has changed over time. AIMS: We performed a systematic review and meta-analysis to estimate the worldwide incidence rate of pediatric ischemic stroke, identify population differences, and assess trends in incidence. METHODS: We screened three databases (Medline, Embase, and Cumulative Index of Nursing and Allied Health Literature (CINAHL)) and a Google Search was performed up to October 2021. The protocol was pre-registered: PROSPERO: CRD42021273749. Data extraction and quality assessment were independently undertaken by two reviewers. A random-effects model was used for meta-analysis using Stata SE17 to calculate the overall incidence rate. Heterogeneity was assessed using I2. Meta-regression and assessment for bias were performed. RESULTS: Out of 4166 records identified, 39 studies were included in the qualitative synthesis and the quantitative meta-analysis. The incidence rate for all ischemic strokes varied from 0.9 to 7.9 per 100,000 person-years, with a pooled incidence of 2.09 (95% confidence interval (CI): 1.57-2.76). The pooled incidence was 1.28 (95% CI: 0.75-2.19) per 100,000 person-years for arterial ischemic stroke, and 0.56 (95% CI: 0.31-1.02) per 100,000 person-years for cerebral venous sinus thrombosis. The incidence of arterial ischemic stroke was high in neonates, less than 28 days old (18.51, 95% CI: 12.70-26.97). Significant heterogeneity was observed in the initial analyses of stroke incidence estimates, and geographical region, cohort age upper limit, length of study, study quality, and study design could not explain this. The incidence rate of childhood stroke appeared remained relatively stable over time. CONCLUSION: Our review provides estimates of global stroke incidence, including stroke subtypes, in children. It demonstrates a particularly high stroke incidence in neonates.

Association of Pediatric ASPECTS and NIH Stroke Scale, Hemorrhagic Transformation, and 12-Month Outcome in Children With Acute Ischemic Stroke.

OBJECTIVE: We aimed to determine whether a modified pediatric Alberta Stroke Program Early CT Score (modASPECTS) is associated with clinical stroke severity, hemorrhagic transformation, and 12-month functional outcomes in children with acute AIS. METHODS: Children (29 days to <18 years) with acute AIS enrolled in two institutional prospective stroke registries at Children's Hospital of Philadelphia and Royal Children's Hospital Melbourne, Australia were retrospectively analyzed to determine whether modASPECTS, in which higher scores are worse, correlated with acute Pediatric NIH Stroke Scale (PedNIHSS) scores (children ≥2 years of age), was associated with hemorrhagic transformation on acute MRI, and correlated with 12-month functional outcome on the Pediatric Stroke Outcome Measure (PSOM). RESULTS: 131 children were included; 91 were ≥2 years of age. Median days from stroke to MRI was 1 (interquartile range [IQR] 0-1). Median modASPECTS was 4 (IQR 3-7). ModASPECTS correlated with PedNIHSS (rho=0.40, P=0.0001). ModASPECTS was associated with hemorrhagic transformation (OR 1.13 95% CI 1.02-1.25, P=0.018). Among children with follow-up (N=128, median 12.2 months, IQR 9.5-15.4 months), worse outcomes were associated with higher modASPECTS (common OR 1.14, 95%CI 1.04-1.24, P=0.005). The association between modASPECTS and outcome persisted when we adjusted for age at stroke ictus and the presence of tumor or meningitis as stroke risk factors (common OR 1.14, 95%CI 1.03-1.25, P=0.008). CONCLUSIONS: ModASPECTS correlates with PedNIHSS scores, hemorrhagic transformation, and 12-month functional outcome in children with acute AIS. Future pediatric studies should evaluate its usefulness in predicting symptomatic intracranial hemorrhage and outcome after acute revascularization therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the modified pediatric ASPECTS on MRI is associated with stroke severity (as measured by the baseline pediatric NIH Stroke Scale), hemorrhagic transformation, and 12-month outcome in children with acute supratentorial ischemic stroke.

Pediatric ASPECTS predicts outcomes following acute symptomatic neonatal arterial stroke.

OBJECTIVE: To test the hypothesis that the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is useful in determining outcomes after neonatal arterial ischemic stroke (NAIS), we assessed accuracy of the modified pediatric ASPECTS (pedASPECTS) to predict cerebral palsy (CP), neurologic impairment, and epilepsy. METHODS: Cross-sectional study included newborns with acute NAIS whose outcomes were assessed at ≥18 months after stroke. PedASPECTS accuracy to predict outcomes was determined by sensitivity, specificity, and receiver operator characteristic (ROC) curves, and correlation between pedASPECTS and infarct volume was determined by the Spearman correlation coefficient. RESULTS: Ninety-six children met the inclusion criteria. Median percentage infarct to supratentorial brain volume was 6.8% (interquartile range [IQR] 3.0%-14.3%). Median pedASPECTS was 7 (IQR 4-10). At a median age of 2.1 years, 35% developed CP, 43% had neurologic impairment, and 7% had epilepsy. Median pedASPECTS predicted outcomes of interest: CP (10, IQR 8-12) vs no CP (5, IQR 4-8) (p < 0.0001), poor (9, IQR 7-12) vs good (6, IQR 4-8) neurologic outcomes (p < 0.0001), and epilepsy (10, IQR 8-12) vs no epilepsy (7, IQR 4-10) (p = 0.033). PedASPECTS accuracy was good for CP (ROC 0.811) and fair for neurologic impairment (ROC 0.760) and epilepsy (ROC 0.761). A pedASPECTS ≥8 had ≥69% sensitivity and ≥54% specificity for clinical outcomes. PedASPECTS correlated with infarct volume (Spearman rank 0.701, p < 0.0001). CONCLUSIONS: This study provides Class II evidence that pedASPECTS has fair to good accuracy for predicting CP, neurologic impairment, and epilepsy after NAIS and correlates with infarct volume. PedASPECTS may assist with early identification of babies requiring close developmental surveillance.

Australian Clinical Consensus Guideline: The diagnosis and acute management of childhood stroke.

Stroke is among the top 10 causes of death in children and survivors carry resulting disabilities for decades, at substantial cost to themselves and their families. Children are not currently able to access reperfusion therapies, due to limited evidence supporting safety and efficacy and long diagnostic delays. The Australian Clinical Consensus Guideline for the Diagnosis and Acute Management of Childhood Stroke was developed to minimize unwarranted variations in care and document best evidence on the risk factors, etiologies, and conditions mimicking stroke that differ from adults. Clinical questions were formulated to inform systematic database searches from 2007 to 2017, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE) was used to grade evidence as strong or weak. The Guideline provides more than 60 evidence-based recommendations to assist prehospital and acute care clinicians in the rapid identification of childhood stroke, choice of initial investigation, to confirm diagnosis, determine etiology, selection of the most appropriate interventions to salvage brain at risk, and prevent recurrence. Recommendations include advice regarding the management of intracranial pressure and congenital heart disease. Implementation of the Guideline will require reorganization of prehospital and emergency care systems, including the development of regional stroke networks, pediatric Code Stroke, rapid magnetic resonance imaging and accreditation of primary pediatric stroke centers with the capacity to offer reperfusion therapies. The Guideline will allow auditing to benchmark timelines of care, access to acute interventions, and outcomes. It will also facilitate the development of an Australian childhood stroke registry, with data linkage to international registries, to allow for accurate data collection on stroke incidence, treatment, and outcomes.

Risk Factors for Peri-Procedural Arterial Ischaemic Stroke in Children with Cardiac Disease.

Improved survival of children with congenital heart disease has led to increasing focus on neurodevelopmental outcome, as close to half of the infants undergoing cardiac surgery are affected by neurodevelopmental disability. Stroke is particularly important as it frequently results in permanent neurologic sequelae. The aim of this study was to investigate risk factors for peri-procedural arterial ischaemic stroke (AIS) in children with cardiac disease. A retrospective case-control analysis of children aged <18 years with radiologically confirmed AIS following a cardiac procedure admitted to the Royal Children's Hospital Melbourne between 1993 and 2010. Each case was matched with two controls with similar cardiac diagnosis, procedure type, age and date of procedure. Demographics and peri-procedural data were collected from medical records and departmental database. Fifty-two cases were identified. Multivariable analysis identified post-procedural infection (OR 6.1, CI 1.3-27, p = 0.017) and length of ICU stay (OR 4.0, CI 1.4-11, p = 0.009) as risk factors for AIS. Although the study is limited to a single-centre cohort, length of ICU stay and post-procedural infection were identified as risk factors for AIS. These findings demonstrate these factors to be important areas to focus attention for stroke prevention in children with cardiac disease.

Focal Cerebral Arteriopathy: Do Steroids Improve Outcome?

BACKGROUND AND PURPOSE: Focal cerebral arteriopathy accounts for up to 35% of arterial ischemic stroke (AIS) in children and is the most important predictor of stroke recurrence. The study objective was to compare outcomes for children with focal cerebral arteriopathy treated with combined corticosteroid antithrombotic treatment (CAT) to those receiving antithrombotic treatment (AT) alone. METHODS: This multicenter retrospective Swiss/Australian cohort study analyzed consecutive children, aged 1 month to 18 years, presenting with first AIS because of a focal cerebral arteriopathy from 2000 to 2014. Children with CAT were compared with those treated with AT. Primary outcome was the presence of neurological deficits at 6 months post-AIS as measured by the Pediatric Stroke Outcome Measure. Secondary outcomes included resolution of stenosis and stroke recurrence. Analysis of covariance was used to adjust for potential confounders (baseline pediatric National Institute of Health Stroke Scale and concomitant acyclovir use). RESULTS: A total of 73 children (51% males) were identified, 21 (29%) of whom received CAT. Mean (SD) age at stroke for the entire group was 7.9 years (4.7). Median (interquartile range) pediatric National Institute of Health Stroke Scale was 3 (2.0-8.0) in the CAT group and 5 (3.0-9.0) in the AT group (P=0.098). Median (interquartile range) Pediatric Stroke Outcome Measure 6 months post-AIS was 0.5 (0-1.5) in the CAT group compared with 1.0 (0.5-2.0) in the AT group (P=0.035), the finding was sustained after adjusting for potential confounders. Complete resolution of stenosis at last MRI was noted in 17 (81%) in the CAT group compared with 24 (59%) in the AT group (P=0.197). Stroke recurrence occurred in 1 patient in each group. CONCLUSIONS: Corticosteroid treatment may provide additional benefit over AT for improved neurological outcome in childhood AIS because of focal cerebral arteriopathy. Larger prospective studies are warranted to further investigate these differences and understand mechanisms by which steroids modify outcome.

Prehospital Emergency Care in Childhood Arterial Ischemic Stroke.

BACKGROUND AND PURPOSE: Immediately calling an ambulance is the key factor in reducing time to hospital presentation for adult stroke. Little is known about prehospital care in childhood arterial ischemic stroke (AIS). We aimed to determine emergency medical services call-taker and paramedic diagnostic sensitivity and to describe timelines of care in childhood AIS. METHODS: This is a retrospective study of ambulance-transported children aged <18 years with first radiologically confirmed AIS, from 2008 to 2015. Interhospital transfers of children with preexisting AIS diagnosis were excluded. RESULTS: Twenty-three children were identified; 4 with unavailable ambulance records were excluded. Nineteen children were included in the study. Median age was 8 years (interquartile range, 3-14); median Pediatric National Institutes of Stroke Severity Scale score was 8 (interquartile range, 3-16). Emergency medical services call-taker diagnosis was stroke in 4 children (21%). Priority code 1 (lights and sirens) ambulances were dispatched for 13 children (68%). Paramedic diagnosis was stroke in 5 children (26%), hospital prenotification occurred in 8 children (42%), and 13 children (68%) were transported to primary stroke centers. Median prehospital timelines were onset to emergency medical services contact 13 minutes, call to scene 12 minutes, time at scene 14 minutes, transport time 43 minutes, and total prehospital time 71 minutes (interquartile range, 60-85). CONCLUSIONS: Emergency medical services call-taker and paramedic diagnostic sensitivity and prenotification rates are low in childhood AIS.

Parental Care-Seeking Behavior and Prehospital Timelines of Care in Childhood Arterial Ischemic Stroke.

BACKGROUND AND PURPOSE: Taking appropriate action in the prehospital setting is important for rapid stroke diagnosis in adults. Data are lacking for children. We aimed to describe parental care-seeking behavior and prehospital timelines of care in childhood arterial ischemic stroke. METHODS: A structured questionnaire was developed, using value-focused event-driven conceptual modeling techniques, to interview parents of children presenting to the emergency department with arterial ischemic stroke from 2008 to 2014. RESULTS: Twenty-five parents (median age 41 years, interquartile range 36-45) were interviewed. Twenty-four children were awake, and 1 child was asleep at stroke onset; 23 had sudden onset symptoms. Location at stroke onset included home (72%), school (8%), or other setting (20%). Carergivers present included parent (76%), another child (8%), teacher (4%), or alone (8%). Eighty-four percent of parents thought symptoms were serious, and 83% thought immediate action was required, but only 48% considered the possibility of stroke. Initial actions included calling an ambulance (36%), wait and see (24%), calling a general practitioner (16%) or family member (8%), and driving to the emergency department or family physician (both 8%). Median time from onset to emergency department arrival was 76 minutes (interquartile range 53-187), being shorter for ambulance-transported patients. CONCLUSIONS: Stroke recognition and care-seeking behavior are suboptimal, with less than half the parents considering stroke or calling an ambulance. Initiatives are required to educate parents about appropriate actions to facilitate time-critical interventions.

Arterial ischemic stroke in children with cardiac disease.

OBJECTIVE: To describe the spectrum of cardiac disorders, timing in relation to interventional procedures, and outcome in children with cardiac disease and arterial ischemic stroke (AIS). METHODS: Children younger than 18 years with cardiac disease and radiologically confirmed AIS admitted to the Royal Children's Hospital Melbourne between 1993 and 2010 were retrospectively identified using ICD-9 and ICD-10 searches. RESULTS: Seventy-six children with cardiac disease and radiologically confirmed AIS were identified with the median age at diagnosis of 5 months (interquartile range 0-58). Cardiac lesions included cyanotic congenital heart disease (CHD) in 42 (55%), acyanotic heart disease in 24 (29%), cardiomyopathies/myocarditis in 6 (8%), infective endocarditis in 3 (4%), and primary arrhythmias in 3 (4%). Stroke occurred following cardiac procedures in 52 patients (68%): 41 post cardiac surgery (4.6 strokes per 1,000 surgical procedures) and 11 post cardiac catheterization (1.7 strokes per 1,000 catheterizations). The median time from procedure to diagnosis of stroke was 3 days (interquartile range 2-7), with 68% (95% confidence interval 58%-79%) of strokes estimated to occur within the periprocedural period. Prevalence of periprocedural stroke varied by diagnostic category, but was most common in patients with cyanotic CHD undergoing palliative surgery (22/2,256, 1%) (p < 0.005). There were 3 AIS-related deaths, and 54 survivors (84%) had persisting neurologic deficits. CONCLUSIONS: Infants with cyanotic CHD were most frequently affected by AIS during the periprocedural period. Prospective cohort studies are required to determine effective primary and secondary prevention strategies.