Rand Askalan

Chickenpox and Stroke in Childhood A Study of Frequency and Causation

Background and Purpose— The purpose of this study was to determine whether infection with varicella is causal for arterial ischemic stroke (AIS) in children. Methods— First, a prospective cohort study was conducted in young children (aged 6 months to 10 years) with AIS at 2 institutions (cohort study). The presence of varicella infection <12 months before AIS was determined and compared with the published frequency of varicella infection in the healthy pediatric population. The clinical and radiographic features of AIS were compared between the varicella and nonvaricella study cohorts. Second, a literature search of varicella-associated AIS was conducted, and the clinical and radiographic features were compared with the study nonvaricella cohort. Results— In the cohort study, 22 (31%) of 70 consecutive children with AIS had a varicella infection in the preceding year compared with 9% in the healthy population. Children in the varicella cohort were more likely to have basal ganglia infarcts (P <0.001), abnormal cerebral vascular imaging (P <0.05), and recurrent AIS or transient ischemic attacks (P <0.05) than those in the nonvaricella cohort. The pooled literature analysis of 51 cases of varicella-associated AIS showed similar findings to the varicella cohort. Conclusion— In young children with AIS, there is a 3-fold increase in preceding varicella infection compared with published population rates, and varicella-associated AIS accounts for nearly one third of childhood AIS. Varicella-associated AIS has characteristic features, including a 2-fold increase in recurrent AIS and transient ischemic attacks. Varicella is an important risk factor for childhood AIS.

Tyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation.

The functional roles of protein tyrosine phosphatases (PTPs) in the developed CNS have been enigmatic. Here we show that striatal enriched tyrosine phosphatase (STEP) is a component of the N-methyl-D-aspartate receptor (NMDAR) complex. Functionally, exogenous STEP depressed NMDAR single-channel activity in excised membrane patches. STEP also depressed NMDAR-mediated synaptic currents whereas inhibiting endogenous STEP enhanced these currents. In hippocampal slices, administering STEP into CA1 neurons did not affect basal glutamatergic transmission evoked by Schaffer collateral stimulation but prevented tetanus-induced long-term potentiation (LTP). Conversely, inhibiting STEP in CA1 neurons enhanced transmission and occluded LTP induction through an NMDAR-, Src-, and Ca(2+)-dependent mechanism. Thus, STEP acts as a tonic brake on synaptic transmission by opposing Src-dependent upregulation of NMDARs.

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.

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.

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.

Cerebral Arteriopathy in Children With Neurofibromatosis Type 1

OBJECTIVE: Cerebrovascular abnormalities are serious but underrecognized complications of neurofibromatosis type 1 (NF1). The aim of this study was to investigate the prevalence, clinical presentation, imaging findings, and prognosis of cerebral arteriopathies in childhood NF1. METHODS: Patients followed at the NF1 clinic at the Hospital for Sick Children, Toronto, Ontario, Canada, between 1990 and 2007 were studied. Patients with confirmed NF1 diagnosis and neuroimaging results were included. All neuroimaging studies were reviewed for the presence of arteriopathy by 2 study pediatric neuroradiologists blinded to clinical information. Clinical records of children with cerebral arteriopathy were reviewed. RESULTS: Among 419 children with confirmed NF1, 266 (63%) received neuroimaging. Among children with neuroimaging results, 17 had cerebral arteriopathy (minimum prevalence rate of 6%). Among the 35 patients who received magnetic resonance angiography (MRA), arteriopathy was more common in patients with NF1 with optic gliomas (11 of 21) compared with those without optic glioma (4 of 14). Forty-seven percent of children developed focal deficits months to years after the diagnosis of the arteriopathy. Follow-up at a mean of 7 years after diagnosis of arteriopathy showed that 35% (6 of 17) had progressive arteriopathy requiring revascularization surgery. Seven patients received aspirin for primary stroke prevention. On retrospective review of imaging studies, a mean delay of 51 months to clinical radiographic reporting of these findings was observed. CONCLUSIONS: The prevalence of cerebral arteriopathy in children with NF1 in this study was at least 6% and was associated with young age and optic glioma. Arteriopathy causes stroke with resultant neurologic deficits. Medical and/or surgical interventions may prevent these complications. Therefore, the addition of vascular imaging (MRA/conventional angiography) to brain imaging studies for early detection of arteriopathy should be considered for children with NF1, particularly young patients with optic glioma.

Stroke recurrence in children with congenital heart disease

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.

A prospective outcome study of neonatal cerebral sinovenous thrombosis.

Neonatal cerebral sinovenous thrombosis is a frequent contributor to neonatal mortality and morbidity. Treatment is controversial, and reported clinical outcomes vary widely. Newborns with radiologically confirmed neonatal cerebral sinovenous thrombosis from 1992 to 2009 were prospectively followed in our Children’s Stroke Clinic for standardized outcomes, including the Pediatric Stroke Outcome Measure. Outcomes were available in 90 of 104 (87%) neonates. Early outcomes included cerebral sinovenous thrombosis-associated death (5) and thrombus propagation (15 [6 associated with new venous infarcts]). Lack of anticoagulation predicted propagation (RR = 13; P = .0007). Complete thrombus recanalization occurred in 90% by 3 months. Late outcomes (median, 2.5 years) were epilepsy (15) and neurological disability (50), which included moderate-severe language (43), sensorimotor (38), and cognitive/behavioral (24) deficits. Overall, 61% had poor outcome (death/any deficit). Concurrent neurological comorbidity at diagnosis (odds ratio = 2.8; P = .029) predicted poor outcome. Clinical trials are urgently needed to establish more effective treatment strategies.

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.

Bacterial endocarditis in a child presenting with acute arterial ischemic stroke: should thrombolytic therapy be absolutely contraindicated?

Thrombolysis is considered to be contraindicated in acute ischemic stroke secondary to infective endocarditis (IE). We report a 12‐year‐old female who presented with acute dense right hemiparesis and aphasia. Cranial magnetic resonance imaging and angiography showed multiple diffusion‐restricted lesions in the left hemisphere and absence of flow in the left internal carotid artery. She was treated with intra‐arterial tissue plasminogen activator within 6 hours of her presentation. Subsequently she was diagnosed with pneumococcal endocarditis and underwent debridement of vegetations and patch repair of the mitral valve. The patient did not have hemorrhagic complications following thrombolytic therapy or surgery. Pathological analysis of the mitral valve vegetations revealed mostly fibrin thrombus. Follow‐up imaging showed complete recanalization of the left internal carotid artery, and the patient had a remarkable neurological recovery. This is the first case report of successful intra‐arterial thrombolytic therapy in childhood IE‐related stroke. We believe that thrombolytic therapy contributed to a favorable outcome in our patient and may be safe in selected patients with childhood IE‐related acute ischemic stroke.