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• The rate of direct bypass failure in children is low (5.7%). • A combined revascularization technique is feasible even for very young children. • High preoperative PSOM predicts worse good clinical outcome on follow-up. • Children < 5.4 years old with moyamoya have worse clinical outcomes. Moyamoya is a progressive cerebrovascular arteriopathy that affects children of any age. The goal of this study was to determine imaging and clinical outcomes as well as complication rates in a pediatric cohort undergoing either a combined direct/indirect or indirect-only revascularization approach. Patients with moyamoya disease or syndrome ≤ 18 years of age at the time of initial surgery were identified, and clinical data were collected retrospectively. Over a 12-year period, 26 patients underwent revascularization procedures on 49 hemispheres with a median follow-up of 2.6 years from surgery. Median age at surgery was 7.3 years (range 1.4–18.0 years). Thirty-three hemispheres (67.3%) underwent combined revascularization with a direct bypass and encephalomyosynangiosis, and sixteen hemispheres (32.7%) underwent indirect-only revascularization. The rate of 30-day perioperative complication was 10.2%, and the rate of postoperative clinical stroke by end of follow-up was 10.2% by hemisphere. There was a 5.7% rate of intraoperative bypass failure requiring conversion to an indirect revascularization approach. On follow-up imaging, 96.9% of direct bypasses remained patent. On multivariate analysis, higher preoperative Pediatric Stroke Outcome Measure (PSOM) scores were associated with lower rates of good clinical outcome on follow-up (unit OR 0.03; p = 0.03). Patients with age < 5.4 years had lower rates of good clinical outcome on follow-up. In this North American cohort, both combined direct/indirect and indirect only revascularization techniques were feasible. However, younger children < 5.4 years of age have worse outcomes than older children, similar to east Asian cohorts. [ABSTRACT FROM AUTHOR]

Focal cerebral arteriopathy (FCA), a major cause of childhood arterial ischemic stroke (AIS), can progress and lead to increased infarct size and/or recurrent stroke. Evaluating treatment options depends on the ability to quantify reliably the degree of stenosis in FCA. We validated the recently introduced FCA severity score (FCASS) in an independent cohort from the Swiss Neuro-Paediatric Stroke Registry (SNPSR). We included children with FCA who had MR or CT angiography and a Pediatric Stroke Outcome Measure (PSOM) at 6-months and 2-years post-stroke. A paediatric neuroradiologist applied the FCASS and the modified pediatric Alberta Stroke Program Early Computed Tomography Score (ASPECTS), a measure of infarct volume, to all available imaging. Two senior paediatric stroke neurologists and a neuroradiology fellow independently assigned FCASS scores to test interrater reliability. Pairwise correlations between FCASS, pedASPECTS, and PSOM were examined. Thirty-two children [median (IQR) age = 5.9 (1.8, 9.6), 19 males] were included. The median maximum FCASS score at any time was 9 (IQR 6, 12; range 3, 16). Larger infarct volume scores correlated with both higher maximum FCASS scores and worse post-stroke outcomes, although we found no direct correlation between FCASS and outcomes. Stroke neurologists tended to assign lower FCASS scores than the neuroradiologist, but interrater reliability was predominantly good. In this independent validation cohort, higher maximum FCASS correlated with greater infarct volume scores that also correlated with worse neurological outcomes. Scoring by non-imaging specialists seems to be valuable, although differences are present. • Treatment trials under development for Focal Cerebral Arteriopathy (FCA)—a unilateral anterior circulation arteriopathy that causes childhood arterial ischemic stroke—require a validated metric for FCA severity. The FCA Severity Score (FCASS) quantifies disease severity and extent. • The goal of the current study was to validate the FCA Severity Score in an independent cohort of FCA cases from the Swiss Neuro-Paediatric Stroke Registry (SNPSR). In this independent validation cohort, higher maximum FCASS correlated with greater infarct volume scores that also correlated with worse neurological outcomes. [ABSTRACT FROM AUTHOR]

Infections play an important role in the pathogenesis of acute ischemic stroke (AIS) in neonates and children. In neonates, chorioamnionitis or intrauterine inflammation has been implicated as a common risk factor for AIS. In infants and children, recent investigations demonstrated that even minor childhood infections are associated with subsequent increased risk for AIS. Post-infectious inflammatory mechanisms following infections with herpesviruses may lead to focal cerebral arteriopathy (FCA), one of the most common causes of AIS in a previously healthy child. Other agents such as parvovirus B19, dengue virus, and SARS-CoV-2 have recently been implicated as other potential triggers. Infections are compelling treatable stroke risk factors, with available therapies for both pathogens and downstream inflammatory effects. However, infections are common in childhood, while stroke is uncommon. The ongoing VIPS II (Vascular effects of Infection in Pediatric Stroke) study aims to identify the array of pathogens that may lead to childhood AIS and whether either unusual strains or unusual combinations of pathogens explain this paradox. Immune modulation with corticosteroids for FCA is another active area of research, with European and U.S. trials launching soon. The results of these new pediatric stroke studies combined with findings emerging from the larger field of immune-mediated post-infectious diseases will likely lead to new approaches to the prevention and treatment of pediatric stroke. This review highlights recent developments from both clinical and animal model research enhancing our understanding of this relationship between infection, inflammation, and stroke in neonates and children. [ABSTRACT FROM AUTHOR]

Purpose: To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors. Methods and Materials: The Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors. Results: During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6). Conclusion: Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively. [ABSTRACT FROM AUTHOR]

Study objective: Dizziness and vertigo are common reasons for visiting the emergency department (ED), but many patients are discharged home without a specific diagnosis. Given the concern that important diagnoses could be missed, we measure the incidence of subsequent major vascular events in patients after discharge home. Methods: We identified all adults discharged home from California EDs with a primary diagnosis of dizziness or vertigo from January to June 2005, using comprehensive encounter records. Events were captured with linked statewide hospital discharge and national mortality data. We used Nelson-Aalen survival analysis for the primary outcome, hospitalization or death for cerebrovascular (acute ischemic or hemorrhagic stroke) or cardiovascular events (acute myocardial infarction, unstable angina, and ventricular arrhythmia), and the secondary outcomes, repeat ED visit for dizziness or vertigo, cerebrovascular events, and cardiovascular events. Results: Among 31,159 patients identified, median age was 56 years and 63.5% were women. During the follow-up period, there were 274 deaths, 231 cerebrovascular events, and 115 cardiovascular events. The 180-day cumulative incidence of vascular event, cerebrovascular event, or cardiovascular event was 0.93% (95% confidence interval [CI] 0.83% to 1.04%), 0.63% (95% CI 0.55% to 0.72%), and 0.32% (0.26% to 0.38%), respectively. The risk of cerebrovascular events was higher in the first month (95% CI 30.2 [24.4 to 37.0] versus 6.5 [5.3 to 7.9] events/10,000 person-months thereafter). Conclusion: Few patients experience a major vascular event after discharge home with a diagnosis of dizziness or vertigo, with a stroke occurring in less than 1 in 500 patients within the first month. Future studies will be required to accurately stratify the risk for individual patients. [Copyright &y& Elsevier]

Pediatric stroke investigators identified as their top research priority a clinical trial of corticosteroids for focal cerebral arteriopathy (FCA). However, FCA is both rare and an acute condition making it infeasible to enroll the large sample sizes needed for standard, confirmatory clinical trials. We present a pragmatic approach to clinical trial design that may inform the approach to other rare disorders. We surveyed pediatric stroke experts to determine the level of evidence that would impact their clinical management of FCA. Incorporating survey results, a randomized, group sequential Bayesian adaptive design was proposed based on a quantitative radiologic outcome measure (change from baseline in change in the FCA Severity Score). Using accumulating information, the design determines whether intervention is better than control with high probability. Among 21 (100%) respondents, the probability of corticosteroid efficacy that would lead the experts to treat was 30% (median). The probability of efficacy that would make them unwilling to randomize (because they would feel all children should receive corticosteroids) was 70%. Simulation studies with the proposed design showed that a total of 42 subjects controls the type I error rate at the desired level 0.20 and yields a smaller average sample size and trial duration compared to a conventional design. Designs in rare diseases require special considerations; this is especially true for this childhood disease, which is both uncommon and acute. This design has incorporated expert consensus to establish the criteria for success, formal monitoring rules for safety, and early stopping rules. [ABSTRACT FROM AUTHOR]

Background: Congenital cerebral arteriovenous fistulas (AVFs), including vein of Galen malformations, presenting in infancy carry variable mortality and morbidity. This study aimed to describe the outcome of neonates with cerebral AVFs who present with refractory cardiac failure.Methods: Retrospective chart review of neonates with refractory cardiac failure due to cerebral AVFs presenting before 28 days of age in a single-center neuro-intensive care nursery over a 12-year period (2008-2020) was conducted.Results: Seventeen neonates were included. Twelve had a vein of Galen malformation, four a non-galenic pial AVF, and one a dural AVF. Seven neonates (41%) died without receiving an embolization procedure. The remaining ten were critically ill. Seven (70%) were mechanically ventilated and on nitric oxide, 5 (50%) were on pressors, and 6 (60%) had renal and/or hepatic dysfunction. Seven (70%) had pre-existing brain injury on imaging. The first embolization procedure occurred at a median age of 4 days (range: 0-8 d). Complications included intracranial hemorrhage in 8 of 10 (80%) and seizures in 5 of 8 (62%). Five (50%) neonates who underwent embolization died. Among the 5 neonates who survived, all have motor impairment. Four (80%) developed hydrocephalus requiring a ventriculoperitoneal shunt, and 2 (40%) developed epilepsy and are nonverbal.Conclusion: In this cohort of critically ill neonates with cerebral AVF, all seven who did not receive embolization and half of ten who were treated died. The five survivors all have neurodevelopmental impairment. This information may be helpful to parents and providers who make decisions regarding life-sustaining treatments for neonates with cerebral AVFs and refractory cardiac failure. [ABSTRACT FROM AUTHOR]

Summary: Background: For childhood-onset arterial ischaemic stroke (AIS), treatment trials are lacking and practices vary from country to country and centre to centre. We aimed to describe frequencies and predictors of acute treatments and early outcomes in the International Pediatric Stroke Study (IPSS), a large international series of childhood AIS. Methods: The IPSS has 33 centres enrolling children with stroke. Data for children aged 28 days to 19 years with AIS from Jan 1, 2003, to Oct 1, 2007, were collected with standardised case-report forms and analysed to identify factors associated with stroke treatment and early prognosis. Findings: Among 661 children with AIS (640 with acute treatment data, 612 with morbidity data, and 643 with mortality data), acute treatments included anticoagulation alone in 171 patients (27%), antiplatelet therapy alone in 177 (28%), antiplatelet and anticoagulation in 103 (16%), and no antithrombotic treatment in 189 (30%). After adjustment for significant covariates, subtypes associated with any use of anticoagulation were dissection (odds ratio 14·09, 95% CI 5·78–37·01; p<0·0001) and cardiac disease (1·87, 1·20–2·92; p=0·01). Factors associated with non-use of anticoagulation included sickle-cell disease subtype (0·12, 0·02–0·95; p=0·04) and the enrolment centre being located in the USA (0·56, 0·39–0·80; p=0·002). By contrast, antiplatelet use was associated with moyamoya (4·88, 2·13–11·12; p=0·0002), whereas non-use was associated with dissection (0·47, 0·22–0·99; p=0·047), low level of consciousness (0·45, 0·31–0·64; p<0·0001), and bilateral ischaemia (0·32, 0·20–0·52; p<0·0001). Outcomes at hospital discharge included neurological deficits in 453 (74%) patients and death in 22 (3%). In multivariate analysis, arteriopathy, bilateral ischaemia, and decreased consciousness at presentation were prognostic of adverse outcome. Interpretation: Acute anticoagulation is commonly prescribed in acute childhood-onset AIS although practice varies with AIS subtype and geographical region. Several factors are prognostic of adverse early outcome, and clinical trials are needed to determine the best treatment strategies. Funding: Canadian Stroke Network; Auxilium Foundation; NIH NCRR; NIH NHLBI. [Copyright &y& Elsevier]

Summary: Stroke is increasingly recognised as a cause of childhood disability and lifelong morbidity: population-based estimates of the annual incidence of childhood stroke (ischaemic and haemorrhagic) range from 2·3 to 13·0 per 100 000 children, and incidence rates in neonates are closer to 1 per 5000 livebirths. Stroke in childhood can have many causes. Diagnosis is often delayed owing to low clinical suspicion and the need to exclude the frequent mimics of stroke in childhood. Outcomes are related to presentation, associated illnesses, the underlying cause, size, and location of the infarct, and stroke subtype, but more than a half of the children who have had a stroke will have long-term neurological sequelae. Furthermore, estimates of recurrence rates range from 6–19% in the first few years. Arteriopathy—including arterial dissection and other progressive and non-progressive arteriopathies—might account for up to 80% of childhood stroke in otherwise healthy children. Because children with cerebrovascular abnormalities are at the highest risk of recurrence (66% at 5 years), understanding of the nature and course of these arteriopathies is crucial to the development of secondary stroke prevention strategies. [Copyright &y& Elsevier]

Cerebrovascular disorders are increasingly recognized as important causes of mortality and morbidity in the pediatric population. However, there have been no clinical trials performed to assess the safety and tolerability of acute interventions or secondary preventative treatments. In 2002, the International Pediatric Stroke Study was launched to create a network of investigators, with an interest in developing standards of practice, as well as design and implement the first-ever clinical trials in pediatric stroke. This article reviews existing studies in pediatric stroke epidemiology, risk factors, outcomes, as well as experience with antithrombotic trials in children. From there, current and future initiatives in the development of clinical trials in pediatric stroke are evaluated. [Copyright &y& Elsevier]

Purpose: To assess, in a retrospective cohort study, rates and predictors of first and recurrent stroke in patients treated with cranial irradiation (CRT) and/or cervical irradiation at ≤18 years of age. Methods and Materials: We performed chart abstraction (n=383) and phone interviews (n=104) to measure first and recurrent stroke in 383 patients who received CRT and/or cervical radiation at a single institution between 1980 and 2009. Stroke was defined as a physician diagnosis and symptoms consistent with stroke. Incidence of first stroke was number of first strokes per person-years of observation after radiation. We used survival analysis techniques to determine cumulative incidence of first and recurrent stroke. Results: Among 325 subjects with sufficient follow-up data, we identified 19 first strokes (13 ischemic, 4 hemorrhagic, 2 unknown subtype) occurring at a median age of 24 years (interquartile range 17-33 years) in patients treated with CRT. Imaging was reviewed when available (n=13), and the stroke was confirmed in 12. Overall rate of first stroke was 625 (95% confidence interval [CI] 378-977) per 100,000 person-years. The cumulative incidence of first stroke was 2% (95% CI 0.01%-5.3%) at 5 years and 4% (95% CI 2.0%-8.4%) at 10 years after irradiation. With each 100-cGy increase in the radiation dose, the stroke hazard increased by 5% (hazard ratio 1.05; 95% CI 1.01-1.09; P=.02). We identified 6 recurrent strokes; 5 had available imaging that confirmed the stroke. Median time to recurrence was 15 months (interquartile range 6 months-3.2 years) after first stroke. The cumulative incidence of recurrent stroke was 38% (95% CI 17%-69%) at 5 years and 59% (95% CI 27%-92%) at 10 years after first stroke. Conclusion: Cranial irradiation puts childhood cancer survivors at high risk of both first and recurrent stroke. Stroke prevention strategies for these survivors are needed. [ABSTRACT FROM AUTHOR]

Clinical and neuroimaging characteristics of congenital hemiparesis were examined in a retrospective cohort study nested within 199,176 births within the Kaiser Permanente Medical Care Program, 1997-2002. Infants with a physician diagnosis of paresis or cerebral palsy were electronically identified, and charts were reviewed to confirm congenital hemiparesis. A neuroradiologist reviewed available head MRI and CT scans. Of 96 infants with congenital hemiparesis (population prevalence 4.8 per 10,000), 81% received either a head magnetic resonance imaging (n = 55) or head computed tomography only (n = 23). Perinatal arterial infarction was the most common (30%) neuroimaging finding in term infants. Infants with right-sided hemiparesis (relative risk 4.6, 95% confidence interval 1.4-14.4) or moderate to severe weakness (relative risk 4.4, 95% confidence interval 1.1-17.7) were more likely to have had a perinatal arterial infarction. Periventricular white matter lesions predominated in preterm infants (71%). Brain malformations observed in 14 (18%) patients included polymicrogyria, heterotopia, and schizencephaly. The 14 infants (18%) with a normal head imaging study were more likely to outgrow all signs of hemiparesis by age 3 than were infants with an abnormal brain image (29% vs 0%, P < 0.001). Neuroimaging studies provide useful diagnostic and prognostic information in infants with congenital hemiparesis. [Copyright &y& Elsevier]