Protocol for a cost-utility analysis of neurostimulation and intensive camp-based therapy for children with perinatal stroke and hemiparesis based on a multicentre clinical trial.

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.

Goals of children with unilateral cerebral palsy in a brain stimulation arm rehabilitation trial.

AIM: To explore relationships between category classifications for children's rehabilitation goals, outcomes, and participant characteristics. METHOD: Children with hemiparetic cerebral palsy due to perinatal stroke rated self-selected goals with the Canadian Occupational Performance Measure (COPM) and completed the Assisting Hand Assessment (AHA) and Box and Block Test (BBT), at baseline and 6 months, in a randomized, controlled 10-day neuromodulation rehabilitation trial using repetitive transcranial magnetic stimulation. Goals were classified with the Canadian Model of Occupational Performance and Engagement and the International Classification of Functioning, Disability and Health. Analysis included standard linear regression. RESULTS: Data for 45 participants (mean age 11y 7mo, SD 3y 10mo, range 6-19y, 29 males, 16 females) on 186 goals were included. Self-care goal percentage corresponded with baseline BBT by age (standardized ß=-0.561, p=0.004). Leisure goal percentage corresponded with baseline BBT (standardized ß=0.419, p=0.010). AHA change corresponded with productivity goals (standardized ß=0.327, p=0.029) and age (standardized ß=0.481, p=0.002). COPM change corresponded with baseline COPM and age by AHA change (p<0.05). INTERPRETATION: Younger children with lower motor function were more likely to select self-care goals while those with better function tended to select leisure goals. Functional improvement corresponded with older age and productivity goals. COPM change scores reflected functional improvement among older children. Children chose functionally and developmentally appropriate goals. Consequently, children should be free to set goals that matter to them. WHAT THIS PAPER ADDS: Children in a brain stimulation trial chose divergent upper extremity functional goals. Younger children with lower ability chose more self-care goals. Children with higher ability chose more leisure goals. Older children's goal ratings reflected objective functional motor gains. Children chose goals appropriate to their function and level of development.

Population Based Birth Prevalence of Disease-Specific Perinatal Stroke.

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.

Structural and functional connectivity of motor circuits after perinatal stroke: A machine learning study.

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.

Bihemispheric alterations in myelination in children following unilateral perinatal stroke.

Background: Stroke is a leading cause of perinatal brain injury with variable outcomes including cerebral palsy and epilepsy. The biological processes that underlie these heterogeneous outcomes are poorly understood. Alterations in developmental myelination are recognized as a major determinant of outcome in preterm brain injury but have not been explored in perinatal stroke. We aimed to characterize myelination in hemiparetic children after arterial perinatal stroke, hypothesizing that ipsilesional myelination would be impaired, the degree of which would correlate with poor outcome. Methods: Retrospective, controlled cohort study. Participants were identified through the Alberta Perinatal Stroke Project (APSP), a population-based research cohort (n > 400). Inclusion criteria were: 1) MRI-confirmed, unilateral arterial perinatal stroke, 2) T1-weighted MRI after 6 months of age, 3) absence of other neurological disorders, 4) neurological outcome that included at least one of the following tests - Pediatric Stroke Outcome Measure (PSOM), Assisting Hand Assessment (AHA), Melbourne Assessment (MA), neuropsychological evaluation (NPE), and robotic sensorimotor measurements. FreeSurfer software measured hemispheric asymmetry in myelination intensity (primary outcome). A second method using ImageJ software validated the detection of myelination asymmetry. A repeated measures ANOVA was used to compare perilesional, ipsilesional remote, and contralesional homologous region myelination between stroke cases and typically developing controls. Myelination metrics were compared to clinical outcome measures (t-test, Pearson's correlation). Results: Twenty youth with arterial stroke (mean age: 13.4 ±â€¯4.2yo) and 27 typically developing controls (mean age: 12.5 ±â€¯3.7yo) were studied in FreeSurfer. Participants with stroke demonstrated lower myelination in the ipsilesional hemisphere (p < 0.0001). Myelination in perilesional regions had lower intensity compared to ipsilesional remote areas (p < .00001) and contralesional homologous areas (p < 0.00001). Ipsilesional remote regions had decreased myelination compared to homologous regions on the contralesional hemisphere (p = 0.016). Contralesional myelination was decreased compared to controls (p < 0.00001). Myelination metrics were not strongly associated with clinical motor, robotic sensorimotor, or neuropsychological outcomes though some complex tests requiring speeded responses had moderate effect sizes. Conclusion: Myelination of apparently uninjured brain in both the ipsilesional and contralesional hemispheres is decreased after perinatal stroke. Differences appear to radiate outward from the lesion. Further study is needed to determine clinical significance.

Corticospinal tract diffusion properties and robotic visually guided reaching in children with hemiparetic cerebral palsy.

Perinatal stroke is the leading cause of hemiparetic cerebral palsy (CP), resulting in life-long disability. In this study, we examined the relationship between robotic upper extremity motor impairment and corticospinal tract (CST) diffusion properties. Thirty-three children with unilateral perinatal ischemic stroke (17 arterial, 16 venous) and hemiparesis were recruited from a population-based research cohort. Bilateral CSTs were defined using diffusion tensor imaging (DTI) and four diffusion metrics were quantified: fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivities. Participants completed a visually guided reaching task using the KINARM robot to define 10 movement parameters including movement time and maximum speed. Twenty-six typically developing children underwent the same evaluations. Partial correlations assessed the relationship between robotic reaching and CST diffusion parameters. All diffusion properties of the lesioned CST differed from controls in the arterial group, whereas only FA was reduced in the venous group. Non-lesioned CST diffusion measures were similar between stroke groups and controls. Both stroke groups demonstrated impaired reaching performance. Multiple reaching parameters of the affected limb correlated with lesioned CST diffusion properties. Lower FA and higher MD were associated with greater movement time. Few correlations were observed between non-lesioned CST diffusion and unaffected limb function though FA was associated with reaction time (R = -0.39, p < .01). Diffusion properties of the lesioned CST are altered after perinatal stroke, the degree of which correlates with specific elements of visually guided reaching performance, suggesting specific relevance of CST structural connectivity to clinical motor function in hemiparetic children.

Segmental Diffusion Properties of the Corticospinal Tract and Motor Outcome in Hemiparetic Children With Perinatal Stroke.

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.

Sensory tractography and robot-quantified proprioception in hemiparetic children with perinatal stroke.

Perinatal stroke causes most hemiparetic cerebral palsy, resulting in lifelong disability. We have demonstrated the ability of robots to quantify sensory dysfunction in hemiparetic children but the relationship between such deficits and sensory tract structural connectivity has not been explored. It was aimed to characterize the relationship between the dorsal column medial lemniscus (DCML) pathway connectivity and proprioceptive dysfunction in children with perinatal stroke. Twenty-nine participants (6-19 years old) with MRI-classified, unilateral perinatal ischemic stroke (14 arterial, 15 venous), and upper extremity deficits were recruited from a population-based cohort and compared with 21 healthy controls. Diffusion tensor imaging (DTI) defined DCML tracts and five diffusion properties were quantified: fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, AD), and fiber count. A robotic exoskeleton (KINARM) tested upper limb proprioception in an augmented reality environment. Correlations between robotic measures and sensory tract diffusion parameters were evaluated. Lesioned hemisphere sensory tracts demonstrated lower FA and higher MD, RD, and AD compared with the non-dominant hemisphere of controls. Dominant (contralesional) hemisphere tracts were not different from controls. Both arterial and venous stroke groups demonstrated impairments in proprioception that correlated with lesioned hemisphere DCML tract diffusion properties. Sensory tract connectivity is altered in the lesioned hemisphere of hemiparetic children with perinatal stroke. A correlation between lesioned DCML tract diffusion properties and robotic proprioceptive measures suggests clinical relevance and a possible target for therapeutic intervention. Hum Brain Mapp 38:2424-2440, 2017. © 2017 Wiley Periodicals, Inc.

Clinical Characteristics, Risk Factors, and Outcomes Associated With Neonatal Hemorrhagic Stroke: A Population-Based Case-Control Study.

Importance: Hemorrhage into the brain of term newborns often results in major injury and lifelong disability. The clinical epidemiology of neonatal hemorrhagic stroke (NHS) remains undefined, hindering the development of strategies to improve outcomes. Objective: To characterize the incidence, types, presentations, associated factors, and outcomes of neonatal hemorrhagic stroke. Design, Setting, and Participants: Population-based, nested case-control study. The Alberta Perinatal Stroke Project, a provincial registry, ascertained NHS cases using exhaustive diagnostic code searching (1992-2010, >2500 medical record reviews). Prospective cases were captured through the Calgary Pediatric Stroke Program (2007-2014). Participants included term neonates with magnetic resonance imaging-confirmed NHS including primary and secondary intracerebral hemorrhage, hemorrhagic transformation of ischemic injury, and presumed perinatal hemorrhagic stroke. Control infants with common data were recruited from a population-based study (4 to 1 ratio). Main Outcomes and Measures: Infants with NHS underwent structured medical record review using data-capture forms and blinded scoring of neuroimaging. Clinical risk factor common data elements were explored using logistic regression. Provincial live births were obtained from Statistics Canada. Outcomes were extrapolated to the Pediatric Stroke Outcome Measure. Results: We identified 86 cases: 51 infants (59%) with NHS, of which 32 (67%) were idiopathic, 30 (35%) were hemorrhagic transformation of primary ischemic injuries (14 with neonatal cerebral sinovenous thrombosis, 11 with hypoxic ischemic encephalopathy, and 5 with neonatal arterial ischemic stroke), and 5 were presumed perinatal hemorrhagic stroke. Sixty-two percent were male. Incidence of pure NHS was 1 in 9500 live births and 1 in 6300 for all forms. Most presented in the first week of life with seizures and encephalopathy. Acute neurosurgical intervention was rare (3 of 86 total cases; 3.5%). Temporal lobe was the most common NHS location (16 of 51 pure NHS cases; 31%). A primary cause was evident in 19 of the 51 cases of non-hemorrhagic transformation NHS (37%). Idiopathic NHS was independently associated with lower maternal age (odds ratio [OR], 0.87; 95% CI, 0.78-0.94), primiparity (OR, 2.98; 95% CI, 1.18-7.50), prior spontaneous abortion (OR, 0.11; 95% CI, 0.02-0.53), difficult fetal transition (bradycardia [OR, 15.0; 95% CI, 2.19-101.9] and low Apgar [OR, 14.3; 95% CI, 2.77-73.5]), and small for gestational age (OR, 14.3; 95% CI, 1.62-126.1). Follow-up of 50 cases at a median of 37 months demonstrated poor neurological outcomes in 21 patients (44%). Conclusions and Relevance: Neonatal hemorrhagic stroke is more common than previously reported, occurring in at least 1 in 6300 live births. Etiologies are approximately equally distributed between idiopathic, secondary, and hemorrhagic transformation. Clinical associations do not suggest a common mechanism or predictability of NHS. Recurrence is rare. Outcomes are often poor, mandating attention to prevention and rehabilitation.

Transcranial direct current stimulation for children with perinatal stroke and hemiparesis.

OBJECTIVE: To determine whether the addition of transcranial direct current stimulation (tDCS) to intensive therapy increases motor function in children with perinatal stroke and hemiparetic cerebral palsy. METHODS: This was a randomized, controlled, double-blind clinical trial. Participants were recruited from a population-based cohort with MRI-classified unilateral perinatal stroke, age of 6 to 18 years, and disabling hemiparesis. All completed a goal-directed, peer-supported, 2-week after-school motor learning camp (32 hours of therapy). Participants were randomized 1:1 to 1 mA cathodal tDCS over the contralesional primary motor cortex (M1) for the initial 20 minutes of daily therapy or sham. Primary subjective (Canadian Occupational Performance Measure [COPM]), objective (Assisting Hand Assessment [AHA]), safety, and secondary outcomes were measured at 1 week and 2 months after intervention. Analysis was by intention to treat. RESULTS: Twenty-four participants were randomized (median age 11.8 ± 2.7 years, range 6.7-17.8). COPM performance and satisfaction scores doubled at 1 week with sustained gains at 2 months (p < 0.001). COPM scores increased more with tDCS compared to sham control (p = 0.004). AHA scores demonstrated only mild increases at both time points with no tDCS effects. Procedures were safe and well tolerated with no decrease in either arm function or serious adverse events. CONCLUSION: tDCS trials appear feasible and safe in hemiparetic children. Lack of change in objective motor function may reflect underdosing of therapy. Marked gains in subjective function with tDCS warrant further study. CLINICALTRIALSGOV IDENTIFIER: NCT02170285. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy does not significantly improve motor function as measured by the AHA.

Diffusion imaging of cerebral diaschisis in childhood arterial ischemic stroke.

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.

Treatment of dysphasia with rTMS and language therapy after childhood stroke: Multimodal imaging of plastic change.

Expressive dysphasia accompanies left inferior frontal gyrus (IFG/Broca) injury. Recovery may relate to interhemispheric balance with homologous, contralesional IFG but is unexplored in children. We evaluated effects of inhibitory rTMS to contralesional IFG combined with intensive speech therapy (SLT). A 15year-old, right-handed male incurred a left middle cerebral artery stroke. After 30months, severe non-fluent dysphasia impacted quality of life. Language networks, neuronal metabolism and white matter pathways were explored using MRI. Language function was measured longitudinally. An intensive SLT program was combined with contralesional inhibitory rTMS of right pars triangularis. Procedures were well tolerated. Language function improved persisting to four months. Post-treatment fMRI demonstrated increased left perilesional IFG activations and connectivity at rest. Bilateral changes in inositol and glutamate metabolism were observed. Contralesional, inhibitory rTMS appears safe in childhood stroke-induced dysphasia. We observed clinically significant improvements after SLT coupled with rTMS. Advanced neuroimaging can evaluate intervention-induced plasticity.

Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS Trial.

OBJECTIVE: To determine whether the addition of repetitive transcranial magnetic stimulation (rTMS) and/or constraint-induced movement therapy (CIMT) to intensive therapy increases motor function in children with perinatal stroke and hemiparesis. METHODS: A factorial-design, blinded, randomized controlled trial (clinicaltrials.gov/NCT01189058) assessed rTMS and CIMT effects in hemiparetic children (aged 6-19 years) with MRI-confirmed perinatal stroke. All completed a 2-week, goal-directed, peer-supported motor learning camp randomized to daily rTMS, CIMT, both, or neither. Primary outcomes were the Assisting Hand Assessment and the Canadian Occupational Performance Measure at baseline, and 1 week, 2 and 6 months postintervention. Outcome assessors were blinded to treatment. Interim safety analyses occurred after 12 and 24 participants. Intention-to-treat analysis examined treatment effects over time (linear mixed effects model). RESULTS: All 45 participants completed the trial. Addition of rTMS, CIMT, or both doubled the chances of clinically significant improvement. Assisting Hand Assessment gains at 6 months were additive and largest with rTMS + CIMT (ß coefficient = 5.54 [2.57-8.51], p = 0.0004). The camp alone produced large improvements in Canadian Occupational Performance Measure scores, maximal at 6 months (Cohen d = 1.6, p = 0.002). Quality-of-life scores improved. Interventions were well tolerated and safe with no decrease in function of either hand. CONCLUSIONS: Hemiparetic children participating in intensive, psychosocial rehabilitation programs can achieve sustained functional gains. Addition of CIMT and rTMS increases the chances of improvement. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that combined rTMS and CIMT enhance therapy-induced functional motor gains in children with stroke-induced hemiparetic cerebral palsy.

Arterial Tortuosity: An Imaging Biomarker of Childhood Stroke Pathogenesis?

BACKGROUND AND PURPOSE: Arteriopathy is the leading cause of childhood arterial ischemic stroke. Mechanisms are poorly understood but may include inherent abnormalities of arterial structure. Extracranial dissection is associated with connective tissue disorders in adult stroke. Focal cerebral arteriopathy is a common syndrome where pathophysiology is unknown but may include intracranial dissection or transient cerebral arteriopathy. We aimed to quantify cerebral arterial tortuosity in childhood arterial ischemic stroke, hypothesizing increased tortuosity in dissection. METHODS: Children (1 month to 18 years) with arterial ischemic stroke were recruited within the Vascular Effects of Infection in Pediatric Stroke (VIPS) study with controls from the Calgary Pediatric Stroke Program. Objective, multi-investigator review defined diagnostic categories. A validated imaging software method calculated the mean arterial tortuosity of the major cerebral arteries using 3-dimensional time-of-flight magnetic resonance angiographic source images. Tortuosity of unaffected vessels was compared between children with dissection, transient cerebral arteriopathy, meningitis, moyamoya, cardioembolic strokes, and controls (ANOVA and post hoc Tukey). Trauma-related versus spontaneous dissection was compared (Student t test). RESULTS: One hundred fifteen children were studied (median, 6.8 years; 43% women). Age and sex were similar across groups. Tortuosity means and variances were consistent with validation studies. Tortuosity in controls (1.346±0.074; n=15) was comparable with moyamoya (1.324±0.038; n=15; P=0.998), meningitis (1.348±0.052; n=11; P=0.989), and cardioembolic (1.379±0.056; n=27; P=0.190) cases. Tortuosity was higher in both extracranial dissection (1.404±0.084; n=22; P=0.021) and transient cerebral arteriopathy (1.390±0.040; n=27; P=0.001) children. Tortuosity was not different between traumatic versus spontaneous dissections (P=0.70). CONCLUSIONS: In children with dissection and transient cerebral arteriopathy, cerebral arteries demonstrate increased tortuosity. Quantified arterial tortuosity may represent a clinically relevant imaging biomarker of vascular biology in pediatric stroke.

Reliability and variability of diffusion tensor imaging (DTI) tractography in pediatric epilepsy.

BACKGROUND: Diffusion tensor imaging (DTI) tractography is useful for isolating white matter (WM) trajectories and exploring microstructural integrity. Tractography can be performed on atypical brain anatomy when landmarks are malformed or displaced but has been criticized for its subjectivity even when investigators have advanced anatomical knowledge. Also, little is known about the variability and reliability of tractography as a tool for assessing white matter damage in clinical populations such as children with pediatric epilepsy. METHODS: Children diagnosed with epilepsy [N=43, mean age=11.7 years, standard deviation=3.7 years, 53% male] underwent a DTI sequence (6 directions, 2×2×3 mm voxels). Tractography for six white matter tracts (anterior forceps, fornices, bilateral arcuate fasciculi, and bilateral anterior cingula) was conducted twice by two experienced tractographers. Percent coefficient of variation (CV; for measuring variability) and intraclass correlation coefficients (ICCs; for measuring reliability) were calculated for tract volume and diffusion variables (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]). RESULTS: Diffusion variables showed low variability (CV=2.7-8.8%) and very high reliability (ICC=.97-.99) except for limbic tracts [fornix (ICC=.75-.94); cingulum (ICC=.71-.98)]. Tract volume measurements showed high variability (CV=21.9-62.0%) and moderate reliability (ICC=.54-.99). Overall, tract volume measurements were much more variable and less reliable than diffusion characteristics. Limbic structures showed more variability compared with others. CONCLUSIONS: This suggests that DTI tractography and resulting diffusivity variables can reliably inform on the integrity of WM structures in a clinical sample with pediatric epilepsy and highlights the importance of reporting reliability information in studies that aim to answer clinical questions about WM integrity.

Reduced ipsilesional cortical volumes in fetal periventricular venous infarction.

BACKGROUND AND PURPOSE: Perinatal stroke causes most term-born hemiplegic cerebral palsy. Many suffer additional sequelae. Periventricular venous infarction (PVI) is a common fetal stroke in which isolated subcortical injury may cause only motor deficits. However, cognitive, language, and behavioral deficits also occur. We hypothesized that ipsilesional cortical gray matter volumes are reduced in PVI. METHODS: Children (12 months to 18 years) with MRI-confirmed PVI were identified through the Alberta Perinatal Stroke Project. We developed an MRI method to quantify sectional gray (GM) and white matter (WM) volumes from lesioned and unlesioned (control) hemispheres (OsiriX software). Differences in cortical GM and WM volumes were compared between hemispheres in preselected regions "above" the lesion (middle) and anterior and posterior to this. Outcomes dichotomized for "cortical dysfunction" (cognitive, behavioral, language) and motor deficit severity (Pediatric Stroke Outcome Measure) were compared with GM volumes. RESULTS: Twenty-two children (81% boys; median age, 8 years) were included. Methods demonstrated high intrarater and inter-rater reliabilities (ρ=0.988, ρ=0.943) and minimal observer bias. Ipsilesional GM volume was significantly reduced in the middle (P=0.007) and posterior (P=0.03) regions. Middle ipsilesional WM volumes were reduced (P<0.001). The degree of GM reduction was not associated with cortical dysfunction or severity of motor deficit. CONCLUSIONS: Ipsilesional GM volume is diminished in PVI. Speculative mechanisms include retrograde neuronal degeneration and disrupted migration. Neuropsychological testing of larger samples is required to determine clinical significance.