Neuroimaging and management advances require review of indications for excluding cerebral venous sinus (sinovenous) thrombosis (CSVT) in children. Our goals were to examine (i) clinical presentations of CSVT, (ii) prothrombotic risk factors and other predisposing events, (iii) clinical and radiological features of brain lesions in CSVT compared with arterial stroke, and (iv) predictors of outcome. We studied 42 children with CSVT from five European paediatric neurology stroke registries. Patients aged from 3 weeks to 13 (median 5.75) years (27 boys; 64%) presented with lethargy, anorexia, headache, vomiting, seizures, focal signs or coma and with CSVT on neuroimaging. Seventeen had prior chronic conditions; of the 25 previously well patients, 23 had recent infections, eight became dehydrated and six had both. Two children had a history compatible with prior CSVT. Anaemia and/or microcytosis (21 probable iron deficiency, five haemolytic, including two with sickle cell disease and one with beta-thalassaemia) was as common (62%) as prothrombotic disorder (13/21 screened). High factor VIII and homozygosity for the thermolabile methylene tetrahydrofolate reductase polymorphism were the commonest prothrombotic disorders. The superficial venous system was involved in 32 patients, the deep in six, and both in four. Data on the 13 children with bland infarction and the 12 with haemorrhage in the context of CSVT were compared with those from 88 children with ischaemic (AIS) and 24 with haemorrhagic (AHS) arterial stroke. In multiple logistic regression, iron deficiency, parietal infarction and lack of caudate involvement independently predicted CSVT rather than arterial disease. Five patients died, three acutely, one after recurrence and one after 6 months being quadriparetic and blind. Follow-up ranged from 0.5 to 10 (median 1) years. Twenty-six patients (62%) had sequelae: pseudotumour cerebri in 12 and cognitive and/or behavioural disabilities in 14, associated with epilepsy in three, hemiparesis in two and visual problems in two. Eighteen patients, including six with haemorrhage, were anticoagulated. Older age [odds ratio (OR) 1.54, 95% confidence limits (CI) 1.12, 2.13, P = 0.008], lack of parenchymal abnormality (OR 0.17, 95% CI 0.02, 1.56, P = 0.1), anticoagulation (OR 24.2, 95% CI 1.96, 299) and lateral and/or sigmoid sinus involvement (OR 16.2, 95% CI 1.62, 161, P = 0.02) were independent predictors of good cognitive outcome, although the last predicted pseudotumour cerebri. Death was associated with coma at presentation. Of 19 patients with follow-up magnetic resonance (MR) venography, three had persistent occlusion, associated with anaemia and longer prodrome. A low threshold for CT or MR venography in children with acute neurological symptoms is essential. Nutritional deficiencies may be modifiable risk factors. A paediatric anticoagulation trial may be required, after the natural history has been further established from registries of cases with and without treatment.
Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia 1 maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northernblot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and β-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.Autosomal recessive periventricular heterotopia with microcephaly (ARPHM) is a severe malformation of the cerebral cortex, characterized by severe developmental delay and recurrent infections 1 . No anomalies extrinsic to the CNS, such as dysmorphic features or grossly abnormal endocrine or other conditions, have been observed in individuals with ARPHM. Magnetic resonance imaging of the brains of affected individuals shows notable periventricular heterotopia, resulting from the failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex ( Fig. 1a-d). Abnormal magnetic resonance image signals in subcortical white matter and elsewhere also suggest a delay in the normal myelination by glial cells.An initial genome-wide screen at 10-cM intervals of two Turkish families with ARPHM identified shared homozygosity at a single locus on chromosome 20q11.21-13.2, which we refined by further marker analysis (Fig. 1e,f). Because the two families had indistinguishable clinical and radiographic features, we assumed that they had an allelic disorder and summed their linkage results. The ARPHM region (66.16-77.75 cM on chromosome 20) that was identical by descent in each of the two families yielded a summed multipoint lod score of 4.41 (Fig. 1g). Two-point analyses gave combined maximal lod scores of 3.28 (pedigree 1 = 1.53 and pedigree 2 = 1.75) at marker D20S109 (Fig. 1h).We sequenced several candidate genes in the minimal linked region and found a different deleterious mutation in ARFGEF2 (encod...
Background Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke (AIS) and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with AIS. Methods and Results Between 1/2003 and 7/2007, 30 centers within the International Pediatric Stroke Study (IPSS) enrolled 667 children (29 days-19 years of age) with AIS and abstracted clinical and radiographic data. Cerebral arteriopathy and its subtypes were defined using published definitions; FCA was defined as cerebral arterial stenosis not attributed to specific diagnoses such as moyamoya, arterial dissection, vasculitis, or post-varicella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. Of 667 subjects, 525 had known vascular imaging results, and 53% of those (n=277) had an arteriopathy. The most common arteriopathies were FCA (n=69, 25%), moyamoya (n=61, 22%), and arterial dissection (n=56; 20%). Predictors of arteriopathy include early school age (5-9 years), recent upper respiratory infections (URI), and sickle cell disease, while prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent URI. Conclusions Arteriopathy is prevalent among children with AIS, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent URI predicted cerebral arteriopathy, and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.
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