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The objective and scope of this Limited Output Transcranial Electrical Stimulation 2023 (LOTES-2023) guidance is to update the previous LOTES-2017 guidance. These documents should therefore be considered together. The LOTES provides a clearly articulated and transparent framework for the design of devices providing limited output (specified low-intensity range) transcranial electrical stimulation for a variety of intended uses. These guidelines can inform trial design and regulatory decisions, but most directly inform manufacturer activities - and hence were presented in LOTES-2017 as "Voluntary industry standard for compliance controlled limited output tES devices". In LOTES-2023 we emphasize that these standards are largely aligned across international standards and national regulations (including those in USA, EU, and South Korea), and so might be better understood as "Industry standards for compliance controlled limited output tES devices". LOTES-2023 is therefore updated to reflect a consensus among emerging international standards, as well as best available scientific evidence. "Warnings" and "Precautions" are updated to align with current biomedical evidence and applications. LOTES standards applied to a constrained device dose range, but within this dose range and for different use-cases, manufacturers are responsible to conduct device-specific risk management. • Updates LOTES-2017 standard. • Detailed voluntary manufacturer guidance for limited output tES to minimize risks, while supporting access and innovation. • Outlined industry guidance that are consistent with and expand on the current regulatory standards. [ABSTRACT FROM AUTHOR]

Background: Pediatric cerebral sinovenous thrombosis is a treatable cause of brain injury, acute symptomatic seizures, and remote epilepsy. Our objective was to prospectively study epilepsy and outcomes in neonates and children one year after cerebral sinovenous thrombosis diagnosis.Methods: Patients with cerebral sinovenous thrombosis were enrolled prospectively from 21 international sites through the Seizures in Pediatric Stroke Study. Clinical data, including acute symptomatic seizures and cerebral sinovenous thrombosis risk factors, were collected at diagnosis. A neuroradiologist who was unaware of the diagnosis reviewed acute imaging. At one year, outcomes including seizure recurrence, epilepsy diagnosis, antiepileptic drug use, and modified Engel score were collected. Outcomes were assessed using the modified Rankin score and the King's Outcome Scale for Childhood Head Injury.Results: Twenty-four participants with cerebral sinovenous thrombosis were enrolled (67% male, 21% neonates). Headache was the most common presenting symptom in non-neonates (47%, nine of 19). Nine (37.5%) presented with acute symptomatic seizures. Six (25%; 95% confidence interval, 10% to 47%) developed epilepsy by one-year follow-up. No clinical predictors associated with epilepsy were identified. King's Outcome Scale for Childhood Head Injury and modified Rankin scores at one year were favorable in 71%. Half of the patients who developed epilepsy (three of six) did not have infarcts, hemorrhage, or seizures identified during the acute hospitalization.Conclusion: Our study provides a prospective estimate that epilepsy occurs in approximately one-quarter of patients by one year after diagnosis of cerebral sinovenous thrombosis. Later epilepsy can develop in the absence of acute seizures or parenchymal injury associated with the acute presentation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Perinatal stroke causes lifelong motor disability, affecting independence and quality of life. Non-invasive neuromodulation interventions such as transcranial direct current stimulation (tDCS) combined with intensive therapy may improve motor function in adult stroke hemiparesis but is under-explored in children. Measuring cortical metabolites with proton magnetic resonance spectroscopy (MRS) can inform cortical neurobiology in perinatal stroke but how these change with neuromodulation is yet to be explored. Methods A double-blind, sham-controlled, randomized clinical trial tested whether tDCS could enhance intensive motor learning therapy in hemiparetic children. Ten days of customized, goal-directed therapy was paired with cathodal tDCS over contralesional primary motor cortex (M1, 20 min, 1.0 mA, 0.04 mA/cm 2 ) or sham. Motor outcomes were assessed using validated measures. Neuronal metabolites in both M1s were measured before and after intervention using fMRI-guided short-echo 3T MRS. Results Fifteen children [age(range) = 12.1(6.6–18.3) years] were studied. Motor performance improved in both groups and tDCS was associated with greater goal achievement. After cathodal tDCS, the non-lesioned M1 showed decreases in glutamate/glutamine and creatine while no metabolite changes occurred with sham tDCS. Lesioned M1 metabolite concentrations did not change post-intervention. Baseline function was highly correlated with lesioned M1 metabolite concentrations ( N -acetyl-aspartate, choline, creatine, glutamate/glutamine). These correlations consistently increased in strength following intervention. Metabolite changes were not correlated with motor function change. Baseline lesioned M1 creatine and choline levels were associated with clinical response. Conclusions MRS metabolite levels and changes may reflect mechanisms of tDCS-related M1 plasticity and response biomarkers in hemiparetic children with perinatal stroke undergoing intensive neurorehabilitation. [ABSTRACT FROM AUTHOR]

Background: Pediatric arterial ischemic stroke remains incompletely understood. Population-based epidemiological data inform clinical trial design but are scant in this condition. We aimed to determine age-specific epidemiological characteristics of arterial ischemic stroke in neonates (birth to 28 days) and older children (29 days to 18 years).Methods: We conducted a 16-year, prospective, national population-based study, the Canadian Pediatric Ischemic Stroke Registry, across all 16 Canadian acute care children's hospitals. We prospectively enrolled children with arterial ischemic stroke from January 1992 to December 2001 and documented disease incidence, presentations, risk factors, and treatments. Study outcomes were assessed throughout 2008, including abnormal clinical outcomes (stroke-related death or neurological deficit) and recurrent arterial ischemic stroke or transient ischemic attack.Results: Among 1129 children enrolled with arterial ischemic stroke, stroke incidence was 1.72/100,000/year, (neonates 10.2/100,000 live births). Detailed clinical and radiological information were available for 933 children (232 neonates and 701 older children, 55% male). The predominant clinical presentations were seizures in neonates (88%), focal deficits in older children (77%), and diffuse neurological signs (54%) in both. Among neonates, 44% had no discernible risk factors. In older children, arteriopathy (49% of patients with vascular imaging), cardiac disorders (28%), and prothrombotic disorders (35% of patients tested) predominated. Antithrombotic treatment increased during the study period (P < 0.001). Stroke-specific mortality was 5%. Outcomes included neurological deficits in 60% of neonates and 70% of older children. Among neonates, deficits emerged during follow-up in 39%. Overall, an initially decreased level of consciousness, a nonspecific systemic presentation, and the presence of stroke risk factors predicted abnormal outcomes. For neonates, predictors were decreased level of consciousness, nonspecific systemic presentation, and basal ganglia infarcts. For older children, predictors were initial seizures, nonspecific systemic presentation, risk factors, and lack of antithrombotic treatment. Recurrent arterial ischemic stroke or transient ischemic attack developed in 12% of older children and was predicted by arteriopathy, presentation without seizures, and lack of antithrombotic treatment. Emerging deficit was predicted by neonatal age at stroke and by cardiac disease.Conclusions: This national data set provides a population-based disease incidence rate and demonstrates the protective effect of antithrombotic treatment in older children, and frequent long-term emerging deficits in neonates and in children with cardiac disorders. Further clinical trials are required to develop effective age-appropriate treatments for children with acute arterial ischemic stroke. [ABSTRACT FROM AUTHOR]

Introduction Mild traumatic brain injury (mTBI) outcomes are variable, and 10–15% may suffer from prolonged symptoms beyond 3 months that impair the child's return to normal activities. Neurophysiological mechanisms of mTBI are incompletely understood, particularly in children, but alterations in cortical excitability have been proposed to underlie post-concussion syndrome. Improved understanding is required to advance interventions and improve outcomes. Objective/Hypothesis To determine if cortical excitability is altered in children with mTBI, and its association with clinical symptoms. Methods This was a cross-sectional controlled cohort study. School-aged children (8–18 years) with mTBI were compared to healthy controls. Cortical excitability was measured using multiple TMS paradigms in children with (symptomatic) and without (recovered) persistent symptoms one-month post-injury. Primary outcome was the cortical silent period (cSP), a potential neurophysiological biomarker of GABAergic inhibition. Secondary outcomes included additional TMS neurophysiology, safety and tolerability. Associations between neurophysiology parameters and clinical symptoms were evaluated. Results Fifty-three children with mTBI (55% male; mean age 14.1 SD: 2.4 years; 35 symptomatic and 27 asymptomatic participants) and 28 controls (46% male; mean age 14.3 SD: 3.1 years) were enrolled. cSP duration was similar between groups (F (2, 73) = 0.55, p = 0.582). Log 10 long interval intracortical inhibition (LICI) was reduced in symptomatic participants compared to healthy controls (F (2, 59) = 3.83, p = 0.027). Procedures were well tolerated with no serious adverse events. Conclusions TMS measures of cortical excitability are altered at one month in children with mTBI. Long interval cortical inhibition is decreased in children who remain symptomatic at one month post-injury. [ABSTRACT FROM AUTHOR]

Applications of non-invasive brain stimulation including therapeutic neuromodulation are expanding at an alarming rate. Increasingly established scientific principles, including directional modulation of well-informed cortical targets, are advancing clinical trial development. However, high levels of disease burden coupled with zealous enthusiasm may be getting ahead of rational research and evidence. Experience is limited in the developing brain where additional issues must be considered. Properly designed and meticulously executed clinical trials are essential and required to advance and optimize the potential of non-invasive neuromodulation without risking the well-being of children and families. Perinatal stroke causes most hemiplegic cerebral palsy and, as a focal injury of defined timing in an otherwise healthy brain, is an ideal human model of developmental plasticity. Advanced models of how the motor systems of young brains develop following early stroke are affording novel windows of opportunity for neuromodulation clinical trials, possibly directing neuroplasticity toward better outcomes. Reviewing the principles of clinical trial design relevant to neuromodulation and using perinatal stroke as a model, this article reviews the current and future issues of advancing such trials in children. [ABSTRACT FROM AUTHOR]

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose–response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3–13 A/m 2 ) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations. [ABSTRACT FROM AUTHOR]

Summary Stroke occurs across the lifespan with unique issues in the fetus, neonate, and child. The past decade has seen substantial advances in paediatric stroke research and clinical care, but many unanswered questions and controversies remain. The pathobiology of perinatal stroke needs to be better understood if prevention strategies are to be realised. Similarly, enhanced understanding of the mechanisms underlying childhood stroke, including cerebral arteriopathies, could inform the development of mechanism-specific treatments. Emerging clinical trials, including studies of neonatal sinovenous thrombosis and childhood arterial stroke, offer the hope of evidence-based treatment options in the near future. Early recognition of stroke in children is a key educational target for both the public and health-care professionals, and has translational potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after stroke onset, improving outcomes and quality of life for affected children and their families. [ABSTRACT FROM AUTHOR]

Background Professional societies recommend screening lipids in healthy children. Dyslipidemia and elevated lipoprotein(a) are risk factors for adult cardiovascular disease and stroke. Their role in childhood arterial ischemic stroke is unexplored. Inconsistencies in testing limit analysis of existing lipid data. The objective of this study is to identify predictors and modifiable barriers to lipid testing in pediatric stroke. Methods In this cross-sectional analysis, children (28 days-18 years) with arterial ischemic stroke were identified from the International Pediatric Stroke Study registry (January 2003-April 2012). Analyzed predictors of recorded lipid or lipoprotein a (Lp(a)) testing were age, sex, race, ethnicity, body mass index (BMI) category, other stroke risk factors, country, US region, and recurrent thrombosis. Results Among 1652 participants (median, 6 years [interquartile range, 1.7-12.7]; 59.0% male; 40.8% white; 7.0% black), at least 1 lipid parameter or Lp (a) was available for 461 (27.9%). Compared with infants, testing was incrementally higher for older age categories. Compared with whites, testing was lower in blacks (adjusted odds ratio [OR], .5; 95% confidence interval [CI], .4-.5; P < .0001). Hispanic ethnicity only predicted testing within the United States (OR, 2.2; 95% CI, 1.4-3.4; P = .001]. Testing was lower in the United States and Australia and higher in Chile. Any thrombotic recurrence and recurrent symptomatic arterial ischemic stroke were associated with testing, unlike male sex, BMI, other stroke risk factors, and region in the United States. Conclusions Only a quarter of children with stroke had recorded lipid testing. Older age, white race, and recurrence predicted testing. In future study adjusting for these predictors may be necessary. Standardized lipid testing in children with arterial ischemic stroke may further our understanding of this potential risk factor. [ABSTRACT FROM AUTHOR]

The objective of this paper is to (1) identify from the literature a potential critical period for the maturation of the corticospinal tract (CST) and (2) report pilot data on an intensive, activity-based therapy applied during this period, in children with lesions to the CST. The best estimate of the CST critical period for the legs is when the child is younger than 2 years of age. Previous interventions for walking in children with CST damage were mainly applied after this age. Our preliminary results with training children younger than 2 years showed improvements in walking that exceeded all previous reports. Further, we refined techniques for measuring motor and sensory pathways to and from the legs, so that changes can be measured at this young age. Previous activity-based therapies may have been applied too late in development. A randomized controlled trial is now underway to determine if intensive leg therapy improves the outcome of children with early stroke. [Copyright &y& Elsevier]

The permanent nature of motor deficits is a consistent cornerstone of cerebral palsy definitions. Such pessimism is disheartening to children, families, and researchers alike and may no longer be appropriate for it ignores the fantastic plastic potential of the developing brain. Perinatal stroke is presented as the ideal human model of developmental neuroplasticity following distinct, well-defined, focal perinatal brain injury. Elegant animal models are merging with human applied technology methods, including noninvasive brain stimulation for increasingly sophisticated models of plastic motor development following perinatal stroke. In this article, how potential central therapeutic targets are identified and potentially modulated to enhance motor function within these models is discussed. Also, future directions and emerging clinical trials are reviewed. [Copyright &y& Elsevier]

Abstract: Perinatal stroke is presented as the ideal human model of developmental neuroplasticity. The precise timing, mechanisms, and locations of specific perinatal stroke diseases provide common examples of well defined, focal, perinatal brain injuries. Motor disability (hemiparetic cerebral palsy) constitutes the primary adverse outcome and the focus of models explaining how motor systems develop in health and after early injury. Combining basic science animal work with human applied technology (functional magnetic resonance imaging, diffusion tensor imaging, and transcranial magnetic stimulation), a model of plastic motor development after perinatal stroke is presented. Potential central therapeutic targets are revealed. The means to measure and modulate these targets, including evidence-based rehabilitation therapies and noninvasive brain stimulation, are suggested. Implications for clinical trials and future directions are discussed. [Copyright &y& Elsevier]

Abstract: Arteriopathy is the leading cause of childhood arterial ischemic stroke, but its mechanisms are poorly understood. This review explores the possible role of inflammatory mechanisms and evidence for inflammatory pathophysiology in specific pediatric cerebral arteriopathies. Pathologically proven small-vessel central nervous system vasculitis provides a definitive inflammatory model where available treatments are likely improving outcomes. In contrast, a common large-vessel arteriopathy presents many features suggestive of inflammation, but definitive proof remains elusive. Recent advances and future research directions, including biomarker, neuroimaging, and pathologic approaches and how they might address these important clinical questions, are discussed. [Copyright &y& Elsevier]

Abstract: Objective: Arterial ischemic stroke (AIS) causes disability in children but plastic developmental neurophysiology is unstudied. Imbalance of interhemispheric inhibition (IHI) in adult subcortical stroke is a therapeutic target. We hypothesized that IHI imbalance occurs in childhood AIS and is modifiable by rTMS. Methods: Eligible SickKids Children’s Stroke Program patients included children >7years with subcortical AIS (>2years previous) and functional hand impairment. TMS with electromyography over first dorsal interosseous measured baseline motor cortex (M1) rest and 1mV thresholds and stimulus–response curves (100–150%). Paired-pulse TMS studied bidirectional short (SIHI) and long (LIHI) interval IHI. Children were matched for age/weakness and randomized to contralesional inhibitory rTMS or sham (8days) with measures repeated. Results: Ten children (mean 13.9 years) had variable weakness (4 mild/2 moderate/4 severe). Stroke M1 motor thresholds were elevated (75±25% versus 55±14%, p =0.05) and decreased with age. Baseline measures suggested excessive LIHI from non-stroke to stroke side (−46±17% versus −28±23%, p =0.08). Following inhibitory rTMS, increases in stroke side maximal MEP amplitudes were suggested and LIHI from stroke to non-stroke side appeared to increase (−20% to −40%). Procedures were well tolerated. Conclusion: TMS measurement of developmental plastic organization and rTMS interventions are feasible in childhood stroke and IHI imbalance may occur. Significance: Improved understanding of developmental plasticity after childhood stroke will facilitate better rehabilitational therapy. [ABSTRACT FROM AUTHOR]

Increasingly distinct patterns of focal ischemic injury in the fetal and perinatal brain are recognized. Improved classification has afforded advances in risk factor identification, pathophysiology hypotheses, outcome prediction, and potential avenues for intervention. Cerebrovascular occlusion leading to perinatal stroke may be arterial or venous, symptomatic or subclinical, and it can occur across multiple time frames. Distinguishing causative factors from mere associations represents a major challenge with important implications for studies of pathogenesis. The adverse outcomes suffered by most children highlight the need for further research. Reviewed here are the current understandings, recent advancements, and future directions for research in perinatal ischemic stroke. [Copyright &y& Elsevier]

Summary: Background: Arterial ischaemic stroke (AIS) can cause disabling hemiparesis in children. We aimed to test whether contralesional, inhibitory repetitive transcranial magnetic stimulation (rTMS) could affect interhemispheric inhibition to improve hand function in chronic subcortical paediatric AIS. Methods: Patients were eligible for this parallel, randomised trial if they were in the SickKids Children''s Stroke Program and had subcortical AIS more than 2 years previously, had transcallosal sparing, were more than 7 years of age, had hand motor impairment, had no seizures or dyskinesia, and were taking no drugs that alter cortical excitability. Patients were paired for age and weakness and were randomised within each pair to sham treatment or inhibitory, low-frequency rTMS over contralesional motor cortex (20 min, 1200 stimuli) once per day for 8 days. An occupational therapist did standardised tests of hand function at days 1 (baseline), 5, 10, and 17 (1 week post-treatment), and the primary outcomes were changes in grip strength and the Melbourne assessment of upper extremity function (MAUEF) between baseline and day 10. Patients, parents, and occupational therapists were blinded to treatment allocation. Analysis was per protocol. Findings: Ten patients with paediatric stroke were enrolled (median age 13·25 [IQR 10·08–16·78] years, mean time post-stroke 6·33 [SD 3·56] years): four with mild weakness, two with moderate weakness, and four with severe weakness. A repeated-measures ANOVA showed a significant interaction between time and the effect of treatment on grip strength (p=0·03). At day 10, grip strength was 2·28 (SD 1·01) kg greater than baseline in the rTMS group and 2·92 (1·20) kg less than baseline in the sham group (p=0·009). Benefits in mean grip strength persisted at day 17 (2·63 [0·56] kg greater than baseline with rTMS and 1·00 [0·70] kg less than baseline with sham treatment; p=0·01). Day 10 MAUEF score improved by more in the rTMS group than in the sham group (7·25 [3·8] vs 0·79 [1·3] points greater than baseline; p=0·002), but this benefit did not persist to day 17. Function of the unaffected hand remained stable. rTMS was well tolerated with no serious adverse events. Interpretation: Contralesional inhibitory rTMS was safe and feasible for patients with paediatric subcortical AIS, and seemed to improve hand function in patients with hemiparesis. Further studies are required to confirm the potential role of rTMS in paediatric neurorehabilitation. Funding: Canadian Stroke Consortium; Canadian Institutes of Health Research; American Academy of Neurology Foundation; Alberta Heritage Foundation for Medical Research. [Copyright &y& Elsevier]

To identify if a predetermined set of potential risk factors are associated with spastic diplegic cerebral palsy (SDCP) in term-born children. This is a case-control study with cases (n = 134) extracted from the Canadian Cerebral Palsy Registry (CCPR) and controls (n = 1950) from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Our primary variable was the SDCP phenotype in term-born children. Possible risk factors were selected a priori and include extreme maternal age (<19 or >35 years), pregnancy complications, maternal disease, substance use, perinatal infection, mode of delivery, perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia), sex, and birth weight. Multivariable analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Multivariable analysis revealed associations between term-born SDCP and pregnancy complications (OR = 4.73; 95% CI = 1.91 to 10.56), maternal disease (OR = 2.52; 95% CI = 1.57 to 3.93), substance use (OR = 3.11; 95% CI = 2.10 to 4.55), perinatal infection (OR = 2.72; 95% CI 1.32 to 5.10), Caesarean section (OR = 2.35; 95% CI = 1.62 to 3.40), and perinatal adversity (OR = 2.91; 95% CI = 1.94 to 4.50). Multiple regression analysis revealed associations between SDCP and pregnancy complications (OR = 3.28; 95% CI 1.20 to 8.15), maternal disease (OR = 2.52; 95% CI 1.50 to 4.12), substance use (OR = 3.59; 95% CI 2.37 to 5.40), perinatal infection (OR = 3.78, 95% CI 1.71 to 7.72), Caesarean section (OR = 2.72; 95% CI 1.82 to 4.03), and perinatal adversity (OR = 4.16; 95% CI 2.67 to 6.70). Antenatal (pregnancy complications, maternal disease, substance use) and perinatal (infections, Caesarean section, and perinatal adversity) risk factors are associated with an increased risk of SDCP in term-born children, suggesting variable interactions between risk factors to provide a clinicopathologic framework that is different from SDCP observed in preterm-born children. [ABSTRACT FROM AUTHOR]

Objectives: To describe current physician referral practices with respect to age at referral to medical specialists for initial diagnosis of cerebral palsy (CP) and rehabilitation specialists for intervention and to identify factors associated with delayed referral.Study Design: National environmental scan of 455 children diagnosed with CP who were born in Canada between 2008 and 2011, selected from 4 sites within the Canadian CP Registry (Edmonton, Calgary, Toronto, and Montreal). Two sources of information were used-children's medical charts and the population-based registry, which provided corresponding data for each child. Primary outcomes extracted from the charts were age at referral for diagnostic assessment, age at diagnosis, age at referral for rehabilitation services, and age at initial rehabilitation intervention. Twelve variables were explored as potential predictors. Descriptive statistics, bivariate analyses, and multiple linear regressions were conducted.Results: Median age (in months) at referral for diagnostic assessment was 8 (mean: 12.7 ± 14.3), diagnosis 16 (mean: 18.9 ± 12.8), referral for rehabilitation services 10 (mean: 13.4 ± 13.5), and rehabilitation initiation 12 (mean: 15.9 ± 12.9). Lower maternal education, mild severity of motor dysfunction, type of CP, early discharge after birth, and region of residence explained between 20% and 32% of the variance in age at referral for assessment, diagnosis, referral for rehabilitation, and rehabilitation initiation.Conclusions: Findings suggest wide variability exists in the age at which young children with CP are referred to specialists for diagnosis and intervention. User-friendly tools are therefore needed to enhance early detection and referral strategies by primary care practitioners, to ensure early interventions to optimize developmental outcomes and enhance opportunities for neural repair at a younger age. [ABSTRACT FROM AUTHOR]

• Application of anodal tDCS concurrent to surgical training enhances unimanual skill acquisition compared to training alone. • Changes in delta EEG activity in the sensorimotor network are associated with surgical skill improvement. • EEG patterns of unimanual and bimanual surgical skill performance differ, primarily within the parietal cortex. • Anodal tDCS modulated alpha frequency band activity during bimanual surgical skill performance. Transcranial direct-current stimulation (tDCS), an increasingly applied form of non-invasive brain stimulation, can augment the acquisition of motor skills. Motor learning investigations of tDCS are limited to simple skills, where mechanisms are increasingly understood. Investigations of meaningful, complex motor skills possessed by humans, such as surgical skills, are limited. This replication and extension of our previous findings used electroencephalography (EEG) to determine how tDCS and complex surgical training alters electrical activity in the sensorimotor network to enhance complex surgical skill acquisition. In twenty-two participants, EEG was recorded during baseline performance of simulation-based laparoscopic surgical skills. Participants were randomized to receive 20 min of primary motor cortex targeting anodal tDCS or sham concurrent to 1 h of surgical skill training. EEG was reassessed following training, during a post-training repetition of the surgical tasks. Our results replicated our previous study suggesting that compared to sham, anodal tDCS enhanced the acquisition of unimanual surgical skill. Surgical training modulated delta frequency band activity in sensorimotor regions. Next, the performance of unimanual and bimanual skills evoked unique EEG profiles, primarily within the beta frequency-band in parietal regions. Finally, tDCS-paired surgical training independently modulated delta and alpha frequency-bands in sensorimotor regions. Application of tDCS during surgical skill training is feasible, safe and tolerable. In conclusion, we are the first to explore electrical brain activity during performance of surgical skills, how electrical activity may change during surgical training and how tDCS alters the brain to enhance skill acquisition. The results provide preliminary evidence of neural markers that can be targeted by neuromodulation to optimize complex surgical training. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Pediatric applications of transcranial magnetic stimulation are rapidly expanding, but lack the safety data established for adults. Transcranial magnetic stimulation-induced neurocardiogenic syncope may represent an age-dependent adverse event that is essentially undescribed in the transcranial magnetic stimulation literature. We report on 2 adolescents (of 10 children studied) with transcranial magnetic stimulation-related neurocardiogenic syncope, identify modifiable risk factors, and suggest measures to improve the safety of future pediatric transcranial magnetic stimulation studies. [Copyright &y& Elsevier]

Background: Risk factors for pediatric stroke are poorly understood and require study to improve prevention. Total cholesterol and triglyceride values peak to near-adult levels before puberty, a period of increased stroke incidence. The role of lipids in childhood arterial ischemic stroke has been minimally investigated.Methods: We performed a cross-sectional analysis of lipid and Lp(a) concentrations in children with arterial ischemic stroke in the International Pediatric Stroke Study to compare the prevalence of dyslipidemia and high- or low-ranking lipid values in our dataset with reported population values. We analyzed sex, body mass index, race, ethnicity, family history, and stroke risk factors for associations with dyslipidemia, high non-high-density lipoprotein cholesterol, and hypertriglyceridemia.Results: Compared with the National Health and Nutrition Examination Survey, a higher proportion of children ≥5 years with arterial ischemic stroke had dyslipidemia (38.4% versus 21%), high total cholesterol (10.6% versus 7.4%), high non-high-density lipoprotein cholesterol (23.1% versus 8.4%), and low high-density lipoprotein cholesterol (39.8% versus 13.4%). The lipid values that corresponded to one standard deviation above the mean (84th percentile) in multiple published national studies generally corresponded to a lower ranking percentile in children aged five years or older with arterial ischemic stroke. Dyslipidemia was more likely associated with an underweight, overweight, or obese body mass index compared with a healthy weight. Ethnic background and an acute systemic illness were also associated with abnormal lipids.Conclusions: Dyslipidemia and hypertriglyceridemia may be more prevalent in children with arterial ischemic stroke compared with stroke-free children. [ABSTRACT FROM AUTHOR]

Summary Objectives Transcranial magnetic stimulation (TMS) has been used to measure cortical excitability as a functional measurement of corticomotor pathways. Given its potential application as an assessment tool in stroke, we aimed to analyze the correlation of TMS parameters with clinical features in stroke using data from 10 different centers. Methods Data of 341 patients with a clinical diagnosis of stroke were collected from studies assessing cortical excitability using TMS. We used a multivariate regression model in which the baseline cortical excitability parameter “resting Motor Threshold (rMT)” was the main outcome and the demographic, anatomic and clinical characteristics were included as independent variables. Results The variable “severity of motor deficit” consistently remained significant in predicting rMT in the affected hemisphere, with a positive β coefficient, in the multivariate models after sensitive analyses and adjusting for important confounders such as site center. Additionally, we found that the correlations between “age” or “time since stroke” and the rMT in the affected hemisphere were significant, as well as the interaction between “time since stroke” and “severity of motor deficit”. Conclusions We have shown that severity of motor deficit is an important predictor for rMT in the affected hemisphere. Additionally, time since stroke seems to be an effect modifier for the correlation between motor deficit and rMT. In the unaffected motor cortex, these correlations were not significant. We discuss these findings in the context of stroke rehabilitation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Perinatal stroke is a leading cause of cerebral palsy and lifelong disability, although parent and family outcomes have not yet been studied in this specific population. The Alberta Perinatal Stroke Project Parental Outcome Measure was developed as a 26-item questionnaire on the impact of perinatal stroke on parents and families. Methods: The items were derived from expert opinion and scientific literature on issues salient to parents of children with perinatal stroke, including guilt and blame, which are not well captured in existing measures of family impact. Data were collected from 82 mothers and 28 fathers who completed the Parental Outcome Measure and related questionnaires (mean age, 39.5 years; mean child age, 7.4 years). Analyses examined the Parental Outcome Measure's internal consistency, test-retest reliability, validity, and factor structure. Results: The Parental Outcome Measure demonstrated three unique theoretical constructs: Psychosocial Impact, Guilt, and Blame. The Parental Outcome Measure has excellent internal consistency (Cronbach α = 0.91) and very good test-retest reliability more than 2-5 weeks (r = 0.87). Regarding validity, the Parental Outcome Measure is sensitive to condition severity, accounts for additional variance in parent outcomes, and strongly correlates with measures of anxiety, depression, stress, quality of life, family functioning, and parent adjustment. Conclusions: The Parental Outcome Measure contributes to the literature as the first brief measure of family impact designed for parents of children with perinatal stroke. [Copyright &y& Elsevier]

Anti-ganglioside antibodies have been associated with acquired neuropathies, including Guillain-Barré sy-ndrome. We describe a case of acute abducens nerve palsy acquired 2 weeks after symptoms of upper respiratory tract infection and rash in a 6-month-old. Elevated anti-GM2 ganglioside immunoglobulin M antibodies were detected in the serum. The palsy slowly improved over time, although eventually surgical intervention was required. Elevated anti-GM2 immunoglobulin M antibodies have previously been reported in Guillain-Barré syndrome variants involving sensory and cranial neuropathies, but never in isolated unilateral cranial nerve VI mononeuropathy. Anti-ganglioside antibodies may play a role in the pathogenesis of postinfectious isolated abducens palsy in young children. [ABSTRACT FROM AUTHOR]

Mitochondrial encephalopathies may be caused by mutations in the respiratory chain complex I subunit genes. Described here are the cases of two pediatric patients who presented with MELAS-like calcarine lesions in addition to novel, bilateral rolandic lesions and epilepsia partialis continua, secondary to MT-ND3 mutations. Data were collected included neurologic symptoms, serial brain imaging, metabolic evaluations, skeletal muscle biopsies, mitochondrial biochemical and molecular testing. Permission for publication was given by the families. Muscle histology revealed nonspecific changes, with no ragged red or blue or COX-negative fibers. Sequencing of the mitochondrial DNA indicated patient 2 to be homoplasmic in muscle for the mt.10158T>C mutation in the ND3 subunit and Patient 1 to be 75% heteroplasmic for the mt.10191T>C mutation, also in ND3. Bilateral rolandic lesions and epilepsia partialis continua accompanied by suspicion of mitochondrial disease are indications to search for an underlying mutation in the MT-ND3 gene. [Copyright &y& Elsevier]