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Ascertaining the etiology of cervical spinal cord dysfunction presents a challenge to clinicians, as the list of differential diagnoses is extensive. Although compressive and inflammatory disorders are common and should be considered immediately, vascular causes are similarly important and acute. The overlap of clinical, magnetic resonance imaging, and cerebrospinal fluid features among the causes of myelopathies may lead to erroneous diagnoses. Such errors may be compounded if routine vascular imaging does not reveal the underlying vasculopathy. We present here three cases in which computed tomography angiography and magnetic resonance angiogram could not clarify the nature of an acute myelopathy, whereas digital subtraction angiography established the diagnosis of spinal cord ischemia., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Prediction of outcomes in perinatal arterial ischemic stroke (PAIS) is challenging. We performed a systematic review and meta-analysis to determine whether infarct characteristics can predict outcomes in PAIS., Methods: A systematic search was conducted using five databases in January 2023. Studies were included if the sample included children with neonatal or presumed PAIS; if infarct size, location, or laterality was indicated; and if at least one motor, cognitive, or language outcome was reported. The level of evidence and risk of bias were evaluated using the Risk of Bias in Non-Randomized Studies of Interventions tool. Meta-analyses were conducted comparing infarct size or location with neurological outcomes when at least three studies could be analyzed., Results: Eighteen full-text articles were included in a systematic review with nine included in meta-analysis. Meta-analyses revealed that small strokes were associated with a lower risk of cerebral palsy/hemiplegia compared with large strokes (risk ratio [RR] = 0.263, P = 0.001) and a lower risk of epilepsy (RR = 0.182, P < 0.001). Middle cerebral artery (MCA) infarcts were not associated with a significantly different risk of cerebral palsy/hemiplegia compared with non-MCA strokes (RR = 1.220, P = 0.337). Bilateral infarcts were associated with a 48% risk of cerebral palsy/hemiplegia, a 26% risk of epilepsy, and a 58% risk of cognitive impairment., Conclusions: Larger stroke size was associated with worse outcomes across multiple domains. Widely heterogeneous reporting of infarct characteristics and outcomes limits the comparison of studies and the analysis of outcomes. More consistent reporting of infarct characteristics and outcomes will be important to advance research in this field., Competing Interests: Declaration of competing interest Dr. Lo receives research grant support from the NINDS and NICHD. Dr. Bridge receives research grant support from the National Institute of Mental Health, the Centers for Disease Control and Prevention, and the Patient-Centered Outcomes Research Institute; he is also a member of the Scientific Advisory Board of Clarigent Health. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Our team designed an innovative, observation-based motor impairment measure-the Pediatric Stroke Hemiplegic Motor Impairment Scale (Pedi HEMIs). Here we present the results of a survey describing common practices in the pediatric stroke community and the initial psychometric properties of the upper extremity subscale of the Pedi HEMIs (Pedi HEMIs-UE)., Methods: This is a cross-sectional study whereby participants completed a battery of assessments including the novel Pedi HEMIs-UE. Internal consistency was measured via Cronbach alpha (α). Intraclass correlation (ICC) was used to assess inter-rater reliability (IRR). Concurrent validity was investigated using Pearson or polychoric correlations and simple linear regressions., Results: The study sample consisted of 18 children aged 1.08 to 15 years. Two participants completed two sets of evaluations, totaling 20 data sets. Cronbach α, a measure of internal consistency, was on average 0.91 (range: 0.89 to 0.92). IRR was excellent with the six raters in almost perfect agreement (ICC = 0.91; 95% confidence interval [CI]: 0.83 to 0.96). Pearson correlation coefficient between the Pedi HEMIs-UE and logit Assisting Hand Assessment (AHA)/mini-AHA was -0.938 (95% CI: -0.979 to -0.827, P < 0.001), indicating excellent concurrent validity., Conclusions: We found excellent feasibility, reliability, and validity of the Pedi HEMIs-UE in a convenience sample of youth with hemiparesis after stroke., Competing Interests: Declaration of competing interest Dr. Suskauer serves on the Scientific Advisory Board role for Myomo. Dr. Sun receives funding from the American Heart Association (Career Development Award [850044]) and the D.C. Women's Board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Extracorporeal membrane oxygenation is a potentially lifesaving intervention for children with severe cardiac or respiratory failure. It is used with increasing frequency and in increasingly more complex and severe diseases. Neurological injuries are important causes of morbidity and mortality in children treated with extracorporeal membrane oxygenation and include ischemic stroke, intracranial hemorrhage, hypoxic-ischemic injury, and seizures. In this review, we discuss the epidemiology and pathophysiology of neurological injury in patients supported with extracorporeal membrane oxygenation, and we review the current state of knowledge for available modalities of monitoring neurological function in these children. These include structural imaging with computed tomography and ultrasound, cerebral blood flow monitoring with near-infrared spectroscopy and transcranial Doppler ultrasound, and physiological monitoring with electroencephalography and plasma biomarkers. We highlight areas of need and emerging advances that will improve our understanding of neurological injury related to extracorporeal membrane oxygenation and help to reduce the burden of neurological sequelae in these children., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

The photophysics associated with the self-assembly of π-peptide molecules into 1-D nanostructures has been well-established, thus revealing the creation of nanoscale electronic conduits in aqueous media. Such materials have therapeutic potential in many biomedical applications. In this work, we report the in vivo deployment of these π-peptide nanostructures in brain tissue using photothrombotic stroke as a model application. A test peptide was used for brain injections, and the nanostructures formed were visualized with electron microscopy. A new peptide bearing a low-energy fluorescence dye was prepared to facilitate direct visualization of π-peptide localization in the brain cavity by way of fluorescence microscopy. This work demonstrates feasibility for in vivo application of π-peptide nanostructures toward pressing biomedical challenges.

Neurological morbidity is common after pediatric stroke, with moderate to severe deficits that can significantly impact education and social function. Care and recovery occur in phases distinguished by the time interval after stroke onset. These phases include the hyperacute and acute periods in which the focus is on cerebral reperfusion and prevention of neurological deterioration, followed by the subacute and chronic phases in which the focus is on secondary stroke prevention and mitigation of disability through rehabilitation, adaptation, and reintegration into the community. In this article, a multidisciplinary group of pediatric stroke experts review the stages of recovery after pediatric stroke with an emphasis on critical assessment time points. Our goal is to encourage increased standardization of outcome assessment to facilitate future clinical trials comparing various treatment and intervention options and advance optimized care for children with stroke., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Following a pediatric stroke, outcome measures selected for monitoring functional recovery and development vary widely. We sought to develop a toolkit of outcome measures that are currently available to clinicians, possess strong psychometric properties, and are feasible for use within clinical settings. A multidisciplinary group of clinicians and scientists from the International Pediatric Stroke Organization comprehensively reviewed the quality of measures in multiple domains described in pediatric stroke populations including global performance, motor and cognitive function, language, quality of life, and behavior and adaptive functioning. The quality of each measure was evaluated using guidelines focused on responsiveness and sensitivity, reliability, validity, feasibility, and predictive utility. A total of 48 outcome measures were included and were rated by experts based on the available evidence within the literature supporting the strengths of their psychometric properties and practical use. Only three measures were found to be validated for use in pediatric stroke: the Pediatric Stroke Outcome Measure, the Pediatric Stroke Recurrence and Recovery Questionnaire, and the Pediatric Stroke Quality of Life Measure. However, multiple additional measures were deemed to have good psychometric properties and acceptable utility for assessing pediatric stroke outcomes. Strengths and weaknesses of commonly used measures including feasibility are highlighted to guide evidence-based and practicable outcome measure selection. Improving the coherence of outcome assessment will facilitate comparison of studies and enhance research and clinical care in children with stroke. Further work is urgently needed to close the gap and validate measures across all clinically significant domains in the pediatric stroke population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pediatric stroke results in life-long morbidity for many patients, but the outcomes can vary depending on factors such as age of injury, or mechanism, size, and location of stroke. In this review, we summarize the current understanding of outcomes in different neurological domains (eg, motor, cognitive, language) for children with stroke of different mechanisms (ie, arterial ischemic stroke, cerebral sinus venous thrombosis, and hemorrhagic stroke), but with a focus on World Health Organization International Classification for Functioning, Disability, and Health (ICF-CY) framework for measuring health and disability for children and youth. We describe outcomes for the population as a whole and certain factors that may further refine prognostication., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO., Methods: We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1β, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course., Results: All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition., Conclusions: High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO., Impact: The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The aim of this study was to determine if plasma cyclohexanone and metabolites are associated with clinical outcomes of children on extracorporeal membrane oxygenation (ECMO) support. We performed a secondary analysis of a prospective observational study of children on ECMO support at two academic centers between July 2010 and June 2015. We measured plasma cyclohexanone and metabolites on the first and last days of ECMO support. Unfavorable outcome was defined as in-hospital death or discharge Pediatric Cerebral Performance Category score > 2 or decline ≥ 1 from baseline. Among 90 children included, 49 (54%) had unfavorable outcome at discharge. Cyclohexanediol, a cyclohexanone metabolite, was detected in all samples and at both time points; concentrations on the first ECMO day were significantly higher in those with unfavorable versus favorable outcome at hospital discharge (median, 5.7 ng/µl; interquartile range [IQR], 3.3-10.6 ng/µl vs. median, 4.2 ng/µl; IQR, 1.7-7.3 ng/µl; p = 0.04). Twofold higher cyclohexanediol concentrations on the first ECMO day were associated with increased risk of unfavorable outcome at hospital discharge (multivariable-adjusted hazard ratio [HR], 1.24 [95% CI, 1.05-1.48]). Higher cyclohexanediol concentrations on the first ECMO day were not significantly associated with new abnormal neuroimaging or 1-year Vineland Adaptive Behavior Scales-II score < 85 or death among survivors., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Pediatric patients with moyamoya arteriopathy are at high risk for developing new onset transient or permanent neurologic deficits secondary to cerebral hypoperfusion, particularly in the perioperative period. It is therefore essential to carefully manage these patients in a multidisciplinary, coordinated effort to reduce the risk of new permanent neurologic deficits. However, little has been published on perioperative management of pediatric patients with moyamoya, particularly in the early postoperative period during intensive care unit admission. Our pediatric neurocritical care team sought to create a multidisciplinary periprocedural evidence- and consensus-based care pathway for high-risk pediatric patients with moyamoya arteriopathy undergoing anesthesia for any reason to decrease the incidence of periprocedural stroke or transient ischemic attack (TIA). We reviewed the literature to identify risk factors associated with perioperative stroke or TIA among patients with moyamoya and to gather data supporting specific perioperative management strategies. A multidisciplinary team from pediatric anesthesia, neurocritical care, nursing, child life, neurosurgery, interventional neuroradiology, neurology, and hematology created a care pathway for children with moyamoya undergoing anesthesia, classifying them as either high or standard risk, and applying an individualized perioperative management plan to high-risk patients. The incidence of neurologic sequelae before and after pathway implementation will be compared in future studies., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Objective: Severe complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include arterial ischemic stroke (AIS) in adults and multisystem inflammatory syndrome in children. Whether stroke is a frequent complication of pediatric SARS-CoV-2 is unknown. This study aimed to determine the proportion of pediatric SARS-CoV-2 cases with ischemic stroke and the proportion of incident pediatric strokes with SARS-CoV-2 in the first 3 months of the pandemic in an international cohort., Methods: We surveyed 61 international sites with pediatric stroke expertise. Survey questions included: numbers of hospitalized pediatric (≤ 18 years) patients with SARS-CoV-2; numbers of incident neonatal and childhood ischemic strokes; frequency of SARS-CoV-2 testing for pediatric patients with stroke; and numbers of stroke cases positive for SARS-CoV-2 from March 1 to May 31, 2020., Results: Of 42 centers with SARS-CoV-2 hospitalization numbers, 8 of 971 (0.82%) pediatric patients with SARS-CoV-2 had ischemic strokes. Proportions of stroke cases positive for SARS-CoV-2 from March to May 2020 were: 1 of 108 with neonatal AIS (0.9%), 0 of 33 with neonatal cerebral sinovenous thrombosis (CSVT; 0%), 6 of 166 with childhood AIS (3.6%), and 1 of 54 with childhood CSVT (1.9%). However, only 30.5% of neonates and 60% of children with strokes were tested for SARS-CoV-2. Therefore, these proportions represent 2.9, 0, 6.1, and 3.0% of stroke cases tested for SARS-CoV-2. Seven of 8 patients with SARS-CoV-2 had additional established stroke risk factors., Interpretation: As in adults, pediatric stroke is an infrequent complication of SARS-CoV-2, and SARS-CoV-2 was detected in only 4.6% of pediatric patients with ischemic stroke tested for the virus. However, < 50% of strokes were tested. To understand the role of SARS-CoV-2 in pediatric stroke better, SARS-CoV-2 testing should be considered in pediatric patients with stroke as the pandemic continues. ANN NEUROL 2021;89:657-665., (© 2020 American Neurological Association.)

Background: Mechanisms of chemotherapy-associated neurotoxicity are poorly understood, and therefore, prevention strategies have not been developed. We hypothesized that a subgroup of children receiving intrathecal cytarabine develops subclinical vasospasm, which may contribute to long-term neurocognitive sequelae of cancer., Methods: We used transcranial Doppler ultrasound to serially evaluate cerebral blood flow velocities in participants ≤25 years old receiving intrathecal cytarabine for hematologic malignancies., Results: Four of 18 participants (22%) met the criteria for subclinical vasospasm within 4 days of intrathecal cytarabine administration. The distribution of oncologic diagnoses differed between the vasospasm and non-vasospasm groups (p = 0.02). Acute myeloid leukemia was identified as a potential risk factor for vasospasm. Children with vasospasm were more likely to have received intravenous cytarabine (75% versus 0%, p = 0.01) and less likely to have received steroids (25% versus 100%, p = 0.01)., Conclusions: A subpopulation of children with hematologic malignancies develops subclinical vasospasm after intrathecal cytarabine treatment. Future research is needed to determine the long-term clinical consequences of cerebral vasospasm in this population., Impact: A subset of children with hematologic malignancies who receive intrathecal cytarabine experience subclinical cerebral vasospasm, as measured by transcranial Doppler ultrasound. Of children receiving intrathecal cytarabine, those who develop cerebral vasospasm are more likely to have diagnosis of acute myeloid leukemia, more likely to receive concurrent intravenous cytarabine, and less likely to receive steroids as part of their chemotherapy regimen, as compared with children without vasospasm. Future research is needed to determine if vasospasm during chemotherapy is associated with higher rates of neurocognitive dysfunction, and if so, to focus on prevention of these long-term sequelae of childhood cancer.

Background: The past decades have seen a transformational shift in the understanding and treatment for neurological diseases affecting infants and children. These advances have been driven in part by the pediatric neurology physician-scientist workforce and its efforts. However, pediatric neurology research faces substantial challenges from internal and external forces including work-life balance demands, COVID-19 pandemic effects, and research funding. Understanding the impact of these challenges on the perceptions, planning, and careers of pediatric neurology physician-scientists is needed to guide the research mission., Methods: Our objective was to survey the research challenges, goals, and priorities of pediatric neurologists. In 2020 we conducted a cross-sectional, 28-question survey emailed to 1,775 members of the Child Neurology Society., Results: One hundred fifty-one individuals responded to the survey. Most respondents were grant investigators (52%) and conducted clinical research (69%). Research areas included epilepsy (23%), neurodevelopmental and autism (16%), neurocritical care and stroke (11%), neurogenetics and neurometabolics (9%), neonatal neurology (8%), and others. The most common funding source was the National Institutes of Health (37%). Shared major research concerns were funding, utilization of remote technology, overcoming disparities, natural history and multicenter studies, global neurology, and diversification of the research portfolio. Commitment to continuing and increasing research efforts was evident., Conclusions: Our survey demonstrates obstacles for physician-scientist researchers in pediatric neurology, but it also shows optimism about continued opportunity. Creative approaches to address challenges will benefit the research mission, maximize the current and future pool of researchers, and help improve the lives of children with neurological disorders., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Since neonatal hypoxia-ischemia (HI) disrupts the hippocampal (Hp) GABAergic network in the mouse and Hp injury in this model correlates with flurothyl seizure susceptibility only in male mice, we hypothesized that GABAergic disruption correlates with flurothyl seizure susceptibility in a sex-specific manner. C57BL6 mice were exposed to HI (Vannucci model) versus sham procedures at P10, randomized to normothermia (NT) or therapeutic hypothermia (TH), and subsequently underwent flurothyl seizure testing at P18. Only in male mice, Hp atrophy correlated with seizure susceptibility. The number of Hp parvalbumin positive interneurons (PV + INs) decreased after HI in both sexes, but TH attenuated this deficit only in females. In males only, seizure susceptibility directly correlated with the number of PV + INs, but not somatostatin or calretinin expressing INs. Hp GABA B receptor subunit levels were decreased after HI, but unrelated to later seizure susceptibility. In contrast, Hp GABA A receptor α1 subunit (GABA A Rα1) levels were increased after HI. Adjusting the number of PV + INs for their GABA A Rα1 expression strengthened the correlation with seizure susceptibility in male mice. Thus, we identified a novel Hp sex-specific GABA-mediated mechanism of compensation after HI that correlates with flurothyl seizure susceptibility warranting further study to better understand potential clinical translation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Childhood stroke is rare, and diagnosis is frequently delayed. The use of pediatric stroke teams has the potential to decrease time to neurology evaluation and imaging, hastening appropriate diagnosis and treatment for acute neurologic presentations in children., Methods: We performed a retrospective analysis of our institutional pediatric stroke or "brain attack" team (pedsBAT) activations from October 2014 to July 2017. Clinical characteristics and timing parameters were compared between pedsBAT activations in the inpatient vs emergency department (ED) / outpatient settings as well as between pediatric and adult BAT activations in the same time period., Results: We identified 120 pedsBAT activations (75% in the ED/outpatient setting) during the study time period. Inpatient pedsBAT activations were more likely than outpatient activations to have heart disease as a risk factor for ischemic stroke and presented more frequently with altered mental status, but there were no differences in the proportion of cerebrovascular diagnoses or timing parameters between the 2 groups. When compared with adult BAT activations, outpatient pedsBAT activations had a longer time from symptom discovery to arrival at the ED, and inpatient pedsBAT activations had longer time from symptom discovery to BAT activation., Conclusions: Compared with adults, the interval leading up to stroke team activation was longer in children, suggesting delays in symptom recognition. Future interventions should be aimed at reducing these delays in presentation to care and stroke alert activation in pediatric patients.

Objective: To test our hypothesis that anticoagulation is associated with better neurologic outcomes in childhood cerebral sinovenous thrombosis (CSVT), we analyzed treatment and outcomes in a population of 410 children from the International Pediatric Stroke Study (IPSS)., Methods: We included patients enrolled in the IPSS registry with a diagnosis of CSVT at age >28 days with radiologic confirmation, in isolation or with concomitant arterial ischemic stroke. The primary outcome was the neurologic status at discharge. We defined unfavorable outcome as severe neurologic impairment or death at discharge. The Pediatric Stroke Outcome Measure was used for long-term outcome in those with follow-up. Predictors of anticoagulation use and outcome were analyzed by logistic regression., Results: Most children (95%) had identifiable risk factors, and 82% received anticoagulation. Shift analysis demonstrated better outcomes at discharge in children who were anticoagulated, and this persisted with longer-term outcomes. In multivariable analysis, anticoagulation was significantly associated with favorable outcomes (adjusted odds ratio [aOR] unfavorable 0.32, p = 0.007) whereas infarct was associated with unfavorable outcome (aOR unfavorable 6.71, p < 0.001). The trauma/intracranial surgery was associated with a lower odds of anticoagulation use (aOR 0.14, p < 0.001)., Conclusions: Within the IPSS registry, children with risk factors of trauma or intracranial surgery were less likely to receive anticoagulation for CSVT. Anticoagulation was associated with a lower odds of severe neurologic impairment or death at hospital discharge, but this finding is limited and needs further confirmation in randomized, controlled, prospective studies., (© 2019 American Academy of Neurology.)

Objective: To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke., Methods: We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with 2-year follow-up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at 2 years by the Pediatric Stroke Outcome Measure. Demographic, clinical, and radiologic outcome predictors were examined. We defined changes in outcome from discharge to 2 years as recovery (improved outcome), emerging deficit (worse outcome), or no change., Results: Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients. Moderate to severe neurological impairment was present in 9.4% of neonates versus 48.8% of children at discharge compared to 8.0% versus 24.7% after 2 years. Predictors of poor outcome included age between 28 days and 1 year (compared to neonates, odds ratio [OR] = 3.58, p < 0.05), underlying chronic disorder (OR = 2.23, p < 0.05), and involvement of both small and large vascular territories (OR = 2.84, p < 0.05). Recovery patterns differed, with emerging deficits more common in children <1 year of age (p < 0.05)., Interpretation: Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common. Age between 28 days and 1 year appears to be a particularly vulnerable period. Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke. ANN NEUROL 2020;87:840-852., (© 2020 American Neurological Association.)

Background and Purpose- Data regarding the safety and efficacy of intravenous tPA (tissue-type plasminogen activator) in childhood acute arterial ischemic stroke are inadequate. The TIPS trial (Thrombolysis in Pediatric Stroke; National Institutes of Health grant R01NS065848)-a prospective safety and dose-finding trial of intravenous tPA in acute childhood stroke-was closed for lack of accrual. TIPS sites have subsequently treated children with acute stroke in accordance with established institutional protocols supporting data collection on outcomes. Methods- Data on children treated with intravenous tPA for neuroimaging-confirmed arterial ischemic stroke were collected retrospectively from 16 former TIPS sites to establish preliminary safety data. Participating sites were required to report all children who were treated with intravenous tPA to minimize reporting bias. Symptomatic intracranial hemorrhage (SICH) was defined as ECASS (European Cooperative Acute Stroke Study) II parenchymal hematoma type 2 or any intracranial hemorrhage associated with neurological deterioration within 36 following tPA administration. A Bayesian beta-binomial model for risk of SICH following intravenous tPA was fit using a prior distribution based on the risk level in young adults (1.7%); to test for robustness, the model was also fit with uninformative and conservative priors. Results- Twenty-six children (age range, 1.1-17 years; median, 14 years; 12 boys) with stroke and a median pediatric National Institutes of Health Stroke Scale score of 14 were treated with intravenous tPA within 2 to 4.5 hours (median, 3.0 hours) after stroke onset. No patient had SICH. Two children developed epistaxis. Conclusions- The estimated risk of SICH after tPA in children is 2.1% (95% highest posterior density interval, 0.0%-6.7%; mode, 0.9%). Regardless of prior assumption, there is at least a 98% chance that the risk is <15% and at least a 93% chance that the risk is <10%. These results suggest that the overall risk of SICH after intravenous tPA in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low.

Contemporary studies of long-term outcomes in children supported on extracorporeal membrane oxygenation (ECMO) in the United States are limited. We enrolled 99 ECMO patients between July 2010 and June 2015 in a two-center prospective observational study that included neurologic and neuropsychologic evaluation at 6 and 12 months, using standardized outcome measures. Pre-ECMO, 20 (20%) had a pre-existing neurologic diagnosis, 40 (40%) had cardiac arrest, and 10 of 47 (21%) children with neuroimaging had acute abnormal findings. Of 50 children eligible for follow-up at 6 or 12 months, 40 (80%) returned for at least one visit. At the follow-up visit of longest interval from ECMO, the median Vineland Adaptive Behavior Scales-II (VABS-II) score was 91 (interquartile range [IQR], 81-98), the median Pediatric Stroke Outcome Measure (PSOM) score was 1 (IQR, 0-2), and the median Mullen Scales of Early Learning composite score was 85 (IQR, 72-96). Presence of new neuroimaging abnormalities during ECMO or within 6 weeks post-ECMO was associated with VABS-II score <85 or death within 12 months after ECMO. The Pediatric Cerebral Performance Category at hospital discharge showed a strong relationship with unfavorable VABS-II and PSOM scores at 6 or 12 months after ECMO. In this study, we report a higher prevalence of pre-ECMO neurologic conditions than previously described. In survivors to hospital discharge, median scores for adaptive behavior and cognitive, neurologic, and quality of life assessments were all below the general population means, but most deficits would be considered minor within each of the domains tested.

Pediatric stroke causes significant morbidity for children resulting in lifelong neurological disability. Although hyperacute recanalization therapies are available for pediatric patients, most patients are ineligible for these treatments. Therefore the mainstay for pediatric stroke treatment relies on rehabilitation to improve outcomes. Little is known about the ideal rehabilitation therapies for pediatric patients with stroke and the unique interplay between the developing brain and our models of stroke recovery. In this review, we first discuss the consequences of pediatric stroke. Second, we examine the scientific evidence that exists between the mechanisms of recovery and how they are different in the pediatric developing brain. Finally, we evaluate potential interventions that could improve outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mechanical thrombectomy has emerged as a standard of care for acute stroke from large vessel occlusion in adults but remains controversial in children. Cerebral vessels are nearly adult size by 5 years of age but the technical feasibility of achieving recanalization in younger and smaller children with current endovascular tools remains unclear., Objective: To systematically review the literature on mechanical thrombectomy for stroke in children less than 5 years of age., Results: Mechanical thrombectomy for acute stroke has been reported in 11 children under the age of 5 years (range 9 months to 4 years). The mean time from symptom onset to groin puncture was 12 hours (range 4-50 hours). Complete recanalization was achieved in 7/12 (58%) vessels attempted, and partial recanalization in 4/12 (33%). Two procedure related complications were reported, with small vessel size felt to be contributory to basilar vasospasm in one case. Favorable neurological outcomes were reported in 7 cases (64%)., Conclusions: Our review of the literature demonstrates that mechanical thrombectomy for acute ischemic stroke may be feasible in carefully selected infants and young children less than 5 years of age using currently available devices. Efficacy in promoting better neurologic outcomes remains unproven, and other questions persist, including whether complications such as vasospasm occur more frequently in young children compared with adults. Further study is needed to determine the safety and efficacy of pediatric mechanical thrombectomy. These data suggest that young children should not be excluded from future studies or clinical treatment on the basis of age alone., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypoxic-ischemic encephalopathy is a common neonatal brain injury associated with significant morbidity and mortality despite the administration of therapeutic hypothermia (TH). Neonatal seizures and subsequent chronic epilepsy are frequent in this patient population and current treatments are partially effective. We used a neonatal murine hypoxia-ischemia (HI) model to test whether the severity of hippocampal and cortical injury predicts seizure susceptibility 8 days after HI and whether TH mitigates this susceptibility. HI at postnatal day 10 (P10) caused hippocampal injury not mitigated by TH in male or female pups. TH did not confer protection against flurothyl seizure susceptibility at P18 in this model. Hippocampal (R2 = 0.33, p = 0.001) and cortical (R2 = 0.33, p = 0.003) injury directly correlated with seizure susceptibility in male but not female pups. Thus, there are sex-specific consequences of neonatal HI on flurothyl seizure susceptibility in a murine neonatal HI model. Further studies are necessary to elucidate the underlying mechanisms of sex dimorphism in seizure susceptibility after neonatal HI., (© 2019 S. Karger AG, Basel.)

Purpose of Review: After decades of hype, cell-based therapies are emerging into the clinical arena for the purposes of promoting recovery after stroke. In this review, we discuss the most recent science behind the role of cell-based therapies in ischemic stroke and the efforts to translate these therapies into human clinical trials., Recent Findings: Preclinical data support numerous beneficial effects of cell-based therapies in both small and large animal models of ischemic stroke. These benefits are driven by multifaceted mechanisms promoting brain repair through immunomodulation, trophic support, circuit reorganization, and cell replacement. Cell-based therapies offer tremendous potential for improving outcomes after stroke through multimodal support of brain repair. Based on recent clinical trials, cell-based therapies appear both feasible and safe in all phases of stroke. Ongoing translational research and clinical trials will further refine these therapies and have the potential to transform the approach to stroke recovery and rehabilitation.

OBJECTIVE Pediatric cerebral venous sinus thrombosis has been previously described in the setting of blunt head trauma; however, the population demographics, risk factors for thrombosis, and the risks and benefits of detection and treatment in this patient population are poorly defined. Furthermore, few reports differentiate between different forms of sinus pathology. A series of pediatric patients with skull fractures who underwent venous imaging and were diagnosed with intrinsic cerebral venous sinus thrombosis or extrinsic sinus compression is presented. METHODS The medical records of patients at 2 pediatric trauma centers were retrospectively reviewed. Patients who were evaluated for blunt head trauma from January 2003 to December 2013, diagnosed with a skull fracture, and underwent venous imaging were included. RESULTS Of 2224 pediatric patients with skull fractures following blunt trauma, 41 patients (2%) underwent venous imaging. Of these, 8 patients (20%) had intrinsic sinus thrombosis and 14 patients (34%) displayed extrinsic compression of a venous sinus. Three patients with intrinsic sinus thrombosis developed venous infarcts, and 2 of these patients were treated with anticoagulation. One patient with extrinsic sinus compression by a depressed skull fracture underwent surgical elevation of the fracture. All patients with sinus pathology were discharged to home or inpatient rehabilitation. Among patients who underwent follow-up imaging, the sinus pathology had resolved by 6 months postinjury in 80% of patients with intrinsic thrombosis as well as 80% of patients with extrinsic compression. All patients with intrinsic thrombosis or extrinsic compression had a Glasgow Outcome Scale score of 4 or 5 at their last follow-up. CONCLUSIONS In this series of pediatric trauma patients who underwent venous imaging for suspected thrombosis, the yield of detecting intrinsic thrombosis and/or extrinsic compression of a venous sinus was high. However, few patients developed venous hypertension or infarction and were subsequently treated with anticoagulation or surgical decompression of the sinus. Most had spontaneous resolution and good neurological outcomes without treatment. Therefore, in the setting of pediatric skull fractures after blunt injury, venous imaging is recommended when venous hypertension or infarction is suspected and anticoagulation is being considered. However, there is little indication for pervasive venous imaging after pediatric skull fractures, especially in light of the potential risks of CT venography or MR venography in the pediatric population and the unclear benefits of anticoagulation.

Pediatric arterial ischemic stroke (AIS) is an uncommon but important cause of neurologic morbidity in neonates and children, with consequences including hemiparesis, intellectual disabilities, and epilepsy. The causes of pediatric AIS are unique to those typically associated with stroke in adults. Familiarity with the risk factors for AIS in children will help with efficient diagnosis, which is unfortunately frequently delayed. Here we review the epidemiology and risk factors for AIS in neonates and children. We also outline consensus-based practices in the evaluation and management of pediatric AIS. Finally we discuss the outcomes observed in this population. While much has been learned in recent decades, many uncertainties sill persist in regard to pediatric AIS. The ongoing development of specialized centers and investigators dedicated to pediatric stroke will continue to answer such questions and improve our ability to effectively care for these patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Brain injuries, such as cerebral hypoxia-ischemia (H-I), induce a regenerative response from the neural stem/progenitors (NSPs) of the subventricular zone (SVZ); however, the mechanisms that regulate this expansion have not yet been fully elucidated. The Notch- Delta-Serrate-Lag2 (DSL) signaling pathway is considered essential for the maintenance of neural stem cells, but it is not known if it is necessary for the expansion of the NSPs subsequent to perinatal H-I injury. Therefore, the aim of this study was to investigate whether this pathway contributes to NSP expansion in the SVZ after H-I and, if so, to establish whether this pathway is directly induced by H-I or regulated by paracrine factors. Here we report that Notch1 receptor induction and one of its ligands, Delta-like 1, precedes NSP expansion after perinatal H-I in P6 rat pups and that this increase occurs specifically in the most medial cell layers of the SVZ where the stem cells reside. Pharmacologically inhibiting Notch signaling in vivo diminished NSP expansion. With an in vitro model of H-I, Notch1 was not induced directly by hypoxia, but was stimulated by soluble factors, specifically leukemia inhibitory factor, produced by astrocytes within the SVZ. These data confirm the importance both of the Notch-DSL signaling pathway in the expansion of NSPs after H-I and in the role of the support cells in their niche. They further support the body of evidence that indicates that leukemia inhibitory factor is a key injury-induced cytokine that is stimulating the regenerative response of the NSPs. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors have no conflicts of interest to report., (© 2016 Wiley Periodicals, Inc.)

Objective: To identify perinatal risk factors that can distinguish arterial ischemic stroke from hypoxic-ischemic encephalopathy at birth., Methods: This is a cohort study of all neonates born at 35 weeks of gestation or greater admitted to our neonatal intensive care unit from January 1, 2010, to December 31, 2015, that compares neonates with stroke with those with hypoxic-ischemic encephalopathy undergoing whole-body hypothermia with abnormal brain magnetic resonance imaging., Results: During this 6-year period, there were 22 neonates with stroke and 47 with hypoxic-ischemic encephalopathy undergoing whole-body hypothermia with abnormal magnetic resonance imaging. Three neonates triaged to hypothermia initially thought to have hypoxic-ischemic encephalopathy were later diagnosed with stroke. All neonates with stroke had a negative thrombophilia workup. Neonates with stroke had a significantly higher incidence of seizures and increased initial platelet counts on univariate analysis. A multivariable model of variables with P<.1 on univariate analysis present within 6 hours of birth found significant increases in nonreassuring fetal heart rate tracings, sentinel events, low Apgar score at 5 minutes, and metabolic acidosis at birth with hypoxic-ischemic encephalopathy. Stroke was associated with a significantly increased initial platelet count., Conclusion: Stroke is associated with increased initial platelet counts and is not associated with cesarean delivery for nonreassuring fetal heart rate tracings, sentinel events, or perinatal metabolic acidosis. Stroke is a form of neonatal brain injury not associated with perinatal risk factors that allow early identification.

We report the case of a 1-month old, 28-week gestational age infant who presented with acute paraplegia after cardiopulmonary arrest. Later imaging confirms cerebral sinovenous thrombosis (CSVT) and a suspected infarction in the conus medullaris of the spinal cord. A prothrombotic state may explain the numerous areas of infarction visualized on neuroimaging. To our knowledge this is the first case report of acute and persistent paraplegia in an infant with CSVT and conus medullaris injury, which may be due to venous infarction of the spinal cord.

Ischemic stroke is a devastating brain injury and an important cause of neurologic disability worldwide and across the lifespan. Despite the physical, social, and economic burdens of this disease there is only a single approved medicine for the treatment of acute stroke, and its use is unfortunately limited to the small fraction of patients presenting within the narrow therapeutic window. Following stroke, there is a period of plasticity involving cell genesis, axon growth, and synaptic modulation that is essential to spontaneous recovery. Treatments focusing on neuroprotection and enhancing recovery have been the focus of intense preclinical studies, but translation of these treatments into clinical use has been disappointing thus far. The important role of epigenetic mechanisms in disease states is becoming increasingly apparent, including in ischemic stroke. These regulators of gene expression are poised to be critical mediators of recovery following stroke. In this review we discuss evidence for the role of epigenetics in neuroplasticity and the implications for stroke recovery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Hemiplegic migraine (HM) is a rare type of migraine with aura that involves motor weakness. Data on conventional and advanced neuroimaging findings during prolonged attacks of HM are limited, particularly in children., Case: A 13-year-old-female with a history of migraine had a typical attack of HM characterized by right-sided hemiplegia, deterioration of vigilance and paraphasia. MRI performed 3 hours after hemiplegia onset revealed normal diffusion tensor imaging (DTI) sequences, but perfusion weighted imaging (PWI) showed a large area of hypoperfusion within the left cerebral hemisphere and susceptibility weighted imaging (SWI) demonstrated a matching area with prominent, hypointense draining sulcal veins. Magnetic resonance angiography (MRA) revealed subtle narrowing of the left middle cerebral artery. The neuroimaging abnormalities completely resolved 24 hours after the attack onset., Conclusion: Multiple conventional and advanced MRI techniques including SWI play a key role in an HM attack to (1) exclude acute arterial ischemic stroke and (2) further understand the pathophysiology of HM.

Isolating a pure population of neural stem cells (NSCs) has been difficult since no exclusive surface markers have been identified for panning or FACS purification. Moreover, additional refinements for maintaining NSCs in culture are required, since NSCs generate a variety of neural precursors (NPs) as they proliferate. Here, we demonstrate that post-natal rat NPs express low levels of pro-apoptotic molecules and resist phosphatidylinositol 3'OH kinase and extracellular regulated kinase 1/2 inhibition as compared to late oligodendrocyte progenitors. Furthermore, maintaining subventricular zone precursors in LY294002 and PD98059, inhibitors of PI3K and ERK1/2 signaling, eliminated lineage-restricted precursors as revealed by enrichment for Nestin(+)/SOX-2(+) cells. The cells that survived formed neurospheres and 89% of these neurospheres were tripotential, generating neurons, astrocytes, and oligodendrocytes. Without this enrichment step, less than 50% of the NPs were Nestin(+)/SOX-2(+) and 42% of the neurospheres were tripotential. In addition, neurospheres enriched using this procedure produced 3-times more secondary neurospheres, supporting the conclusion that this procedure enriches for NSCs. A number of genes that enhance survival were more highly expressed in neurospheres compared to late oligodendrocyte progenitors. Altogether, these studies demonstrate that primitive neural precursors can be enriched using a relatively simple and inexpensive means that will facilitate cell replacement strategies using stem cells as well as other studies whose goal is to reveal the fundamental properties of primitive neural precursors., (© 2013 International Society for Neurochemistry.)

Background: Keutel syndrome is a rare autosomal-recessive condition characterized by abnormal cartilage calcification. Neuroimaging findings associated with this condition have been randomly described in the literature., Objective: To systematically evaluate the neuroimaging findings in a series of children with Keutel syndrome to broaden our base of knowledge., Materials and Methods: Four children with confirmed Keutel syndrome were reviewed for the brain, head and neck imaging findings., Results: Three of the four children, all siblings, showed evidence of moyamoya syndrome. All four siblings had pinna cartilage calcification., Conclusion: We propose that Keutel syndrome be considered and included among the secondary causes of moyamoya syndrome. In children with petrified auricle and neurological symptoms, Keutel syndrome should be considered and brain MRI with MRA is required.

Recombinant tissue plasminogen activator (t-PA) is the only FDA approved therapy for acute ischemic stroke. Cerebral microbleeds (CMBs) or cerebral amyloid angiopathy (CAA) are currently not contraindications, however, data regarding this complex issue are limited. We report 2 cases of fatal intracerebral hemorrhage (sICH) after IV t-PA, each with evidence of CAA. Patients with CAA may have increased risk for IV thrombolysis-associated sICH. We highlight the severe and catastrophic pattern of ICH, which may be a defining characteristic, and discuss the limitations of our current understanding of the risk of thrombolysis-associated ICH in patients with CAA and/or CMBs.

In countries such as the United States where rubella virus infections are rare, congenital rubella syndrome (CRS) may not be recognized in a timely manner. However, the syndrome still appears in this country, often in infants of mothers emigrating from countries with absent or suboptimal national vaccination programs. We describe a case of CRS in a term baby born to a recent US immigrant who developed a primary varicella infection in late pregnancy and demonstrated IgG titers to rubella at delivery. At presentation, the neonate had both classical findings as well as less reported vascular and neurological abnormalities seen in infants with CRS.

Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ∼5-7 years, and the majority of children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioral and pharmacological approaches. Evidence supports TS being an inherited disorder; however, the precise genetic abnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.

There is an increase in the numbers of neural precursors in the SVZ (subventricular zone) after moderate ischaemic injuries, but the extent of stem cell expansion and the resultant cell regeneration is modest. Therefore our studies have focused on understanding the signals that regulate these processes towards achieving a more robust amplification of the stem/progenitor cell pool. The goal of the present study was to evaluate the role of the EGFR [EGF (epidermal growth factor) receptor] in the regenerative response of the neonatal SVZ to hypoxic/ischaemic injury. We show that injury recruits quiescent cells in the SVZ to proliferate, that they divide more rapidly and that there is increased EGFR expression on both putative stem cells and progenitors. With the amplification of the precursors in the SVZ after injury there is enhanced sensitivity to EGF, but not to FGF (fibroblast growth factor)-2. EGF-dependent SVZ precursor expansion, as measured using the neurosphere assay, is lost when the EGFR is pharmacologically inhibited, and forced expression of a constitutively active EGFR is sufficient to recapitulate the exaggerated proliferation of the neural stem/progenitors that is induced by hypoxic/ischaemic brain injury. Cumulatively, our results reveal that increased EGFR signalling precedes that increase in the abundance of the putative neural stem cells and our studies implicate the EGFR as a key regulator of the expansion of SVZ precursors in response to brain injury. Thus modulating EGFR signalling represents a potential target for therapies to enhance brain repair from endogenous neural precursors following hypoxic/ischaemic and other brain injuries.

Perinatal hypoxia/ischemia (H/I) is the leading cause of neurologic injury resulting from birth complications. Recent advances in critical care have dramatically improved the survival rate of infants suffering this insult, but approximately 50% of survivors will develop neurologic sequelae such as cerebral palsy, epilepsy or cognitive deficits. Here we demonstrate that tripotential neural stem/progenitor cells (NSPs) participate in the regenerative response to perinatal H/I as their numbers increase 100% by 3 d and that they alter their intrinsic properties to divide using expansive symmetrical cell divisions. We further show that production of new striatal neurons follows the expansion of NSPs. Increased proliferation within the NSP niche occurs at 2 d after perinatal H/I, and the proliferating cells express nestin. Of those stem-cell related genes that change, the membrane receptors Notch1, gp-130, and the epidermal growth factor receptor, as well as the downstream transcription factor Hes5, which stimulate NSP proliferation and regulate stem cellness are induced before NSP expansion. The mechanisms for the reactive expansion of the NSPs reported here reveal potential therapeutic targets that could be exploited to amplify this response, thus enabling endogenous precursors to restore a normal pattern of brain development after perinatal H/I.

This case report describes a child with an expanded CTA/CTG repeat in one allele of the spinocerebellar ataxia 8 gene. This patient presented with ataxia at a much earlier age than is typical for patients with this condition. This unique patient further highlights the complexity of the role that this molecular defect plays in the onset and course of the disease.

The subventricular zones (SVZs) are essential sources of new cells in the developing brain and remnants of these germinal zones persist into adulthood. As these cells have the capacity to replenish neurons and glia that are turning over, many investigators have assessed the SVZ's role in replacing neural cells eliminated by brain injuries. A review of the literature reveals that the progenitors within the SVZs are vulnerable to chemical, radiation and ischemia-induced damage, whereas the neural stem cells are resilient. With moderate insults, the SVZ can recover, but it cannot recover after more severe injury. Thus, the vulnerability of these cells has important ramifications when considering therapeutic interventions for the treatment of brain tumors and for the prospect of recovery after ischemia. The cells of the perinatal and adult SVZ not only have the capacity to replenish their own numbers, but they also have the capacity to replace neurons and glia after ischemic and traumatic brain injuries. Moreover, the mechanisms underlying these regenerative responses are beginning to be revealed. By reviewing, comparing and contrasting the responses of the SVZs to different injuries, our goal is to provide a foundation from which current and future studies on the potential of the SVZs for cell replacement can be evaluated.

Each year hundreds of thousands of people must cope with the severe neurological consequences of a stroke. Current therapeutic strategies for stroke focus on acute treatment and neuroprotection. Unfortunately, these practices do little to reduce the long-term morbidity associated with the injury. To develop effective therapies that promote regeneration, we must have an understanding of the cellular and molecular events involved in the recovery from an insult. Neural stem and progenitor cells are likely to be affected during this period. Here we review how the proliferation, migration, and maturation of these precursors are affected by ischemia. Furthermore, we summarize data available on the underlying mechanisms and the therapeutic implications of these studies. The studies that we review provide compelling evidence that neural precursors resident in the brain initiate a compensatory response to stroke that results in the production of new neurons. Moreover, administration of growth factors can enhance this compensatory response. Based on these encouraging results, we may eventually be able to manipulate these precursors to improve recovery of function in individuals afflicted by this devastating injury., (Copyright 2003 Wiley-Liss, Inc.)