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Aim: To explore the feasibility and possible effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the supplementary motor area (SMA) on tic severity and motor system neurophysiology in children with Tourette syndrome.Method: Ten children with Tourette syndrome (eight males, two females; 9-15y) participated in this open-label, phase 1 clinical trial. Treatment consisted of 1800 low-frequency (1Hz) neuronavigated robotic rTMS (100% resting motor threshold) to the SMA, bilaterally for 15 sessions. The primary outcome was a change in Yale Global Tic Severity Scale (YGTSS) total score from baseline to posttreatment. Secondary outcome measures included changes in magnetic resonance spectroscopy metabolite concentrations, TMS neurophysiology measures, TMS motor maps, and clinical assessments (anxiety, depression) from baseline to the end of treatment.Results: The YGTSS score decreased from baseline after treatment (p<0.001; Cohen's d=2.9). All procedures were well-tolerated.Interpretation: Robot-driven, neuronavigated bilateral rTMS of the SMA is feasible in children with Tourette syndrome and appears to reduce tic severity. What this paper adds Repetitive transcranial magnetic stimulation (rTMS) is feasible to use in children with Tourette syndrome. rTMS is tolerated by children with Tourette syndrome. Precise targeting of the supplementary motor area using functional magnetic resonance imaging is also feasible in these children. [ABSTRACT FROM AUTHOR]

Background: Perinatal stroke is a leading cause of hemiparetic cerebral palsy and lifelong disability. Neurodevelopmental outcomes are difficult to predict and markers of long-term poor outcome continue to be investigated. Deceleration in growth of head circumference has been associated with worse developmental outcomes in neonatal brain injury. We hypothesized that perinatal stroke would result in decreased rates of head growth during childhood that would be associated with worse developmental outcomes. Methods: Patients with magnetic resonance imaging (MRI)–confirmed neonatal arterial ischemic stroke and arterial presumed perinatal ischemic stroke were identified from a population-based research cohort (Alberta Perinatal Stroke Project). Demographics and occipital-frontal circumference data were collected from medical records. Head growth was compared to typically developing control charts using a 2-tailed t test. The Fisher exact test was used to examine associations between Pediatric Stroke Outcome Measures (PSOM) scores and occipital-frontal head circumference. Results: Three hundred fifteen occipital-frontal head circumference measurements were collected from 102 patients (48 female, 54 male), over a median of 3.2 years (standard deviation = 5.18, range = 0-18.3). After 3 months for female patients and 1 year for male patients, occipital-frontal head circumference deviated and remained below normal growth trajectories (P <.05) with a large effect size (Cohen d >0.8). Poor outcome (PSOM ≥ 1) was associated with smaller occipital-frontal head circumference (P <.05). Conclusion: Head growth deceleration is observed in children with perinatal arterial ischemic stroke and is associated with poor outcome. Head circumference may be a tool to alert clinicians to the potential of abnormal neurologic outcome. [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]

Perinatal stroke injures developing motor systems, resulting in hemiparetic cerebral palsy. Diffusion tensor imaging can explore structural connectivity. We used diffusion tensor imaging to assess corticospinal tract diffusion in hemiparetic children with perinatal stroke. Twenty-eight children (6-18 years) with unilateral stroke underwent diffusion tensor imaging. Four corticospinal tract assessments included full tract, partial tract, minitract and region of interest. Diffusion characteristics (fractional anisotropy, mean, axial, and radial diffusivity) were calculated. Ratios (lesioned/nonlesioned) were compared across segments and to validated long-term motor outcomes (Pediatric Stroke Outcome Measure, Assisting Hand Assessment, Melbourne Assessment). Fractional anisotropy and radial diffusivity ratios decreased as tract size decreased, while mean diffusivity showed consistent symmetry. Poor motor outcomes were associated with lower fractional anisotropy in all segments and radial diffusivity correlated with both Assisting Hand Assessment and Melbourne Assessment. Diffusion imaging of segmented corticospinal tracts is feasible in hemiparetic children with perinatal stroke. Correlations with disability support clinical relevance and utility in model development for personalized rehabilitation. [ABSTRACT FROM AUTHOR]

Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE = 30 ms, voxel = 4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration = 10.8 ± 1.9 vs. 12.0 ± 1.2, P < 0.01], creatine [Cre 8.0 ± 0.9 vs. 7.4 ± 0.9, P < 0.05] and myo-Inositol [Ins 6.5 ± 0.84 vs. 5.8 ± 1.1, P < 0.01]. Lesioned motor cortex NAA and creatine were strongly correlated with motor performance in children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy. Hum Brain Mapp 38:1574-1587, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: Diffusion-weighted imaging magnetic resonance imaging may detect changes in brain structures remote but connected to stroke consistent with neuropathological descriptions of diaschisis. Early diffusion-weighted imaging demonstrates restriction in corticospinal pathways after arterial ischemic stroke of all ages that correlates with motor outcome. Aim/hypothesis: We hypothesized that cerebral diaschisis is measurable in childhood arterial ischemic stroke and explored associations with outcome. Methods: This sub-study of the validation of the Pediatric NIH Stroke Scale study prospectively enrolled children with acute arterial ischemic stroke and both acute and early follow-up (5-14 days) diffusion-weighted imaging. Inclusion criteria were (1) unilateral middle cerebral artery arterial ischemic stroke, (2) acute and subacute diffusion-weighted imaging (b=1000), and (3) 12 month neurological follow-up (Pediatric Stroke Outcome Measure). A validated method using ImageJ software quantified diffusion-weighted imaging diaschisis in anatomically connected structures. Diaschisis measures were corrected for infarct volume, compared to age, imaging timing, and outcomes (Chi square/Fisher, Mann-Whitney test). Results: Nineteen children (53% male, median 8.1 years) had magnetic resonance imaging at medians of 21 and 168 h post-stroke onset. Diaschisis was common and evolved over time, observed in one (5%) on acute but eight (42%) by follow-up diffusion-weighted imaging. Thalamic and callosal diaschisis were most common (5, 26%). Estimates of perilesional diaschisis varied (54±18% of infarct volume). Children with diaschisis tended to be younger (7.02±5.4 vs. 11.82±4.3 years, p=0.08). Total diaschisis score was associated with poor cognitive outcomes (p=0.03). Corticospinal tract diaschisis was associated with motor outcome (p=0.004). Method reliability was excellent. Conclusions: Diffusion-weighted imaging diaschisis occurs in childhood arterial ischemic stroke. Mistaking diaschisis for new areas of infarction carries important clinical implications. Improved recognition and study are required to establish clinical relevance. [ABSTRACT FROM AUTHOR]

Introduction: Large/medium vessel vasculitis is an important etiology of childhood stroke. Early research suggests vessel wall enhancement on postcontrast MRI may be a marker of intracranial vasculitis yet no systematic descriptions of normal periarterial enhancement exist in the literature. The aim was to describe normal periarterial enhancement in the pediatric population. Methods: We included all children who had an MR scan between January 2007 and December 2010, with normal parenchymal imaging, no clinical concern of vasculopathy, and axial and coronal postcontrast fat-saturated T1-weighted images with 3-mm slice thickness. Intensity of periarterial enhancement was graded on a three-point scale by two investigators for all intracranial large and medium arteries. Results: A total of 44 patients aged 4 months to 16 years were included. Inter- and intra-rater reliability in enhancement grading was high (all kappa >0.65). Thin, linear, noncircumferential periarterial enhancement was common and usually symmetrical. It was most commonly prominent in the cavernous and petrous segments of the internal carotid artery and the M1 segment of the middle cerebral artery. Periarterial enhancement was rarely observed at segments surrounded by CSF, including supraclinoid segments of the internal carotid arteries, P1 segments of the posterior cerebral arteries, V4 segments of the vertebral artery, and the basilar arteries. Conclusion: Normal periarterial enhancement is common and usually symmetrical along major intracranial arteries but rarely seen around arterial segments bordered by CSF. Knowledge of these findings may be useful for a sensitive and specific interpretation of MR scans of patients with clinical concerns of vasculitis. [ABSTRACT FROM AUTHOR]

Craniocervical arterial dissection is a frequent cause of childhood arterial ischemic stroke requiring prompt diagnosis and treatment. However, there is no universal guideline for diagnostic cerebrovascular imaging in children. We assessed the role of time-of-flight magnetic resonance angiography in diagnosing craniocervical arterial dissection. We included children (1 month to 18 years) with craniocervical arterial dissection and ischemic stroke from January 1998 to June 2007. Institutional protocol required magnetic resonance imaging (MRI)/ magnetic resonance angiography for all ischemic stroke cases and conventional cerebral angiography if magnetic resonance angiography showed any arteriopathy. Among 233 ischemic stroke cases, craniocervical arterial dissection was diagnosed in 13 patients (5.6%; 10 males), with a mean age of 7.5 years. Initial time-of-flight magnetic resonance angiography missed dissection in 8 patients (61.5%) because the neck vessels were not scanned (n = 2), of suboptimal technique (n = 3), and of diagnostic error (n = 3). T1 fat-saturated MRI and contrast-enhanced magnetic resonance angiography were not performed in 12 patients. If suspicion for arterial dissection is high, T1 fat-saturated neck imaging and contrast-enhanced magnetic resonance angiography should be considered to maximize detection. [ABSTRACT FROM AUTHOR]

This commentary is on the letter to the editor by Debillon et al. on pages 980–981 of this issue. [ABSTRACT FROM AUTHOR]

Background: Detailed kinematics of motor impairment of the contralesional ("affected") and ipsilesional ("unaffected") limbs in children with hemiparetic cerebral palsy are not well understood. We aimed to 1) quantify the kinematics of reaching in both arms of hemiparetic children with perinatal stroke using a robotic exoskeleton, and 2) assess the correlation of kinematic reaching parameters with clinical motor assessments.Methods: This prospective, case-control study involved the Alberta Perinatal Stroke Project, a population-based research cohort, and the Foothills Medical Center Stroke Robotics Laboratory in Calgary, Alberta over a four year period. Prospective cases were collected through the Calgary Stroke Program and included term-born children with magnetic resonance imaging confirmed perinatal ischemic stroke and upper extremity deficits. Control participants were recruited from the community. Participants completed a visually guided reaching task in the KINARM robot with each arm separately, with 10 parameters quantifying motor function. Kinematic measures were compared to clinical assessments and stroke type.Results: Fifty children with perinatal ischemic stroke (28 arterial, mean age: 12.5 ± 3.9 years; 22 venous, mean age: 11.5 ± 3.8 years) and upper extremity deficits were compared to healthy controls (n = 147, mean age: 12.7 ± 3.9 years). Perinatal stroke groups demonstrated contralesional motor impairments compared to controls when reaching out (arterial = 10/10, venous = 8/10), and back (arterial = 10/10, venous = 6/10) with largest errors in reaction time, initial direction error, movement length and time. Ipsilesional impairments were also found when reaching out (arterial = 7/10, venous = 1/10) and back (arterial = 6/10). The arterial group performed worse than venous on both contralesional and ipsilesional parameters. Contralesional reaching parameters showed modest correlations with clinical measures in the arterial group.Conclusions: Robotic assessment of reaching behavior can quantify complex, upper limb dysfunction in children with perinatal ischemic stroke. The ipsilesional, "unaffected" limb is often abnormal and may be a target for therapeutic interventions in stroke-induced hemiparetic cerebral palsy. [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]

Background: Neonatal arterial ischemic stroke is a leading cause of cerebral palsy and lifelong disability. Diffusion-weighted imaging has revolutionized diagnosis and facilitated outcome prognostication in acute neonatal arterial ischemic stroke. Diaschisis refers to changes in brain areas functionally connected but structurally remote from primary injury. We hypothesized that acute diffusion-weighted imaging can quantify cerebral diaschisis and is associated with outcome from neonatal arterial ischemic stroke.Methods: Subjects were identified from a prospective, population-based research cohort (Alberta Perinatal Stroke Project). Inclusion criteria were unilateral middle cerebral artery neonatal arterial ischemic stroke, diffusion-weighted magnetic resonance imaging within 10 days of birth, and more than 12-months follow-up (pediatric stroke outcome measure). Diaschisis was characterized and quantified using a validated software method (ImageJ). Volumetric analysis assessed atrophy of affected structures. Diaschisis scores were corrected for infarct size and compared with outcomes (Mann-Whitney).Results: From 20 eligible neonatal arterial ischemic strokes, two were excluded for poor image quality. Of 18 remaining (61% male, median age 3.2 days), 16 (89%) demonstrated diaschisis. Thalamus (88%) was the most common location in addition to corpus callosum (50%). Age at imaging was not associated with diaschisis. Affected structures demonstrated atrophy on imaging. Long-term outcomes available in 81% (median age 7.5 years) were not associated with diaschisis scores.Conclusions: Cerebral diaschisis occurs in neonatal arterial ischemic stroke and can be quantified with diffusion-weighted imaging. Occurrence is common and should not be mistaken for additional infarction. Determining clinical significance will require larger samples with well-characterized long-term outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

On June 5, 2015 the International Pediatric Stroke Study and the Stroke Imaging Laboratory for Children cohosted a unique workshop focused on developing neuroimaging research in pediatric stroke. Pediatric neurologists, neuroradiologists, interventional neuroradiologists, physicists, nurse practitioners, neuropsychologists, and imaging research scientists from around the world attended this one-day meeting. Our objectives were to (1) establish a group of experts to collaborate in advancing pediatric neuroimaging for stroke, (2) develop consensus clinical and research magnetic resonance imaging protocols for pediatric stroke patients, and (3) develop imaging-based research strategies in pediatric ischemic stroke. This article provides a summary of the meeting proceedings focusing on identified challenges and solutions and outcomes from the meeting. Further details on the workshop contents and outcomes are provided in three additional articles in the current issue of Pediatric Neurology. [ABSTRACT FROM AUTHOR]

Background: Smaller hippocampal volumes, as assessed by magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) indexed alterations in brain metabolites have been identified in adults with major depressive disorder (MDD). Our group has found similar effects in MDD youth. However, this has not been studied in youth with treatment resistant MDD (TRD), nor has the interaction between regional N-acetyl-aspartate and volume deficits. N-acetyl-aspartate is an amino acid in the synthesis pathway of glutamate, and serves a marker of neuronal viability/number.Methods: Fifteen typically developing youth (16-22 years of age; 7 males, 8 females) and eighteen youth with TRD (14-22 years of age; 8 males, 10 females) underwent 1H-MRS and MRI on a 3T scanner. A short echo PRESS protocol was used with voxels in the right and left hippocampi (6mL each). Hippocampal volume was evaluated using FreeSurfer.Results: Compared with the typically developing group, youth with TRD had lower concentrations of N-acetyl-aspartate in the left hippocampus (p=0.004), and a trend for smaller left hippocampal volume (p=0.067). In TRD subjects, hippocampal N-acetyl-aspartate was inversely correlated with left (r=-0.68, p=0.003) but not right hippocampal volume. Right hippocampal glutamate+glutamine was greater in TRD youth compared to typically developing controls (p=0.007).Conclusions: These results suggest a neurochemical and structural deficit in the hippocampi of youth with TRD. These findings fit with the role of N-acetyl-aspartate in glutamate neurotransmission and the effect of glutamate on brain morphology. [ABSTRACT FROM AUTHOR]