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Perinatal stroke describes a group of focal, vascular brain injuries that occur early in development, often resulting in lifelong disability. Two types of perinatal stroke predominate, arterial ischemic stroke (AIS) and periventricular venous infarction (PVI). Though perinatal stroke is typically considered a motor disorder, other comorbidities commonly exist including attention-deficit hyperactivity disorder (ADHD) and deficits in executive function. Rates of ADHD symptoms are higher in children with perinatal stroke and deficits in executive function may also occur but underlying mechanisms are not known. We measured resting state functional connectivity in children with perinatal stroke using previously established dorsal attention, frontoparietal, and default mode network seeds. Associations with parental ratings of executive function and ADHD symptoms were examined. A total of 120 participants aged 6-19 years [AIS N = 31; PVI N = 30; Controls N = 59] were recruited. In comparison to typically developing peers, both the AIS and PVI groups showed lower intra- and inter-hemispheric functional connectivity values in the networks investigated. Group differences in between-network connectivity were also demonstrated, showing weaker anticorrelations between task-positive (frontoparietal and dorsal attention) and task-negative (default mode) networks in stroke groups compared to controls. Both within-network and between-network functional connectivity values were highly associated with parental reports of executive function and ADHD symptoms. These results suggest that differences in functional connectivity exist both within and between networks after perinatal stroke, the degree of which is associated with ADHD symptoms and executive function., (© 2023. The Author(s).)

Competing Interests: Disclosures None.

Background and Objectives: Neonatal brain injury is a common and devastating diagnosis conferring lifelong challenges for children and families. The role of mechanical forces applied to the head, often referred to as "birth trauma," are often considered although evidence for this association is lacking. The objective of this study was to investigate the association between common types of neonatal brain injury and scalp swelling using a novel method to quantify scalp swelling as an unbiased proxy for mechanical forces applied to the head., Methods: Case-control study using population-based, prospectively collected tertiary care center databases and healthy controls from the Human Connectome Development Project. Included were infants born 32-42 weeks gestational age and MRI in the first 9 days. Outcomes categories included healthy neonates, hypoxic ischemic encephalopathy (HIE) with or without brain injury, or stroke (ischemic or hemorrhagic). Volume of scalp swelling was objectively quantified by a novel imaging method blinded to brain injury. Variables included mode of delivery and use of instrumentation. Statistical tests included Kruskal-Wallis test, chi square, and multivariable and multinomial logistic regression., Results: There were 309 infants included (55% male): 72 healthy controls, 77 HIE without brain injury on MRI, 78 HIE with brain injury, and 82 with stroke (60 ischemic, 22 hemorrhagic). Scalp swelling was present in 126 (40.8%, 95% confidence interval [CI] 35.2%-46.5%) with no difference in proportions between outcome groups. Compared to healthy controls, median volume was higher in those with HIE without brain injury (17.5 mL, 95% CI 6.8-28.2), HIE with brain injury (12.1 mL, 95% CI 5.5-18.6), but not ischemic stroke (4.7 mL, 95% CI -1.2-10.6) nor hemorrhagic stroke (8.3 mL, 95% CI -2.2-18.8). Scalp swelling was associated with instrumented delivery (OR 2.1, 95% CI 1.0-4.1), but not associated with increased odds of brain injury in those with HIE (OR 1.5, 95% CI 0.76-3.30). Scalp swelling measures were highly reliable (ICC = 0.97)., Discussion: "Birth trauma" quantified by scalp swelling volume was more common in infants with difficult deliveries, but not associated with greater odds of brain injury due to hypoxia or stroke. These results may help parents and practitioners to dissociate the appearance of trauma with the risk of brain injury., (© 2023 American Academy of Neurology.)

Perinatal stroke causes most hemiparetic cerebral palsy and cognitive dysfunction may co-occur. Compensatory developmental changes in the intact contralesional hemisphere may mediate residual function and represent targets for neuromodulation. We used morphometry to explore cortical thickness, grey matter volume, gyrification, and sulcal depth of the contralesional hemisphere in children, adolescents, and young adults after perinatal stroke and explored associations with motor, attention, and executive function. Participants aged 6-20 years (N = 109, 63% male) with unilateral perinatal stroke underwent T1-weighted imaging. Participants had arterial ischemic stroke (AIS; n = 36), periventricular venous infarction (PVI; n = 37) or were controls (n = 36). Morphometry was performed using the Computational Anatomy Toolbox (CAT12). Group differences and associations with motor and executive function (in a smaller subsample) were assessed. Group comparisons revealed areas of lower cortical thickness in contralesional hemispheres in both AIS and PVI and greater gyrification in AIS compared to controls. Areas of greater grey matter volume and sulcal depth were also seen for AIS. The PVI group showed lower grey matter volume in cingulate cortex and less volume in precuneus relative to controls. No associations were found between morphometry metrics, motor, attention, and executive function. Cortical structure of the intact contralesional hemisphere is altered after perinatal stroke. Alterations in contralesional cortical morphometry shown in perinatal stroke may be associated with different mechanisms of damage or timing of early injury. Further investigations with larger samples are required to more thoroughly explore associations with motor and cognitive function., (© 2023. The Author(s).)

Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, resulting in a focal lesion. Our understanding of mechanisms of injury and repair associated with focal injury in the developing brain remains rudimentary. Neuroimaging can reveal important insights into these mechanisms. In adult stroke population, multi-center neuroimaging studies are common and have accelerated the translation process leading to improvements in treatment and outcome. These studies are centered on the growing evidence that neuroimaging measures and other biomarkers (e.g., from blood and cerebrospinal fluid) can enhance our understanding of mechanisms of risk and injury and be used as complementary outcome markers. These factors have yet to be studied in pediatric stroke because most neuroimaging studies in this population have been conducted in single-centred, small cohorts. By pooling neuroimaging data across multiple sites, larger cohorts of patients can significantly boost study feasibility and power in elucidating mechanisms of brain injury, repair and outcomes. These aims are particularly relevant in pediatric stroke because of the decreased incidence rates and the lack of mechanism-targeted trials. Toward these aims, we developed the Pediatric Stroke Neuroimaging Platform (PEDSNIP) in 2015, funded by The Brain Canada Platform Support Grant, to focus on three identified neuroimaging priorities. These were: developing and harmonizing multisite clinical protocols, creating the infrastructure and methods to import, store and organize the large clinical neuroimaging dataset from multiple sites through the International Pediatric Stroke Study (IPSS), and enabling central searchability. To do this, developed a two-pronged approach that included building 1) A Clinical-MRI Data Repository (standard of care imaging) linked to clinical data and longitudinal outcomes and 2) A Research-MRI neuroimaging data set acquired through our extensive collaborative, multi-center, multidisciplinary network. This dataset was collected prospectively in eight North American centers to test the feasibility and implementation of harmonized advanced Research-MRI, with the addition of clinical information, genetic and proteomic studies, in a cohort of children presenting with acute ischemic stroke. Here we describe the process that enabled the development of PEDSNIP built to provide the infrastructure to support neuroimaging research priorities in pediatric stroke. Having built this Platform, we are now able to utilize the largest neuroimaging and clinical data pool on pediatric stroke data worldwide to conduct hypothesis-driven research. We are actively working on a bioinformatics approach to develop predictive models of risk, injury and repair and accelerate breakthrough discoveries leading to mechanism-targeted treatments that improve outcomes and minimize the burden following childhood stroke. This unique transformational resource for scientists and researchers has the potential to result in a paradigm shift in the management, outcomes and quality of life in children with stroke and their families, with far-reaching benefits for other brain conditions of people across the lifespan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Repetitive transcranial magnetic stimulation (rTMS) shows promise in improving speech production in post-stroke aphasia. Limited evidence suggests pairing rTMS with speech therapy may result in greater improvements. Twenty stroke survivors (>6 months post-stroke) were randomized to receive either sham rTMS plus multi-modality aphasia therapy (M-MAT) or rTMS plus M-MAT. For the first time, we demonstrate that rTMS combined with M-MAT is feasible, with zero adverse events and minimal attrition. Both groups improved significantly over time on all speech and language outcomes. However, improvements did not differ between rTMS or sham. We found that rTMS and sham groups differed in lesion location, which may explain speech and language outcomes as well as unique patterns of BOLD signal change within each group. We offer practical considerations for future studies and conclude that while combination therapy of rTMS plus M-MAT in chronic post-stroke aphasia is safe and feasible, personalized intervention may be necessary., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: There is increasing evidence for early, active rehabilitation to enhance motor function following early brain injury. This is clear for interventions targeting the upper extremity, whereas passive treatment approaches for the lower extremity persist. The purpose of this trial is to evaluate the effectiveness of early, intensive rehabilitation targeting the lower extremity and delivered in a parent-therapist partnership model for children with perinatal stroke., Methods: We describe a protocol for a waitlist-control, single-blind, mixed methods effectiveness randomized controlled trial, with an embedded qualitative study using interpretative description. Participants are children with perinatal stroke aged eight months to three years with signs of hemiparesis. Participants will be randomly allocated to an immediate ELEVATE (Engaging the Lower Extremity Via Active Therapy Early) intervention group, or a waitlist-control group, who will receive usual care for six months. The ELEVATE intervention involves one hour of training four days per week for 12 weeks, with a pediatric therapist and a parent or guardian each delivering two sessions per week. The intervention targets the affected lower extremity by progressively challenging the child while standing and walking. The primary outcome measure is the Gross Motor Function Measure-66. Secondary outcomes include the Pediatric Quality of Life Inventory™, Young Children's Participation and Environment Measure, and an instrumented measure of spasticity. A cost-effectiveness analysis and qualitative component will explore benefit to costs ratios and parents' perspectives of early, intensive rehabilitation, and their role as a partner in the rehabilitation, respectively., Discussion: This study has the potential to change current rehabilitation for young children with perinatal stroke if the ELEVATE intervention is effective. The parent interviews will provide further insight into benefits and challenges of a partnership model of rehabilitation. The mixed methods design will enable optimization for transfer of this collaborative approach into physical therapy practice., Trial Registration: ClinicalTrials.gov NCT03672864 . Registered 17 September 2018., (© 2022. The Author(s).)

Importance: Perinatal arterial ischemic stroke (PAIS) is a focal brain injury in term neonates that is identified postnatally but is presumed to occur near the time of birth. Many pregnancy, delivery, and fetal factors have been associated with PAIS, but early risk detection is lacking; thus, targeted treatment and prevention efforts are currently limited., Objective: To develop and validate a diagnostic risk prediction model that uses common clinical factors to predict the probability of PAIS in a term neonate., Design, Setting, and Participants: In this diagnostic study, a prediction model was developed using multivariable logistic regression with registry-based case data collected between January 2003, and March 2020, from the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and Alberta Pregnancy Outcomes and Nutrition study. Criteria for inclusion were term birth and no underlying medical conditions associated with stroke diagnosis. Records with more than 20% missing data were excluded. Variable selection was based on peer-reviewed literature. Data were analyzed in September 2021., Exposures: Clinical pregnancy, delivery, and neonatal factors associated with PAIS as common data elements across the 4 registries., Main Outcomes and Measures: The primary outcome was the discriminative accuracy of the model predicting PAIS, measured by the concordance statistic (C statistic)., Results: Of 2571 term neonates in the initial analysis (527 [20%] case and 2044 [80%] control individuals; gestational age range, 37-42 weeks), 1389 (54%) were male, with a greater proportion of males among cases compared with controls (318 [60%] vs 1071 [52%]). The final model was developed using 1924 neonates, including 321 cases (17%) and 1603 controls (83%), and 9 clinical factors associated with risk of PAIS in term neonates: maternal age, tobacco exposure, recreational drug exposure, preeclampsia, chorioamnionitis, intrapartum maternal fever, emergency cesarean delivery, low 5-minute Apgar score, and male sex. The model demonstrated good discrimination between cases and controls (C statistic, 0.73; 95% CI, 0.69-0.76) and good model fit (Hosmer-Lemeshow P = .20). Internal validation techniques yielded similar C statistics (0.73 [95% CI, 0.69-0.77] with bootstrap resampling, 10-fold cross-validated area under the curve, 0.72 [bootstrap bias-corrected 95% CI, 0.69-0.76]), as did a sensitivity analysis using cases and controls from Alberta, Canada, only (C statistic, 0.71; 95% CI, 0.65-0.77)., Conclusions and Relevance: The findings suggest that clinical variables can be used to develop and internally validate a model to predict the risk of PAIS in term neonates, with good predictive performance and strong internal validity. Identifying neonates with a high probability of PAIS who could then be screened for early diagnosis and treatment may be associated with reductions in lifelong morbidity for affected individuals and their families.

Background: Perinatal stroke injures motor regions of the brain, compromising movement for life. Early, intensive, active interventions for the upper extremity are efficacious, but interventions for the lower extremity remain understudied., Objective: To determine the feasibility and potential efficacy of ELEVATE-Engaging the Lower Extremity Via Active Therapy Early-on gross motor function., Methods: We conducted a single-blind, two-arm, randomized controlled trial (RCT), with the Immediate Group receiving the intervention while the Delay Group served as a 3-month waitlist control. A separate cohort living beyond commuting distance was trained by their parents with guidance from physical therapists. Participants were 8 months to 3 years old, with MRI-confirmed perinatal ischemic stroke and early signs of hemiparesis. The intervention was play-based, focused on weight-bearing, balance and walking for 1 hour/day, 4 days/week for 12 weeks. The primary outcome was the Gross Motor Function Measure-66 (GMFM-66). Secondary outcomes included steps and gait analyses. Final follow-up occurred at age 4., Results: Thirty-four children participated (25 RCT, 9 Parent-trained). The improvement in GMFM-66 over 12 weeks was greater for the Immediate than the Delay Group in the RCT (average change 3.4 units higher) and greater in younger children. Average step counts reached 1370-3750 steps/session in the last week of training for all children. Parent-trained children also improved but with greater variability., Conclusions: Early, activity-intensive lower extremity therapy for young children with perinatal stroke is feasible and improves gross motor function in the short term. Longer term improvement may require additional bouts of intervention., Clinical Trial Registration: This study was registered at ClinicalTrials.gov (NCT01773369).

Background: Perinatal stroke causes hemiparetic cerebral palsy (HCP) and lifelong disability. Constraint-induced movement therapy (CIMT) and neurostimulation may enhance motor function, but the individual factors associated with responsiveness are undetermined., Objective: We explored the clinical and neurophysiological factors associated with responsiveness to CIMT and/or brain stimulation within a clinical trial., Methods: PLASTIC CHAMPS was a randomized, blinded, sham-controlled trial (n = 45) of CIMT and neurostimulation paired with intensive, goal-directed therapy. Primary outcome was the Assisting Hand Assessment (AHA). Classification trees created through recursive partitioning suggested clinical and neurophysiological profiles associated with improvement at 6-months., Results: Both clinical (stroke side (left) and age >14 years) and neurophysiological (intracortical inhibition/facilitation and motor threshold) were associated with responsiveness across treatment groups with positive predictive values (PPV) approaching 80%., Conclusion: This preliminary analysis suggested sets of variables that may be associated with response to intensive therapies in HCP. Further modeling in larger trials is required.

Perinatal stroke occurs early in life and often leads to a permanent, disabling weakness to one side of the body. To test the hypothesis that non-lesioned hemisphere sensorimotor network structural connectivity in children with perinatal stroke is different from controls, we used diffusion imaging and graph theory to explore structural topology between these populations. Children underwent diffusion and anatomical 3T MRI. Whole-brain tractography was constrained using a brain atlas creating an adjacency matrix containing connectivity values. Graph theory metrics including betweenness centrality, clustering coefficient, and both neighbourhood and hierarchical complexity of sensorimotor nodes were compared to controls. Relationships between these connectivity metrics and validated sensorimotor assessments were explored. Eighty-five participants included 27 with venous stroke (mean age = 11.5 ± 3.7 years), 26 with arterial stroke (mean age = 12.7 ± 4.0 years), and 32 controls (mean age = 13.3 ± 3.6 years). Non-lesioned primary motor (M1), somatosensory (S1) and supplementary motor (SMA) areas demonstrated lower betweenness centrality and higher clustering coefficient in stroke groups. Clustering coefficient of M1, S1, and SMA were inversely associated with clinical motor function. Hemispheric betweenness centrality and clustering coefficient were higher in stroke groups compared to controls. Hierarchical and average neighbourhood complexity across the hemisphere were lower in stroke groups. Developmental plasticity alters the connectivity of key nodes within the sensorimotor network of the non-lesioned hemisphere following perinatal stroke and contributes to clinical disability., (© 2022. The Author(s).)

The goal of this study was to examine executive functioning, math performance, and visuospatial processing skills of children with perinatal stroke, which have not been well explored in this population. Participants included 18 children with perinatal stroke (aged 6-16 years old) and their primary caregiver. Each child completed standardized tests of executive function and visuospatial processing skills, Intelligence Quotient (IQ), and math achievement. Performance on executive function, IQ, math, and visuospatial processing tests was significantly lower in children with perinatal stroke when compared to normative means. Poorer inhibitory control was associated with worse math performance. Increased age at testing was associated with better performance on visuospatial ability (using standardized scores), and females performed better than males on a test of inhibitory control. Children with perinatal stroke displayed a range of neuropsychological impairments, and difficulties with executive function (inhibition) may contribute to math difficulties in this population.

Introduction: Perinatal stroke affects millions of children and results in lifelong disability. Two forms prevail: arterial ischemic stroke (AIS), and periventricular venous infarction (PVI). With such focal damage early in life, neural structures may reorganize during development to determine clinical function, particularly in the contralesional hemisphere. Such processes are increasingly understood in the motor system, however, the role of the basal ganglia, a group of subcortical nuclei that are critical to movement, behaviour, and learning, remain relatively unexplored. Perinatal strokes that directly damage the basal ganglia have been associated with worse motor outcomes, but how developmental plasticity affects bilateral basal ganglia structure is unknown. We hypothesized that children with perinatal stroke have alterations in bilateral basal ganglia volumes, the degree of which correlates with clinical motor function., Methods: Children with AIS or PVI, and controls, aged 6-19 years, were recruited from a population-based cohort. MRIs were acquired on a 3 T GE MR750w scanner. High-resolution T1-weighted images (166 slices, 1 mm isotropic voxels) underwent manual segmentations of bilateral caudate and putamen. Extracted volumes were corrected for total intracranial volume. A structure volume ratio quantified hemispheric asymmetry of caudate and putamen (non-dominant/dominant hemisphere structure volume) with ratios closer to 1 reflecting a greater degree of symmetry between structures. Participants were additionally dichotomized by volume ratios into two groups, those with values above the group mean (0.8) and those below. Motor function was assessed using the Assisting Hand Assessment (AHA) and the Box and Blocks test in affected (BBTA) and unaffected (BBTU) hands. Group differences in volumes were explored using Kruskal-Wallis tests, and interhemispheric differences using Wilcoxon. Partial Spearman correlations explored associations between volumes and motor function (factoring out age, and whole-brain white matter volume, a proxy for lesion extent)., Results: In the dominant (non-lesioned) hemisphere, volumes were larger in AIS compared to PVI for both the caudate (p < 0.05) and putamen (p < 0.01) but comparable between stroke groups and controls. Non-dominant (lesioned) hemisphere volumes were larger for controls than AIS for the putamen (p < 0.05), and for the caudate in PVI (p = 0.001). Interhemispheric differences showed greater dominant hemisphere volumes for the putamen in controls (p < 0.01), for both the caudate (p < 0.01) and putamen (p < 0.001) in AIS, and for the caudate (p = 0.01) in PVI. Motor scores did not differ between AIS and PVI thus groups were combined to increase statistical power. Better motor scores were associated with larger non-dominant putamen volumes (BBTA: r = 0.40, p = 0.011), and larger putamen volume ratios (BBTA: r = 0.52, p < 0.001, AHA: r = 0.43, p < 0.01). For those with relatively symmetrical putamen volume ratios (ratio > group mean of 0.8), age was positively correlated with BBTA (r = 0.54, p < 0.01) and BBTU (r = 0.69, p < 0.001). For those with more asymmetrical putamen volume ratios, associations with motor function and age were not seen (BBTA: r = 0.21, p = 0.40, BBTU: r = 0.37, p = 0.13)., Conclusion: Specific perinatal stroke lesions affect different elements of basal ganglia development. PVI primarily affected the caudate, while AIS primarily affected the putamen. Putamen volumes in the lesioned hemisphere are associated with clinical motor function. The basal ganglia should be included in evolving models of developmental plasticity after perinatal stroke., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Perinatal stroke affects ∼1 in 1000 births and concomitant cognitive impairments are common but poorly understood. Rates of Attention Deficit/Hyperactivity Disorder (ADHD) are increased 5-10× and executive dysfunction can be disabling. We used diffusion imaging to investigate whether stroke-related differences in frontal white matter (WM) relate to cognitive impairments. Anterior forceps were isolated using tractography and sampled along the tract. Resulting metrics quantified frontal WM microstructure. Associations between WM metrics and parent ratings of ADHD symptoms (ADHD-5 rating scale) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)) were explored. Eighty-three children were recruited (arterial ischemic stroke [AIS] n = 26; periventricular venous infarction [PVI] n = 26; controls n = 31). WM metrics were altered for stroke groups compared to controls. Along-tract analyses showed differences in WM metrics in areas approximating the lesion as well as more remote differences at midline and in the nonlesioned hemisphere. WM metrics correlated with parental ratings of ADHD and executive function such that higher diffusivity values were associated with poorer function. These findings suggest that underlying microstructure of frontal white matter quantified via tractography may provide a relevant biomarker associated with cognition and behavior in children with perinatal stroke., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

There is limited understanding of the effect of perinatal stroke on child and adolescent learning and memory abilities. This study sought to evaluate the clinical utility of the Child and Adolescent Memory Profile (ChAMP) in quantifying memory performance in youth with perinatal stroke. Children and adolescents aged 6-16 years old with a history of perinatal stroke (PS; n = 41) completed two subtests from the ChAMP (Lists and Objects). Age, sex, and ethnicity-matched healthy control (HC) data were obtained from the test publisher's standardization data set. Participants with a history of PS performed significantly worse (p < .05) with medium effect size ( ƞ p  ≥ .06) than HC on the ChAMP Screening Index and on all ChAMP Lists and Objects scaled scores. Classification accuracy for the ChAMP scores ranged from 57% to 68% with the area under the curve ranging from .62-.75. No significant group differences on ChAMP performance (p > .05) were found for stroke side (left versus right-sided) or for seizure history (present versus absent). This study supports the utility of the ChAMP in perinatal stroke patients by demonstrating significantly worse performance in verbal and visual memory than HC. Classification accuracy is limited, but supportive for the Screening Index and Objects Delayed scores. The ChAMP may be a useful tool for evaluating cognition in this population when taken alongside the context of other tests, background history, and clinical observations.2  ≥ .06) than HC on the ChAMP Screening Index and on all ChAMP Lists and Objects scaled scores. Classification accuracy for the ChAMP scores ranged from 57% to 68% with the area under the curve ranging from .62-.75. No significant group differences on ChAMP performance (p > .05) were found for stroke side (left versus right-sided) or for seizure history (present versus absent). This study supports the utility of the ChAMP in perinatal stroke patients by demonstrating significantly worse performance in verbal and visual memory than HC. Classification accuracy is limited, but supportive for the Screening Index and Objects Delayed scores. The ChAMP may be a useful tool for evaluating cognition in this population when taken alongside the context of other tests, background history, and clinical observations.

Background: Hemiparetic cerebral palsy impacts millions of people worldwide. Assessment of bilateral motor function in real life remains a major challenge. We evaluated quantification of upper extremity movement in hemiparetic children using bilateral actigraphy. We hypothesized that movement asymmetry correlates with standard motor outcome measures., Methods: Hemiparetic and control participants wore bilateral wrist Actiwatch2 (Philips) for 48 h with movement counts recorded in 15-s intervals. The primary outcome was a novel statistic of movement asymmetry, the Actigraphic Movement Asymmetry Index (AMAI). Relationships between AMAI and standard motor outcomes (Assisting Hand Assessment, Melbourne Assessment, and Box and Block Test [BB]) were explored with Pearson or Spearman correlation., Results: 30 stroke (mean 11 years 2 months (3 years 10 months); 13 female, 17 male) and 23 control (mean 11 years 1 month (4 years 5 months); 8 female, 15 male) were enrolled. Stroke participants demonstrated higher asymmetry. Correlations between AMAI and standard tests were moderate and strongest during sleep (BB: r = 0.68, p < 0.01)., Conclusions: Standard tests may not reflect the extent of movement asymmetry during daily life in hemiparetic children. Bilateral actigraphy may be a valuable complementary tool for measuring arm movement, potentially enabling improved evaluation of therapies with a focus on child participation., (© 2021. The Author(s).)

Background and Purpose: Perinatal stroke is the leading cause of hemiparetic cerebral palsy resulting in lifelong disability for millions of people worldwide. Options for motor rehabilitation are limited, especially for the most severely affected children. Brain computer interfaces (BCIs) sample brain activity to allow users to control external devices. Functional electrical stimulation enhances motor recovery after stroke, and BCI-activated functional electrical stimulation was recently shown to improve upper extremity function in adult stroke. We aimed to determine the ability of children with perinatal stroke to operate a simple BCI., Methods: Twenty-one children with magnetic resonance imaging–confirmed perinatal stroke (57% male, mean [SD] 13.5 [2.6] years, range 9–18) were compared with 24 typically developing controls (71% male, mean age [SD] 13.7 [3.7] years, range 6–18). Participants trained on a simple EEG-based BCI over 2 sessions (10 trials each) utilizing 2 different mental imagery strategies: (1) motor imagery (imagine opening and closing of hands) and (2) goal oriented (imagine effector object moving toward target) to complete 2 tasks: (1) drive a remote controlled car to a target and (2) move a computer cursor to a target. Primary outcome was Cohen Kappa with a score >0.40 suggesting BCI competence., Results: BCI performance was comparable between stroke and control participants. Mean scores were 0.39 (0.18) for stroke versus 0.42 (0.18) for controls (t[42]=0.478, P=0.94). No difference in performance between venous (M=0.45, SD=0.29) and arterial (M=0.34, SD=0.22) stroke (t[82]=1.89, P=0.090) was observed. No effect of task or strategy was observed in the stroke participants. Over 90% of stroke participants demonstrated competency on at least one of the 4 task-strategy combinations., Conclusions: Children with perinatal stroke can achieve proficiency in basic tasks using simple BCI systems. Future directions include exploration of BCI-functional electrical stimulation systems for rehabilitation for children with hemiparesis and other forms of cerebral palsy.

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain-computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Background: Studies using clinical measures have suggested that proprioceptive dysfunction is related to motor impairment of the upper extremity following adult stroke. We used robotic technology and clinical measures to assess the relationship between position sense and reaching with the hemiparetic upper limb in children with perinatal stroke., Methods: Prospective term-born children with magnetic resonance imaging-confirmed perinatal ischemic stroke and upper extremity deficits were recruited from a population-based cohort. Neurotypical controls were recruited from the community. Participants completed two tasks in the Kinarm robot: arm position-matching (three parameters: variability [Var xy ], contraction/expansion [Area xy ], systematic spatial shift [Shift xy ]) and visually guided reaching (five parameters: posture speed [PS], reaction time [RT], initial direction error [IDE], speed maxima count [SMC], movement time [MT]). Additional clinical assessments of sensory (thumb localization test) and motor impairment (Assisting Hand Assessment, Chedoke-McMaster Stroke Assessment) were completed and compared to robotic measures., Results: Forty-eight children with stroke (26 arterial, 22 venous, mean age: 12.0 ± 4.0 years) and 145 controls (mean age: 12.8 ± 3.9 years) completed both tasks. Position-matching performance in children with stroke did not correlate with performance on the visually guided reaching task. Robotic sensory and motor measures correlated with only some clinical tests. For example, AHA scores correlated with reaction time (R = - 0.61, p < 0.001), initial direction error (R = - 0.64, p < 0.001), and movement time (R = - 0.62, p < 0.001)., Conclusions: Robotic technology can quantify complex, discrete aspects of upper limb sensory and motor function in hemiparetic children. Robot-measured deficits in position sense and reaching with the contralesional limb appear to be relatively independent of each other and correlations for both with clinical measures are modest. Knowledge of the relationship between sensory and motor impairment may inform future rehabilitation strategies and improve outcomes for children with hemiparetic cerebral palsy.

Perinatal stroke is a focal vascular brain injury that occurs from the fetal period to 28 days of postnatal age. With an overall incidence of up to 1 in 1,000 live births, the most focused lifetime risk for stroke occurs near birth. Perinatal stroke can be classified by the timing of diagnosis, vessel involvement, and type of injury. Timing of diagnosis may be in the acute neonatal period or retrospectively after a period of normal development, followed by abnormal neurologic findings, with the injury presumed to have occurred around the time of birth. Strokes may be arterial or venous, ischemic, and/or hemorrhagic. Within these classifications, 6 perinatal stroke diseases are recognizable, based on clinical and radiographic features. Morbidity is high in perinatal stroke, because it accounts for most cases of hemiparetic cerebral palsy, with disability lasting a lifetime. Additional complications include disorders of sensation and vision, language delays, cognitive and learning deficits, epilepsy, and mental health consequences that affect the entire family. Advances in neonatal neurocritical care may afford opportunity to minimize brain injury and improve outcomes. In the chronic timeframe, progress made in neuroimaging and brain mapping is revealing the developmental plasticity that occurs, informing new avenues for neurorehabilitation. This review will summarize the diagnosis and management of each perinatal stroke disease, highlighting their similarities and distinctions and emphasizing a patient- and family-centered approach to management., (Copyright © 2021 by the American Academy of Pediatrics.)

Perinatal stroke occurs around the time of birth and leads to lifelong neurological disabilities including hemiparetic cerebral palsy. Magnetic resonance imaging (MRI) has revolutionized our understanding of developmental neuroplasticity following early injury, quantifying volumetric, structural, functional, and metabolic compensatory changes after perinatal stroke. Such techniques can also be used to investigate how the brain responds to treatment (interventional neuroplasticity). Here, we review the current state of knowledge of how established and emerging neuroimaging modalities are informing neuroplasticity models in children with perinatal stroke. Specifically, we review structural imaging characterizing lesion characteristics and volumetrics, diffusion tensor imaging investigating white matter tracts and networks, task-based functional MRI for localizing function, resting state functional imaging for characterizing functional connectomes, and spectroscopy examining neurometabolic changes. Key challenges and exciting avenues for future investigations are also considered.

Objective . To develop consensus recommendations for the use of repetitive transcranial magnetic stimulation (rTMS) as an adjunct intervention for upper extremity motor recovery in stroke rehabilitation clinical trials. Participants . The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) convened a multidisciplinary team of clinicians and researchers from institutions across Canada to form the CanStim Consensus Expert Working Group. Consensus Process . Four consensus themes were identified: (1) patient population, (2) rehabilitation interventions, (3) outcome measures, and (4) stimulation parameters. Theme leaders conducted comprehensive evidence reviews for each theme, and during a 2-day Consensus Meeting, the Expert Working Group used a weighted dot-voting consensus procedure to achieve consensus on recommendations for the use of rTMS as an adjunct intervention in motor stroke recovery rehabilitation clinical trials. Results . Based on best available evidence, consensus was achieved for recommendations identifying the target poststroke population, rehabilitation intervention, objective and subjective outcomes, and specific rTMS parameters for rehabilitation trials evaluating the efficacy of rTMS as an adjunct therapy for upper extremity motor stroke recovery. Conclusions . The establishment of the CanStim platform and development of these consensus recommendations is a first step toward the translation of noninvasive brain stimulation technologies from the laboratory to clinic to enhance stroke recovery.

Introduction: Perinatal stroke leads to cerebral palsy (CP) and lifelong disability for thousands of Canadian children. Hemiparesis, referring to impaired functionality in one side of the body, is a common complication of perinatal stroke. Standard long-term care for hemiparetic CP focuses on rehabilitation therapies. Early research suggests that patients with hemiparesis may benefit from adjunctive neuromodulation treatments such as transcranial direct current stimulation (tDCS). tDCS uses electric current to stimulate targeted areas of the brain non-invasively, potentially enhancing the effects of motor learning therapies. This protocol describes an economic evaluation to be conducted alongside a randomised controlled trial (RCT) to assess the incremental cost of tDCS added to a camp-based therapy compared with camp-based therapy alone per quality-adjusted life year (QALY) gained in children with hemiparetic CP., Methods and Analysis: The Stimulation for Perinatal Stroke Optimising Recovery Trajectories (SPORT) trial is a multicentre RCT evaluating tDCS added to a 2-week camp-based therapy for children aged 6-18 years with perinatal ischaemic stroke and disabling hemiparetic CP affecting the upper limb. Outcomes are assessed at baseline, 1 week, 2 months and 6 months following intervention. Cost and quality of life data are collected at baseline and 6 months and results will be used to conduct a cost-utility analysis (CUA). The evaluation will be conducted from the perspectives of the public healthcare system and society. The CUA will be conducted over a 6-month time horizon., Ethics and Dissemination: Ethical approval for the SPORT trial and the associated economic evaluation has been given by the research ethics boards at each of the study sites. The findings of the economic evaluation will be submitted for publication in a peer reviewed academic journal and submitted for presentation at conference., Trial Registration Number: NCT03216837; Post-results., Competing Interests: Competing interests: PB: reports paid employment from Medlior Health Outcomes Research a health research consultancy. Medlior Health Outcomes Research conducts health research for pharmaceutical, medical device, government and academic companies/institutions. No compensation from Medlior Health Outcomes Research was received related to this project. JH, AK, MEM, WU and JZ: none to report., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Continuous spike and wave in slow-wave sleep (CSWS), an epileptic encephalopathy, occurs after perinatal stroke where it is associated with cognitive decline. CSWS features a distinct EEG pattern, electrical status epilepticus in sleep (ESES). Biomarkers for the prediction of ESES have not been identified but will facilitate earlier diagnosis and treatment. We hypothesized that spike-frequency and differences in power spectra would be predictive of subsequent ESES., Methods: A cross-sectional study comparing EEG spike-frequency and Power before the development of ESES in patients with perinatal stroke, patients with focal epilepsy, and appropriate controls., Results: 43 patients met the inclusion criteria; 11 stroke-ESES, 10 stroke controls, 14 epilepsy-ESES, 8 epilepsy controls. ESES patients had higher pre-diagnosis mean spike-frequency (24.0 ± 24 versus 6.6 ± 9.1 SW/min, p = 0.002) than patients that did not develop ESES; these differences present ~ 3 years before ESES diagnosis. Pre-diagnosis, normalized delta power (1-4 Hz) was higher in the stroke-ESES group (105.7 ± 58 dB/Hz) compared to stroke controls (57.4 ± 45 dB/Hz, p = 0.036)., Conclusion: Spike-frequency and delta power may represent EEG biomarkers of the risk of developing ESES in children with perinatal stroke., Significance: EEG biomarkers may be used by clinicians to assess which patients are more at-risk for ESES. Using spike-frequency, clinicians may be able to identify patients at risk of developing ESES., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To employ diffusion imaging connectome methods to explore network development in the contralesional hemisphere of children with perinatal stroke and its relationship to clinical function. We hypothesized alterations in global efficiency of the intact hemisphere would correlate with clinical disability., Methods: Children with unilateral perinatal arterial (n = 26) or venous (n = 27) stroke and typically developing controls (n = 32) underwent 3T diffusion and T1 anatomical MRI and completed established motor assessments. A validated atlas coregistered to whole-brain tractography for each individual was used to estimate connectivity between 47 regions. Graph theory metrics (assortativity, hierarchical coefficient of regression, global and local efficiency, and small worldness) were calculated for the left hemisphere of controls and the intact contralesioned hemisphere of both stroke groups. Validated clinical motor assessments were then correlated with connectivity outcomes., Results: Global efficiency was higher in arterial strokes compared to venous strokes ( p < 0.001) and controls ( p < 0.001) and was inversely associated with all motor assessments (all p < 0.012). Additional graph theory metrics including assortativity, hierarchical coefficient of regression, and local efficiency also demonstrated consistent differences in the intact hemisphere associated with clinical function., Conclusions: The structural connectome of the contralesional hemisphere is altered after perinatal stroke and correlates with clinical function. Connectomics represents a powerful tool to understand whole brain developmental plasticity in children with disease-specific cerebral palsy., (© 2020 American Academy of Neurology.)

Background: Perinatal stroke often leads to lifelong motor impairment. Two common subtypes differ in timing, location, and mechanism of injury: periventricular venous infarcts (PVI) are fetal white matter lesions while most arterial ischemic strokes (AIS) are cortical injuries acquired near term birth. Both alter motor system development and primary motor cortex (M1) plasticity, often with retained ipsilateral corticospinal fibers from the non-lesioned motor cortex (M1')., Methods: Task-based functional magnetic resonance imaging was used to define patterns of motor cortex activity during paretic and unaffected hand movement. Peak coordinates of M1, M1', and the supplementary motor area in the lesioned and intact hemispheres were compared to age-matched controls. Correlations between displacements and clinical motor function were explored., Results: Forty-nine participants included 14 PVI (12.59 ± 3.7 years), 13 AIS (14.91 ± 3.9 years), and 22 controls (13.91 ± 3.4 years). AIS displayed the greatest M1 displacement from controls in the lesioned hemisphere while PVI locations approximated controls. Peak M1' activations were displaced from the canonical hand knob in both PVI and AIS. Extent of M1 and M1' displacement were correlated (r = 0.50, P = 0.025) but were not associated with motor function. Supplementary motor area activity elicited by paretic tapping was displaced in AIS compared to controls (P = 0.003)., Conclusion: Motor network components may be displaced in both hemispheres after perinatal stroke, particularly in AIS and those with ipsilateral control of the affected limb. Modest correlations with clinical function may support that more complex models of developmental plasticity are needed to inform targets for individualized neuromodulatory therapies in children with perinatal stroke., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Perinatal stroke encompasses multiple disease-specific cerebrovascular syndromes that cause lifelong neurodevelopmental morbidity for millions worldwide. Acute presentations include neonatal arterial ischemic stroke (NAIS), neonatal cerebral sinovenous thrombosis, and neonatal hemorrhagic stroke (NHS). Delayed presentations include arterial presumed perinatal ischemic stroke, periventricular venous infarction, and presumed perinatal hemorrhagic stroke. Our objective was to define the birth prevalence of all subtypes of perinatal stroke by using a population-based cohort., Methods: The Alberta Perinatal Stroke Project is a research cohort established in 2008 in southern Alberta, Canada, with prospective (2008-2017) and retrospective (1990-2008) enrollment leveraging universal health care at a single tertiary care pediatric center. The primary outcome was the estimated birth prevalence of each perinatal stroke syndrome, secondary outcomes were birth prevalence over time, sex ratios, and change in age at diagnosis. Analysis included Poisson regression, Wilcoxon rank test, and Fisher exact test., Results: The overall estimated birth prevalence of term-born perinatal stroke was 1:1100. The estimated birth prevalence was 1:3000 for NAIS, 1:7900 for arterial presumed perinatal ischemic stroke, 1:6000 for periventricular venous infarction, 1:9100 for cerebral sinovenous thrombosis, 1:6800 for NHS, and 1:65000 for presumed perinatal hemorrhagic stroke. The apparent birth prevalence of NAIS and NHS increased over time. There were more males affected than females. The age at diagnosis decreased for late-presenting stroke types., Conclusions: The estimated birth prevalence of term perinatal stroke is higher than previous estimates, which may be explained by population-based sampling of disease-specific states. This emphasizes the need for further studies to better understand the disease-specific pathophysiology to improve treatment and prevention strategies., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose. The funder/sponsor did not participate in the work, (Copyright © 2020 by the American Academy of Pediatrics.)

Objective: To examine the relationship between neonatal inflammatory cytokines and perinatal stroke using a systems biology approach analyzing serum and blood-spot cytokines from 47 patients., Methods: This was a population-based, controlled cohort study with prospective and retrospective case ascertainment. Participants were recruited through the Alberta Perinatal Stroke Project. Stroke was classified as neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or periventricular venous infarction (PVI). Biosamples were stored blood spots (retrospective) and acute serum (prospective). Controls had comparable gestational and maternal ages. Sixty-five cytokines were measured (Luminex). Hierarchical clustering analysis was performed to create heat maps. The Fisher linear discriminant analysis was used to create projection models to determine discriminatory boundaries between stroke types and controls., Results: A total of 197 participants were analyzed (27 with NAIS, 8 with APPIS, 12 with PVI, 150 controls). Cytokines were quantifiable with quality control measures satisfied (standards testing, decay analysis). Linear discriminant analysis had high accuracy in using cytokine profiles to separate groups. Profiles in participants with PVI and controls were similar. NAIS separation was accurate (sensitivity 77%, specificity 97%). APPIS mapping was also distinguishable from NAIS (sensitivity 86%, specificity 99%). Classification tree analysis generated similar diagnostic accuracy., Conclusions: Unique inflammatory biomarker signatures are associated with specific perinatal stroke diseases. Findings support an acquired pathophysiology and suggest the possibility that at-risk pregnancies might be identified to develop prevention strategies., Classification of Evidence: This study provides Class III evidence that differences in acute neonatal serum cytokine profiles can discriminate between patients with specific perinatal stroke diseases and controls., (© 2020 American Academy of Neurology.)

Aim: Some conditions within specific populations are so rare rigorous evidence is unavailable. Childhood hyperkinesis is one example, yet presents an opportunity to examine sensation's contribution to motor function., Methods: The patient experienced functional difficulty from hyperkinesis as a result of childhood stroke. Home-based passive neuromuscular electrical stimulation (NMES) was implemented an hour/day, six days/week, over 6 weeks (36 hours). Clinical and robotic measures (Assisting Hand Assessment, Box and Block Test, Jebsen Taylor Test of Hand Function, Kinarm) were administered before and after the intervention and at 9 months., Results: NMES was feasible and well tolerated. Clinically important gains of arm function were maintained at 9 months. Robotic measures showed improved hyperkinesis, namely reduced movement segmentation and improved target approximation, in addition to improved proprioceptive function after NMES., Conclusion: This case study illustrates the use of NMES within a previously unexplored population and highlights the potential importance of sensory systems to motor gains.

Background: Activities of daily living frequently require children to make rapid decisions and execute desired motor actions while inhibiting unwanted actions. Children with hemiparetic cerebral palsy due to perinatal stroke may have deficits in executive functioning in addition to motor impairments. The objective of this study was to use a robotic object hit and avoid task to assess the ability of children with hemiparetic cerebral palsy to make rapid motor decisions., Methods: Forty-five children with hemiparetic cerebral palsy due to perinatal stroke and 146 typically developing children (both groups ages 6-19 years) completed a robotic object hit and avoid task using the Kinarm Exoskeleton. Objects of different shapes fell from the top of the screen with increasing speed and frequency. Children were instructed to hit two specific target shapes with either hand, while avoiding six distractor shapes. The number of targets and distractors hit were compared between children with hemiparetic cerebral palsy and typically developing children, accounting for age effects. We also compared performance to a simpler object hit task where there were no distractors., Results: We found that children with hemiparetic cerebral palsy hit a greater proportion of total distractors compared to typically developing children, demonstrating impairments in inhibitory control. Performance for all children improved with age. Children with hemiparetic cerebral palsy hit a greater percentage of targets with each arm on the more complex object hit and avoid task compared to the simpler object hit task, which was not found in typically developing children., Conclusions: Children with hemiparetic cerebral palsy due to perinatal stroke demonstrated impairments in rapid motor decision making including inhibitory control, which can impede their ability to perform real-world tasks. Therapies that address both motor performance and executive functions are necessary to maximize function in children with hemiparetic cerebral palsy.

Background: While motor deficits are the hallmark of hemiparetic cerebral palsy, children may also experience impairments in visuospatial attention that interfere with participation in complex activities, including sports or driving. In this study, we used a robotic object hitting task to assess bilateral sensorimotor control and visuospatial skills in children with hemiparesis due to perinatal arterial ischemic stroke (AIS) or periventricular venous infarct (PVI). We hypothesized that performance would be impaired bilaterally and be related to motor behavior and clinical assessment of visuospatial attention., Methods: Forty-nine children with perinatal stroke and hemiparetic cerebral palsy and 155 typically developing (TD) children participated in the study. Participants performed a bilateral object hitting task using the KINARM Exoskeleton Robot, in which they used virtual paddles at their fingertips to hit balls that fell from the top of the screen with increasing speed and frequency over 2.3 min. We quantified performance across 13 parameters including number of balls hit with each hand, movement speed and area, biases between hands, and spatial biases. We determined normative ranges of performance accounting for age by fitting 95% prediction bands to the TD children. We compared parameters between TD, AIS, and PVI groups using ANCOVAs accounting for age effects. Lastly, we performed regression analysis between robotic and clinical measures., Results: The majority of children with perinatal stroke hit fewer balls with their affected arm compared to their typically developing peers. We also found deficits with the ipsilesional ("unaffected") arm. Children with AIS had greater impairments than PVI. Despite hitting fewer balls, we only identified 18% of children as impaired in hand speed or movement area. Performance on the Behavioral Inattention Test accounted for 21-32% of the variance in number of balls hit with the unaffected hand., Conclusions: Children with perinatal stroke-induced hemiparetic cerebral palsy may have complex bilateral deficits reflecting a combination of impairments in motor skill and visuospatial attention. Clinical assessments and interventions should address the interplay between motor and visuospatial skills.

Aim: To characterize fatigue in children with hemiparesis with perinatal stroke and explore associations with measures of motor performance and corticospinal excitability., Method: Forty-five children (16 females, 29 males), aged 6 to 18 years (mean [SD] 12y [4]), with magnetic resonance imaging-confirmed perinatal stroke participated. Associations between fatigue (Pediatric Quality of Life Inventory Version 3.0 cerebral palsy module fatigue subscale), motor performance (Assisting Hand Assessment [AHA], Box and Blocks Test, grip strength), and excitability of corticospinal projections to both hands were examined using ranked tests of correlation, robust regression, and the Mann-Whitney U test., Results: Nearly half of the participants (n=21) reported experiencing fatigue in the previous month. Function in the less affected hand (Box and Blocks Test, grip strength) was correlated with fatigue scores. Participants with preserved ipsilateral projections to the more affected hand had less fatigue, and scores correlated with the excitability of these projections. Fatigue scores were not associated with age, sex, or AHA score., Interpretation: Fatigue is common in children with hemiparesis with perinatal stroke and is associated with motor performance and the presence and excitability of ipsilateral corticospinal projections from the contralesional hemisphere to the more affected hand., What This Paper Adds: Fatigue is common in children with hemiparesis with perinatal stroke. Fatigue was associated with motor performance and strength in the less affected, but not the more affected, hand. Fatigue was associated with the presence and excitability of ipsilateral corticospinal projections from the contralesional hemisphere., (© 2019 Mac Keith Press.)

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.

Developmental neuroplasticity allows young brains to adapt via experiences early in life and also to compensate after injury. Why certain individuals are more adaptable remains underexplored. Perinatal stroke is an ideal human model of neuroplasticity with focal lesions acquired near birth in a healthy brain. Machine learning can identify complex patterns in multi-dimensional datasets. We used machine learning to identify structural and functional connectivity biomarkers most predictive of motor function. Forty-nine children with perinatal stroke and 27 controls were studied. Functional connectivity was quantified by fluctuations in blood oxygen-level dependent (BOLD) signal between regions. White matter tractography of corticospinal tracts quantified structural connectivity. Motor function was assessed using validated bimanual and unimanual tests. RELIEFF feature selection and random forest regression models identified predictors of each motor outcome using neuroimaging and demographic features. Unilateral motor outcomes were predicted with highest accuracy (8/54 features r = 0.58, 11/54 features, r = 0.34) but bimanual function required more features (51/54 features, r = 0.38). Connectivity of both hemispheres had important roles as did cortical and subcortical regions. Lesion size, age at scan, and type of stroke were predictive but not highly ranked. Machine learning regression models may represent a powerful tool in identifying neuroimaging biomarkers associated with clinical motor function in perinatal stroke and may inform personalized targets for neuromodulation., (Copyright © 2020. Published by Elsevier Inc.)

Perinatal strokes are a diverse but specific group of focal cerebrovascular injuries that occur early in brain development and affect an estimated 5 million people worldwide. The objective of this review is to describe the epidemiology, clinical presentations, pathophysiology, outcomes, and management for the 6 subtypes of perinatal stroke. Some perinatal strokes are symptomatic in the first days of life, typically with seizures, including neonatal arterial ischemic stroke, neonatal hemorrhagic stroke, and cerebral sinovenous thrombosis. The remaining subtypes present in the first year of life or later, usually with motor asymmetry and include arterial presumed perinatal ischemic stroke, presumed perinatal hemorrhagic stroke, and in utero periventricular venous infarction. The consequences of these injuries include cerebral palsy, epilepsy, and cognitive and behavioral challenges, in addition to the psychosocial impact on families. While there have been significant advances in understanding mechanisms of both injury and recovery, there is still a great deal to learn regarding causation and the optimization of outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: We aimed to characterize the phenotype and outcome of children with bilateral, large vessel perinatal arterial ischemic stroke., Methods: Patients with bilateral, large vessel perinatal arterial ischemic stroke were identified from a large, population-based cohort (Alberta Perinatal Stroke Project). Subjects were included if stroke involving a major cerebral artery territory was documented in both cerebral hemispheres on magnetic resonance imaging. Standardized variables were extracted from charts including clinical presentations, associated potential risk factors, and outcomes. Outcome measures included the Pediatric Stroke Outcome Measure, Gross Motor Function Classification System, and epilepsy frequency score. Electroencephalographies were reviewed for sleep, epileptiform activity, and background., Results: Of 174 children with perinatal arterial ischemic stroke, eight (5%) had bilateral large artery infarcts. Patients were followed for a mean of 9.7 years (range 1.8 to 14.6 years). One child died. All children had a total Pediatric Stroke Outcome Measure of ≥2 (median 8, range 2 to 10) and Gross Motor Function Classification System ≥ II. Seven of eight (88%) children had a history of epilepsy., Conclusions: Children with bilateral, large vessel perinatal stroke are at high risk of severe cognitive and motor sequelae. Epilepsy may also be more common than unilateral strokes. Cautious discussions with families regarding prognosis are recommended., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: We aimed to determine if the mirror movements that often result in children with unilateral cerebral palsy (CP) after perinatal stroke represent a clinical biomarker of developmental plasticity., Method: This was a prospective, controlled cohort study. Mirror movements in children with unilateral CP from a population-based cohort were compared to those of typically developing controls. The population with stroke was assessed further via electromyography (EMG), motor function, and corticospinal organization investigations. Mirror movements were quantified (0-5) bidirectionally. EMG mirror movements were quantified during voluntary contraction. Motor function was quantified by validated measures including the Assisting Hand Assessment (AHA). Corticospinal organization was categorized as ipsilateral or contralateral using transcranial magnetic stimulation (TMS). The relationships between mirror movements, function, and corticospinal organization were assessed (t-tests, Pearson rank correlation coefficients)., Results: Ninety-two participants were scored (55 males, 37 females, mean [SD] 12y [5y 6mo], range 4-17y), 63 with complete motor outcomes and 39 with TMS data. EMG ratios correlated with clinical mirror movements (r=0.562, p=0.008). Mild mirror activity in controls declined with age (r=-0.459, p<0.001). Mirroring was stronger with tasks performed by the affected hand (p<0.001). Mirror movements correlated with AHA scores (r=-0.255, p=0.04) and poor motor outcome (p<0.001). Unaffected hand mirror activity was higher in children with ipsilateral corticospinal tract arrangements (p<0.001)., Interpretation: Clinical mirror movements correlate with disability and corticospinal organization in children with unilateral CP with perinatal stroke. This simple bedside biomarker could facilitate patient selection for personalized rehabilitation., What This Paper Adds: Mirror movements are a clinical indicator of corticospinal organization in children with unilateral cerebral palsy with perinatal stroke. Mirroring is strongest in children with ipsilateral corticospinal tract reorganization. The concept of a 'directionality factor' to mirror movements highlights additional, clinically relevant functional correlations., (© 2019 Mac Keith Press.)

Perinatal stroke causes lifelong disability, particularly hemiparetic cerebral palsy. Arterial ischemic strokes (AIS) are large, cortical, and subcortical injuries acquired near birth due to acute occlusion of the middle cerebral artery. Periventricular venous infarctions (PVI) are smaller, subcortical strokes acquired prior to 34 weeks gestation involving injury to the periventricular white matter. Both stroke types can damage motor pathways, thus, we investigated resulting alterations in functional motor networks and probed function. We measured blood oxygen level dependent (BOLD) fluctuations at rest in 38 participants [10 arterial patients (age = 14.7 ± 4.1 years), 10 venous patients (age = 13.5 ± 3.7 years), and 18 typically developing controls (TDCs) (age = 15.3 ± 5.1 years)] and explored strength and laterality of functional connectivity in the motor network. Inclusion criteria included MRI-confirmed, unilateral perinatal stroke, symptomatic hemiparetic cerebral palsy, and 6-19 years old at time of imaging. Seed-based functional connectivity analyses measured temporal correlations in BOLD response over the whole brain using primary motor cortices as seeds. Laterality indices based on mean z-scores in lesioned and nonlesioned hemispheres explored laterality. In AIS patients, significant differences in both strength and laterality of motor network connections were observed compared with TDCs. In PVI patients, motor networks largely resembled those of healthy controls, albeit slightly weaker and asymmetric, despite subcortical damage and hemiparesis. Functional connectivity strengths were not related to motor outcome scores for either stroke group. This study serves as a foundation to better understand how resting-state fMRI can assess motor functional connectivity and potentially be applied to explore mechanisms of interventional therapies after perinatal stroke., (© 2018 Wiley Periodicals, Inc.)

Successful language acquisition during development is imperative for lifelong function. Complex language networks develop throughout childhood. Perinatal stroke may cause significant language disabilities but function can also be remarkably normal. Studying such very early brain injury populations may inform developmental plasticity models of language networks. We examined functional connectivity (FC) of language networks in children with arterial and venous perinatal stroke and typically developing controls (TDC) in a population-based, controlled, cohort study. Resting state functional MRI was performed at 3 T (TR/TE = 2000/30 ms, 150 volumes, 3.6mm 3 voxels). Seed-based analyses used bilateral inferior frontal and superior temporal gyri. A subset of stroke participants completed clinical language testing. Sixty-six children participated (median age: 12.85±3.8y, range 6-19; arterial N = 17; venous N = 15; TDC N = 34]. Children with left hemisphere strokes had comparable FC in their right hemispheres compared to TDC. Inter- and intra-hemispheric connectivity strengths were similar between TDC and PVI but lower for AIS. Reduced FC was associated with poorer language comprehension. Language networks can be estimated using resting-state fMRI in children with perinatal stroke. Altered connectivity may occur in both hemispheres, is more pronounced with arterial lesions, and is associated with clinical function. Our results have implications for therapeutic language interventions after early stroke., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Perinatal stroke causes most hemiparetic cerebral palsy and leads to lifelong disability. Understanding developmental neuroplasticity following early stroke is increasingly translated into novel therapies. Diaschisis refers to alterations brain structures remote from, but connected to, stroke lesions. Ipsilesional thalamic diaschisis has been described following adult stroke but has not been investigated in perinatal stroke. We hypothesized that thalamic diaschisis occurs in perinatal stroke and its degree would be inversely correlated with clinical motor function., Methods: Population-based, controlled cohort study. Participants were children (<19 years) with unilateral perinatal stroke (arterial ischemic stroke [AIS] or periventricular venous infarction [PVI]), anatomical magnetic resonance imaging (MRI) >6 months of age, symptomatic hemiparetic cerebral palsy, and no additional neurologic disorders. Typically developing controls had comparable age and gender proportions. T1-weighted anatomical scans were parcellated into 99 regions of interest followed by generation of regional volumes. The primary outcome was thalamic volume expressed as ipsilesional (ILTV), contralesional (CLTV) and thalamic ratio (CLTV/ILTV). Standardized clinical motor assessments were correlated with thalamic volume metrics., Results: Fifty-nine participants (12.9 years old ±4.0 years, 46% female) included 20 AIS, 11 PVI, and 28 controls. ILTV was reduced in both AIS and PVI compared to controls (p < .001, p = .029, respectively). Ipsilesional thalamic diaschisis was not associated with clinical motor function. However, CLTV was significantly larger in AIS compared to both controls and PVI (p = .005, p < .001, respectively). CLTV was inversely correlated with all four clinical motor assessments (all p < .003)., Conclusion: Bilateral thalamic volume changes occur after perinatal stroke. Ipsilesional volume loss is not associated with clinical motor function. Contralesional volume is inversely correlated with clinical motor function, suggesting the thalamus is involved in the known developmental plasticity that occurs in the contralesional hemisphere after early unilateral injury., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bacterial meningitis is a severe infection of the nervous system with a high complication rate including stroke. The purpose of this study is to assess the incidence, risk factors, patterns, and outcomes in pediatric meningitis complicated by stroke., Methods: The study design was a population-based, 10-year retrospective (2002 to 2012) cohort study set in Southern Alberta, Canada. The inclusion criteria were: (1) age from newborn to 18 years, (2) brain magnetic resonance imaging (MRI) including diffusion-weighted imaging during admission, and (3) laboratory confirmed acute bacterial meningitis. The main outcomes were demographics, clinical presentations, risk factors, laboratory findings, radiographic findings, and neurological outcomes., Findings: Forty-three patients had confirmed bacterial meningitis and diffusion MRI (9 neonates (21%), 89% male; 22 infants aged one month to one year (51%), 50% male; and 12 children older than one year (28%), 58% male, median age four years (interquartile range 7.9 years). Ischemic stroke was confirmed in 16/43 (37%), often multifocal (94%). Patients with stroke were significantly more likely to have seizures (P = 0.025), otitis media (P = 0.029), and multiple presentations to hospital (P = 0.013). Mortality was 25% in children with stroke compared with 4% in those without (P = 0.067). Survivors with stroke were more likely to have neurological deficits at follow-up (69% versus 26%, P = 0.019)., Conclusions: More than one-third of children with acute bacterial meningitis and clinically indicated MRI had ischemic stroke. Stroke was associated with clinical factors including duration of illness, seizures, and causative organisms. Stroke was associated with higher mortality and morbidity, warranting consideration of increased MRI screening and new approaches to treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Clinical trials are suggesting efficacy of intensive therapy combined with brain stimulation to improve hand function in hemiparetic children with perinatal stroke. However, individual variability exists and the underlying neuroplasticity mechanisms are unknown. Exploring primary motor cortex (M1) neurophysiology, and how it changes with such interventions, may provide valuable biomarkers for advancing personalized neurorehabilitation., Methods: Forty-five children (age 6-19 years) with hemiparesis participated in PLASTIC CHAMPS, a blinded, sham-controlled, factorial clinical trial. All received 80 hours of goal-directed intensive upper extremity therapy. They were randomized into 4 groups: repetitive transcranial magnetic stimulation (rTMS) of contralesional M1, constraint therapy, both, or neither. Stimulus recruitment curves (SRC), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) for lesioned and contralesional M1 were investigated using TMS. Clinical assessments including the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) were conducted pre- and postintervention., Results: All children completed the intervention and both function (AHA) and goal performance (COPM) improved with additive effects of rTMS and constraint ( P < .01). After intervention, motor-evoked potential (MEP) amplitudes from the contralesional M1 to the less-affected hand increased (n = 16, P < .02). SRC from the contralesional M1 to the less-affected hand increased (n = 25, P < .01). SICI of the contralesional M1 to the less-affected hand decreased (n = 30, P < .04). No changes were observed for ICF in either hemisphere ( P > .12)., Conclusion: TMS applied before/after intensive neuromodulation therapies can explore M1 neurophysiology and plasticity in children with cerebral palsy. Increased MEP sizes and decreased SICI may reflect mechanisms of interventional plasticity and be potential biomarkers of individualized medicine.

The Canadian Stroke Best Practice Consensus Statement Acute Stroke Management during Pregnancy is the second of a two-part series devoted to stroke in pregnancy. The first part focused on the unique aspects of secondary stroke prevention in a woman with a prior history of stroke who is, or is planning to become, pregnant. This document focuses on the management of a woman who experiences an acute stroke during pregnancy. This consensus statement was developed in recognition of the need for a specifically tailored approach to the management of this group of patients in the absence of any broad-based, stroke-specific guidelines or consensus statements, which do not exist currently. The foundation for the development of this document was the concept that maternal health is vital for fetal well-being; therefore, management decisions should be based first on the confluence of two clinical considerations: (a) decisions that would be made if the patient wasn't pregnant and (b) decisions that would be made if the patient hadn't had a stroke, then nuanced as needed. While empirical research in this area is limited, this consensus document is based on the best available literature and guided by expert consensus. Issues addressed in this document include initial emergency management, diagnostic imaging, acute stroke treatment, the management of hemorrhagic stroke, anesthetic management, post stroke management for women with a stroke in pregnancy, intrapartum considerations, and postpartum management. These statements are appropriate for healthcare professionals across all disciplines and system planners to ensure pregnant women who experience a stroke have timely access to both expert neurological and obstetric care.

Perinatal stroke encompasses a heterogeneous group of focal neurological injuries early in brain development that probably affects more than 5 million people worldwide. Many such injuries are symptomatic in the first days of life, including neonatal arterial ischaemic stroke, cerebral sinovenous thrombosis, and neonatal haemorrhagic stroke. The remaining focal neurological injuries usually present later in the first year with motor asymmetry, such as arterial presumed perinatal ischaemic stroke, periventricular venous infarction, and presumed perinatal haemorrhagic stroke. The numerous sequelae of these injuries include hemiparesis (cerebral palsy), epilepsy, and cognitive, language, and behavioural challenges. In this Review we summarise each perinatal stroke disease, examining the epidemiology, pathophysiology, acute management, and outcomes, including the effect on parents and families, and emerging therapies to mitigate these lifelong morbidities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)