Recurrent stroke: the role of thrombophilia in a large international pediatric stroke population.

Risk factors for arterial ischemic stroke in children include vasculopathy and prothrombotic risk factors but their relative importance to recurrent stroke is uncertain. Data on recurrent stroke from databases held in Canada (Toronto), Germany (Kiel-Lübeck/Münster), and the UK (London/Southampton) were pooled. Data were available from 894 patients aged 1 month to 18 years at first stroke (median age, 6 years) with a median follow-up of 35 months. Among these 894 patients, 160 (17.9%) had a recurrence between 1 day and 136 months after the first stroke (median, 3.1 months). Among 288 children with vasculopathy, recurrence was significantly more common [hazard ratio (HR) 2.5, 95% confidence interval (95% CI) 1.92-3.5] compared to the rate in children without vasculopathy. Adjusting for vasculopathy, isolated antithrombin deficiency (HR 3.9; 95% CI: 1.4-10.9), isolated elevated lipoprotein (a) (HR 2.3; 95% CI: 1.3-4.1), and the presence of more than one prothrombotic risk factor (HR 1.9; 95% CI: 1.12-3.2) were independently associated with an increased risk of recurrence. Recurrence rates calculated per 100 person-years were 10 (95% CI: 3-24) for antithrombin deficiency, 6 (95% CI: 4-9) for elevated lipoprotein (a), and 13 (95% CI: 7-20) for the presence of more than one prothrombotic risk factor. Identifying children at increased risk of a second stroke is important in order to intensify measures aimed at preventing such recurrences.

Arterial Wall Imaging in Pediatric Stroke.

BACKGROUND AND PURPOSE: Arteriopathy is common in childhood arterial ischemic stroke (AIS) and predicts stroke recurrence. Currently available vascular imaging techniques mainly image the arterial lumen rather than the vessel wall and have a limited ability to differentiate among common arteriopathies. We aimed to investigate the value of a magnetic resonance imaging-based technique, namely noninvasive arterial wall imaging (AWI), for distinguishing among arteriopathy subtypes in a consecutive cohort of children presenting with AIS. METHODS: Children with confirmed AIS and magnetic resonance angiography underwent 3-Tesla AWI including T1-weighted 2-dimensional fluid-attenuated inversion recovery fast spin echo sequences pre- and post-gadolinium contrast. AWI characteristics, including wall enhancement, wall thickening, and luminal stenosis, were documented for all. RESULTS: Twenty-six children with AIS had AWI. Of these, 9 (35%) had AWI enhancement. AWI enhancement was associated with anterior circulation magnetic resonance angiography abnormality and cortical infarction in 8 of 9 (89%) children and normal magnetic resonance angiography with posterior circulation subcortical infarction in 1 (1 of 9; 11%) child. AWI enhancement was not seen in 17 (65%), 10 (59%) of whom had an abnormal magnetic resonance angiography. Distinct patterns of pre- and postcontrast signal abnormality were demonstrated in the vessel wall in the region of interest in children with transient cerebral arteriopathy, arterial dissection, primary central nervous system angiitis, dissecting aneurysm, and cardioembolic stroke. CONCLUSIONS: AWI is a noninvasive, high-resolution magnetic resonance AWI technique, which can be successfully used in children presenting with AIS. Patterns of AWI enhancement are recognizable and associated with specific AIS pathogeneses. Further studies are required to assess the additional diagnostic utility of AWI over routine vascular imaging techniques, in childhood AIS.

Spatial gene expression analysis of neuroanatomical differences in mouse models.

MRI is a powerful modality to detect neuroanatomical differences that result from mutations and treatments. Knowing which genes drive these differences is important in understanding etiology, but candidate genes are often difficult to identify. We tested whether spatial gene expression data from the Allen Brain Institute can be used to inform us about genes that cause neuroanatomical differences. For many single-gene-mutation mouse models, we found that affected neuroanatomy was not strongly associated with the spatial expression of the altered gene and there are specific caveats for each model. However, among models with significant neuroanatomical differences from their wildtype controls, the mutated genes had preferential spatial expression in affected neuroanatomy. In mice exposed to environmental enrichment, candidate genes could be identified by a genome-wide search for genes with preferential spatial expression in the altered neuroanatomical regions. These candidates have functions related to learning and plasticity. We demonstrate that spatial gene expression of single-genes is a poor predictor of altered neuroanatomy, but altered neuroanatomy can identify candidate genes responsible for neuroanatomical phenotypes.

Utility of Neurovascular Imaging in Acute Neonatal Arterial Ischemic Stroke.

OBJECTIVE: To evaluate the prevalence of magnetic resonance angiography (MRA) findings and clinically characterize neonates with arterial ischemic stroke (AIS) who have abnormal or variable vasculature. STUDY DESIGN: This was a single-center, retrospective study of patients with neonatal stroke from 1991 to 2012. We reviewed charts and neuroimaging, including MRA, in neonates with AIS. Clinical data of patients with MRA findings were compared with the control group of neonates with AIS and a normal MRA. RESULTS: We identified 142 cases of neonatal AIS, of which 81 patients had magnetic resonance imaging and MRA. Among the neonates with arterial neuroimaging, 29 had arterial findings (for a prevalence rate of 20%-35%). The majority of the findings were stenotic or hypoplastic branches. Two patients had presumed carotid artery dissection. Low Apgar scores and the presence of sepsis were significantly (P <.05) more common in neonates with MRA findings. CONCLUSION: The prevalence of arterial abnormalities or variations in neonatal AIS has been underestimated because neurovascular imaging is often not performed. We recommend an MRA for neonates with AIS, particularly those who have low Apgar scores and/or sepsis, to rule out a vasculopathy that may warrant therapeutic intervention.

A pediatric institutional acute stroke protocol improves timely access to stroke treatment.

AIM: We aimed to evaluate whether an institutional acute stroke protocol (ASP) could accelerate the diagnosis and secondary treatment of pediatric stroke. METHOD: We initiated an ASP in 2005. We compared 209 children (125 males, 84 females; median age 4.8y, interquartile range [IQR] 1.2-9.3y, range 0.09-17.7y) diagnosed with arterial ischemic stroke 'pre-protocol' (1992-2004) to 112 children (60 males, 52 females; median age 5.8y, IQR 1.0-11.4y, range 0.08-17.7y) diagnosed 'post-protocol' (2005-2012) for time-to-diagnosis, mode of diagnostic imaging, and time-to-treatment with antithrombotic medication (aspirin or anticoagulants). RESULTS: Overall, the interval from symptom onset to diagnosis was similar post-protocol compared to pre-protocol (20.3 vs 22.7h; p=0.109), although mild strokes (Pediatric National Institute of Health Stroke Scale [PedNIHSS] 0-4), were diagnosed faster post-protocol (12.1 vs 36.3h; p=0.003). Magnetic resonance imaging (MRI) was the initial diagnostic modality more often post-protocol (25% vs 1.4%; p<0.001). Initial MRI was more accurate for diagnosing stroke than initial CT (100% vs 47%; p<0.001) with similar time-to-diagnosis. The proportion of children receiving antithrombotic medication within 24 hours doubled in the post-protocol period (83% vs 36%; p<0.001). INTERPRETATION: A pediatric ASP accelerated time-to-treatment, time-to-diagnosis in children with subtle strokes, and increased MRI as initial imaging, reducing the need for computed tomography. Implementing optimized ASPs can facilitate more timely access to diagnosis and management of children with acute stroke.

Late-onset group B streptococcal meningitis has cerebrovascular complications.

OBJECTIVE: To describe cerebrovascular diseases related to late-onset group B Streptococcus (GBS) meningitis. STUDY DESIGN: Retrospective case series. Patients treated for cerebrovascular complication of late-onset GBS meningitis over 5 years were identified through neuroradiology and microbiology databases. Patient charts were reviewed with regard to clinical presentation, laboratory findings, including GBS subtype, treatment, clinical course, and outcome. Cerebral magnetic resonance imaging was reviewed with special emphasis on stroke pattern and cerebrovascular findings. RESULTS: Fourteen patients were identified. In 6 out of 9 patients serotype III was causative and positive for surface protein hvgA in 5. Ten had arterial ischemic stroke accompanied by a cerebral sinovenous thrombosis in 2 patients. Evidence of cerebral vasculopathy was found in 4 cases. The stroke pattern was variable with cortical, multifocal ischemia, basal ganglia involvement, or had a clear territorial arterial infarction. Ten patients were treated with anticoagulation. No significant bleeding complications, and no recurrent strokes occurred. Twelve patients had clinical and/or subclinical seizures. Developmental outcome was good in 8 cases. Six patients had moderate to severe developmental delay. Central nervous system complications included subdural empyema, hydrocephalus, epilepsy, microcephaly, and hemiplegia. CONCLUSIONS: Late-onset GBS meningitis can be complicated by severe cerebrovascular disease, including arterial ischemic stroke and cerebral sinovenous thrombosis. These complications may be underestimated. We recommend a low threshold for cerebral imaging in these cases. Future studies on the exact incidence, the role of GBS subtypes, and on safety and efficiency of preventive anticoagulation therapy are warranted.

Antithrombotic therapy for secondary stroke prevention in bacterial meningitis in children.

OBJECTIVE: To assess the safety and efficacy of antithrombotic therapy (ATT) for secondary stroke prevention of childhood bacterial meningitis. STUDY DESIGN: A retrospective study of cases of stroke associated with bacterial meningitis in 2 pediatric hospitals during a period of 15 years. Patients were included in the study if they were between 28 days and 18 years of age and had at least 2 serial neuroimaging studies during the acute phase of their illness. The safety of ATT was assessed by the presence or absence of intracranial hemorrhage. Efficacy was assessed by the failure in preventing stroke recurrence. Neurologic outcome was determined by the last documented Pediatric Stroke Outcome Measure score. RESULTS: Twenty-two cases of childhood bacterial meningitis complicated by stroke were identified. Six cases were treated with heparin after either initial or recurrent infarction. None of the cases receiving heparin had further recurrence. Aspirin (acetylsalicylic acid [ASA]) was started after the initial or after recurrent infarction in 10 cases. Four (40%) had infarctions on ASA; 3 of these patients subsequently received heparin. In the 14 cases in which no ATT was begun, 8 (57%) had further recurrence of infarction. None of the patients, whether receiving heparin or ASA, had intracranial hemorrhage. CONCLUSION: In this small sample, heparin and ASA appeared to be safe in childhood bacterial meningitis complicated by stroke and may be effective in improving outcome. Heparin may be more effective than aspirin in preventing recurrent infarction.

TLR-3 receptor activation protects the very immature brain from ischemic injury.

BACKGROUND: We have shown that preconditioning by lipopolysaccharide (LPS) will result in 90% reduction in ischemic brain damage in P7 rats. This robust LPS neuroprotection was not observed in P3 or P5 pups (corresponding to human premature infant). LPS is a known Toll-like receptor 4 (TLR-4) ligand. We hypothesized that TLRs other than TLR-4 may mediate preconditioning against cerebral ischemic injury in the developing brain. METHODS: TLR-2, TLR-3, TLR-4, and TLR-9 expression was detected in brain sections from P3, P5, and P7 rats by immuno-staining. In subsequent experiments, P5 rats were randomly assigned to TLR-3 specific agonist, poly I:C, or saline treated group. At 48 h after the injections, hypoxic-ischemic (HI) injury was induced by unilateral carotid artery ligation followed by hypoxia for 65 min. Brains were removed 1 week after HI injury and infarct volumes were compared in H&E stained sections between the two groups. RESULTS: TLR-2 and TLR-3 were highly expressed in brains of P3 and P5 but not in P7 rats. The number of TLR-4 positive cells was lower in P3 and P5 compared to P7 brains (P <0.05). TLR-3 was predominately expressed in P5 pups (P <0.05). There was no significant difference in TLR-9 expression in the three age groups. There was a significant reduction in infarct volume (P=0.01) in poly I:C compared to saline pre-treated P5 pups. Pre-treatment with poly I:C downregulated NF-κB and upregulated IRF3 expression in P5 rat ischemic brains. Pre-treatment with poly I:C did not offer neuroprotection in P7 rat brains. CONCLUSION: TLRs expression and function is developmentally determined. Poly I:C-induced preconditioning against ischemic injury may be mediated by modulation of TLR-3 signaling pathways. This is the first study to show that TLR-3 is expressed in the immature brain and mediates preconditioning against ischemic injury.

Stroke recurrence in children with congenital heart disease.

OBJECTIVE: Pediatric arterial ischemic stroke (AIS) carries an important morbidity and mortality burden. Congenital heart disease (CHD) is among the most important risk factors for pediatric AIS. Data on stroke recurrence in childhood CHD are lacking, resulting in uncertainty regarding optimal strategies for preventing recurrence. METHODS: In the Canadian Pediatric Ischemic Stroke Registry-Toronto site, we identified children (birth to 18 years) with CHD diagnosed with AIS during 1992-2008. Data were abstracted from both stroke and cardiac surgery databases. Time-dependent outcomes (death and recurrent stroke) following sentinel stroke were parametrically modeled in competing risk analysis. Factors predicting stroke recurrence in parametric survival models were sought in parametric survival model analyses using backward variable selection of variables. RESULTS: A total of 135 patients (19 with recurrence, 116 without recurrence) were studied. In competing risk analysis, 10 years following sentinel stoke, 27% had experienced a stroke recurrence, 26% had died, and 47% were alive and free from recurrence. Stroke recurrence risk decreased over time from sentinel stroke. Approximately 50% of patients were receiving anticoagulation at recurrence. Significant factors associated with recurrence included the presence of a mechanical valve, prothrombotic condition, and an acute infection at the time of sentinel stroke. Hazard of mortality after recurrence was similar to mortality after sentinel stroke (hazard ratio, 1.3; p = 0.75). INTERPRETATION: Stroke recurrence was relatively common in neonates and children with CHD. Identified groups of patients at increased risk may require more aggressive secondary prophylaxis, especially in the early poststroke period.

Association between radiographic Wallerian degeneration and neuropathological changes post childhood stroke.

AIM: Wallerian degeneration is a radiological finding thought to reflect corticospinal tract degeneration. This finding on magnetic resonance imaging (MRI) is routinely used as a predictor of poor prognosis in childhood stroke. However, its validity has never been established. Our objective was to correlate Wallerian degeneration seen on MRI with histopathology. METHOD: We searched the databases of the Department of Pathology and Children's Stroke registry at the Hospital for Sick Children, Toronto for autopsy specimens exhibiting focal infarcts from children born at term who underwent MRI after a stroke. The specimens were examined for Wallerian degeneration and then correlated with the pre-mortem MRI findings. RESULTS: Seven children (four females, three males) with a median age of 11 years (1-17 y) at the time of stroke met the inclusion criteria for this study. Of the seven children included in the study with ischaemic or haemorrhagic infarcts, six had concordant Wallerian degeneration findings on both MRI and post-mortem histopathological examination. The median time between stroke and death was 20 days (3-1825 d). INTERPRETATION: Our results show for the first time that the radiographic finding of Wallerian degeneration is a valid biomarker of corticospinal tract degeneration in children who have had ischaemic or haemorrhagic stroke.

Basilar artery strokes in children: good outcomes with conservative medical treatment.

AIM: To describe outcomes and outcome predictors in childhood basilar artery stroke (BAS). METHOD: We prospectively enrolled children with BAS with or without basilar artery occlusion (BAO) in the Toronto Children's Stroke Registry from 1992 to 2009. We assessed presenting features and outcomes including Pediatric Stroke Outcome Measure scores. RESULTS: Among 578 children with acute arterial ischemic stroke, 27 had BAS (4.6% including neonates, 6% excluding neonates). Twenty-four (14 males, 10 females) children met study criteria (mean age at stroke was 8 y 10 mo; range 0-17 y). Eleven children had BAO. Aspirin or anticoagulation was given to 15 children. None received tissue plasminogen activator or endovascular treatments. At mean follow-up (3 y 2 mo, range 1 mo-11 y 8 mo), 12 had a 'good outcome' (seven normal, five insignificant deficit) and 12 had 'poor outcome' (10 moderate or severe deficit, two acute deaths). Larger infarct size (≥50% of axial brainstem diameter) independently predicted poor outcome (p=0.02; odds ratio 21.2, 95% confidence interval 1.6-274.9) but not BAO, altered level of consciousness, or age. INTERPRETATION: Compared with adults, in childhood BAS death is rare and survivors frequently have good outcomes. Aggressive endovascular interventions may not be justifiable in this population.

The pediatric stroke outcome measure: a validation and reliability study.

BACKGROUND AND PURPOSE: The Pediatric Stroke Outcome Measure (PSOM) is an objective, disease-specific outcome measure containing 115 test items suitable for newborn to adult ages. The PSOM measures neurological deficit and function across 5 subscales: right sensorimotor, left sensorimotor, language production, language comprehension, and cognitive/behavior yielding a final 10-point deficit score. The goal of this study was to examine PSOM construct validity in measuring neurological outcome in pediatric stroke survivors and interrater reliability (IRR) for both prospective and retrospective scoring. METHODS: For construct validity, PSOM subscale scores were correlated with scores on standardized neuropsychological measures matched by functional domain. We assessed IRR by comparing same-day "live" PSOM scores from 2 independent raters in 10 children (prospective IRR) and by comparing PSOM scores estimated from medical dictations across 5 raters in another 10 children (retrospective IRR). RESULTS: We analyzed PSOM scores from 203 children with ischemic stroke. PSOM subscales show good construct validity (ρ=0.2-0.4; P<0.05). PSOM subscale scores of normal/abnormal demonstrate strong agreement for domain-matched neuropsychology scores (alternative chance-corrected statistic=0.4-0.8). IRR was excellent with the 2 prospective raters' scores in almost perfect agreement (intraclass correlation coefficient, 0.93; 95% CI, 0.76-0.98). Retrospective IRR demonstrated strong agreement with an intraclass correlation coefficient of 0.77 (95% CI, 0.56-0.92). CONCLUSIONS: The PSOM is a valid and reliable outcome measure for pediatric stroke. It is useful for retrospective scoring from health records and prospective serial longitudinal outcome assessments and is ideally suited for prospective clinical trials in pediatric stroke.

Intellectual ability and executive function in pediatric moyamoya vasculopathy.

AIM: Moyamoya vasculopathy is characterized by progressive stenosis of the major arteries of the Circle of Willis, resulting in compromised cerebral blood flow and increased risk of stroke. The objectives of the current study were to examine intellectual and executive functioning of children with moyamoya and to evaluate the impact of moyamoya type, stroke (clinical or silent), vasculopathy laterality, and disease duration on neurocognitive abilities. METHOD: Thirty pediatric participants (mean age 10 y 10 mo, SD 4 y; 18 females, 12 males) completed age-appropriate Wechsler Intelligence Scales before any therapeutic revascularization procedures. Reports of executive function were obtained from parents and teachers using the Behavior Rating Index of Executive Function. RESULTS: Children with moyamoya scored significantly lower than the test standardization samples on all indices of intelligence and ratings of executive functioning (p<0.001). Patients did not differ by type of moyamoya or history of stroke. Patients with bilateral disease and stroke scored significantly lower than those with unilateral disease on measures of overall intellectual function (p=0.035) and verbal comprehension (p=0.04). Deficits in metacognitive executive functions were also more pronounced in bilateral patients according to teacher ratings. INTERPRETATION: Children with moyamoya are at risk for intellectual and executive problems, exacerbated by bilateral disease and clinical stroke history.

Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study.

BACKGROUND AND PURPOSE: Stroke is an important cause of death and disability among children. Clinical trials for childhood stroke require a valid and reliable acute clinical stroke scale. We evaluated interrater reliability (IRR) of a pediatric adaptation of the National Institutes of Health Stroke Scale. METHODS: The pediatric adaptation of the National Institutes of Health Stroke Scale was developed by pediatric and adult stroke experts by modifying each item of the adult National Institutes of Health Stroke Scale for children, retaining all examination items and scoring ranges of the National Institutes of Health Stroke Scale. Children 2 to 18 years of age with acute arterial ischemic stroke were enrolled in a prospective cohort study from 15 North American sites from January 2007 to October 2009. Examiners were child neurologists certified in the adult National Institutes of Health Stroke Scale. Each subject was examined daily for 7 days or until discharge. A subset of patients at 3 sites was scored simultaneously and independently by 2 study neurologists. RESULTS: IRR testing was performed in 25 of 113 a median of 3 days (interquartile range, 2 to 4 days) after symptom onset. Patient demographics, total initial pediatric adaptation of the National Institutes of Health Stroke Scale scores, risk factors, and infarct characteristics in the IRR subset were similar to the non-IRR subset. The 2 raters' total scores were identical in 60% and within 1 point in 84%. IRR was excellent as measured by concordance correlation coefficient of 0.97 (95% CI, 0.94 to 0.99); intraclass correlation coefficient of 0.99 (95% CI, 0.97 to 0.99); precision measured by Pearson ρ of 0.97; and accuracy measured by the bias correction factor of 1.0. CONCLUSIONS: There was excellent IRR of the pediatric adaptation of the National Institutes of Health Stroke Scale in a multicenter prospective cohort performed by trained child neurologists.

The effect of postischemic hypothermia on apoptotic cell death in the neonatal rat brain.

BACKGROUND AND OBJECTIVE: Hypothermia is the most effective neuroprotective therapy against ischemic injury in the developing brain. However, the mechanism of hypothermic neuroprotection is not well understood. We sought to investigate whether hypothermia mediates neuroprotection by modulating ischemia-induced apoptosis. METHODS: Seven-day-old rat pups were randomly assigned to either control or hypoxia-ischemia (HI) groups. In the HI group, the internal carotid artery was ligated and cut. This was followed by transient hypoxia at 8% oxygen for 90 min. In the control rats, the internal carotid was isolated but not ligated. Immediately after the hypoxic episode, pups in the HI group were either placed in water baths maintained at 28°C for 24 h (core temperatures at 31°C) or they remained in a normothermic environment. Animals were sacrificed at 24, 48 and 72 h and 1 week after the HI insult. Brain sections were processed for immunohistochemistry and Western blots. RESULTS: Caspase 3 expression was significantly higher in the core compared with the peri-infarct area at all time points in normothermic rats. Hypothermia reduced caspase 3 expression in the core but had little effect in the peri-infarct area. Hypothermia reduced apoptosis-inducing factor translocation to the nucleus in the core and peri-infarct area. Concurrently, X-linked inhibitor of apoptosis (XIAP) expression was significantly potentiated in the hypothermic-ischemic core but not in the peri-infarct area. CONCLUSION: Hypothermic modulation of caspase-dependent apoptosis may be mediated by upregulating XIAP. However, the effect of hypothermia on caspase-independent apoptosis may be mediated by XIAP-independent mechanisms. Importantly, these effects are mediated in both the core and the penumbral regions of ischemic lesion.

Lipopolysaccharide-induced preconditioning against ischemic injury is associated with changes in toll-like receptor 4 expression in the rat developing brain.

Lipopolysaccharide (LPS) preconditioning reduces ischemic injury in adult brain by activating Toll-like receptor 4 (TLR-4). We sought to investigate the effect of brain maturity on the efficacy of LPS preconditioning against hypoxic-ischemic (HI) injury in the developing rat brain. Rat pups at the specified age were randomly assigned to LPS-treated (0.1 mg/kg) or saline-treated groups. HI injury was induced 48 h later by occluding the right common carotid artery followed by transient hypoxia. Brains were removed 1 wk after HI injury, and infarct volumes were compared between the two groups. TLR-4 expression was also compared among different ages. We found that LPS treated P7, P9, and P14 rat pups had significantly smaller infarct volume compared with saline-treated pups (p = 0.006, 0.03, and 0.01, respectively). This significant reduction in infarct volume was not observed in P3 and P5 rats. TLR-4 expression was significantly higher in older rats compared with P3 and P5 rats (p < 0.01). These findings indicate that LPS-induced preconditioning is a robust neuroprotective phenomenon in the ischemic developing brain that is age dependent. Pattern of TLR-4 expression is also affected by brain maturity and likely to be responsible for differences in the efficacy of LPS preconditioning.

Antithrombotic treatment in neonatal cerebral sinovenous thrombosis: results of the International Pediatric Stroke Study.

OBJECTIVE: To identify predictors of antithrombotic treatment in neonates with cerebral sinovenous thrombosis (CSVT) in a large multinational study. STUDY DESIGN: Neonates with CSVT from 10 countries were enrolled in the International Pediatric Stroke Study from 2003 through 2007. Term neonates with CSVT who presented with neurologic symptoms or signs of systemic illness and neuroimaging evidence of thrombus or flow interruption within cerebral venous system were included. RESULTS: Of 341 neonates enrolled, 84 had isolated CSVT. Neuroimaging findings, available in 67/84 neonates, included venous ischemic infarction in 5, hemorrhagic infarction or other intracranial hemorrhage in 13, both infarction and hemorrhage in 26, and no parenchymal lesions in 23. Treatment data, available in 81/84 neonates, included antithrombotic medications in 52% (n = 43), comprising heparin (n = 14), low molecular weight heparin (n = 34), warfarin (n = 1), and aspirin (n = 2). By univariate logistic regression analysis, deep venous system thrombosis (P = .05) and location in the United States (P = .001) predicted nontreatment. Presence of infarction, hemorrhage, dehydration, systemic illness, and age did not predict treatment or nontreatment. In multivariate analysis only geographic location remained significant. CONCLUSIONS: In neonatal CSVT, regional antithrombotic treatment practices demonstrate considerable variability and uncertainty about indications for antithrombotic therapy. Additional studies are warranted.

Cognitive outcome following unilateral arterial ischaemic stroke in childhood: effects of age at stroke and lesion location.

AIM: Plasticity in the developing brain is a controversial issue. Although language and motor function often recover remarkably well following early brain injury, recent evidence suggests that damage to the developing brain results in significant long-term neuropsychological impairment. Our aim was to investigate the relationship among age at injury, lesion location and intellectual outcome. METHOD: Using age-appropriate Wechsler scales of intellectual ability, we explored this issue by evaluating a large group (n=145) of children (89 males, 56 females) who experienced unilateral arterial ischaemic stroke during the perinatal period (diagnosed mean 73d, SD 29d), between the ages of 1 month and 5 years (mean 2y 10mo, SD 1y 9mo), or between the ages of 6 and 16 years (mean 11y 1mo SD 3y 6mo). The mean age at assessment was 8 years (SD 3y 10mo) in the perinatal group, 7 years 5 months (SD 2y 9mo) in the 1 month to 5 years group, and 12 years 5 months (SD 3y 9mo) in the 6 to 16 years group. The mean time interval between stroke and assessment was 8 years (SD 18d) for perinatal, 4 years 6 months (SD 1y 5mo) for 1 month to 5 years, and 1 year 4 months (SD 2y 9mo) for 6 to 16 years. The relationship between age at stroke and lesion location (subcortical, cortical, or combined) as it pertains to cognitive outcome was also examined. RESULTS: Measures of overall intelligence, verbal ability, working memory, and processing speed were significantly lower in children who had had a stroke than in the normative sample (all z>2.5, all p<0.01). The perinatal group performed more poorly than the other two groups on most cognitive measures, regardless of lesion location. The combined lesion location group performed more poorly than those with damage to either cortical or subcortical areas alone. Further investigation revealed different periods of peak vulnerability for subcortical lesions (perinatal) and cortical lesions (1mo-5y). INTERPRETATION: Lesion location modulates the relationship between age at stroke and cognitive outcome.

Late emergence of cognitive deficits after unilateral neonatal stroke.

BACKGROUND AND PURPOSE: Neonatal arterial ischemic stroke (AIS) affects a surprisingly large number of children each year, yet little is known about the long-term neuropsychological implications. METHODS: Using age-appropriate Wechsler scales of intellectual ability, this longitudinal study examined 26 children with a history of acutely diagnosed unilateral neonatal AIS as preschoolers (3 years 6 months to 5 years 11 months) and again as grade-school students (6 years 1 month to 12 years 5 months), and contrasted performance with the normative sample of the test. RESULTS: As preschoolers, patients' performance did not differ from the normative sample for Full Scale IQ, Verbal IQ, or Performance IQ, and there were no significant differences associated with infarct laterality. As school-age children, performance was significantly lower than the normative sample for Full Scale IQ Working Memory and Processing Speed, but not for Verbal IQ or Performance IQ. Contrasts between Time 1 and Time 2 revealed a significant decline in Full Scale IQ, which reflected emerging deficits in nonverbal reasoning, working memory, and processing speed. Individual subject analyses revealed that 69% of the children showed significant declines in 1 or more IQ index measures. We found no significant differences in cognitive performance associated with lesion laterality, though males performed more poorly than females on several cognitive measures at Time 2. CONCLUSIONS: These findings suggest that children with unilateral neonatal stroke, particularly males, are at increased risk for emerging deficits in higher-level cognitive skills during the school years. Continued follow-up of these children is needed, even those with no apparent deficits as toddlers or preschoolers.