Guillaume Sébire

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex

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 maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot 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.

Predictors of Cerebral Arteriopathy in Children With Arterial Ischemic Stroke Results of the International Pediatric Stroke Study

Background— Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with arterial ischemic stroke. Methods and Results— Between January 2003 and July 2007, 30 centers within the International Pediatric Stroke Study enrolled 667 children (age, 29 days to 19 years) with arterial ischemic stroke 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 postvaricella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. 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 to 9 years), recent upper respiratory infections, and sickle cell disease, whereas prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent upper respiratory infection. Conclusions— Arteriopathy is prevalent among children with arterial ischemic stroke, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent upper respiratory infection predicted cerebral arteriopathy and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.

Toward the definition of cerebral arteriopathies of childhood.

Purpose of review To facilitate and standardize the diagnosis of cerebrovascular conditions in childhood, particularly in the field of arterial ischemic diseases. Recent findings Progress in diagnostic techniques in the past decade have led to newly established etiologies for childhood stroke, most of which represent some form of vascular pathology. These advances must be integrated into a modern nomenclature system with revised definitions of stroke and arterial wall diseases-arteriopathies-in childhood. Summary This nomenclature system is intended to facilitate and enhance clinical research in childhood stroke, particularly multicenter collaborative studies.

Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study

Summary Background The relative importance of previous diagnosis and hereditary prothrombotic risk factors for cerebral venous thrombosis (CVT) in children in determining risk of a second cerebral or systemic venous thrombosis (VT), compared with other clinical, neuroimaging, and treatment variables, is unknown. Methods We followed up the survivors of 396 consecutively enrolled patients with CVT, aged newborn to 18 years (median 5·2 years) for a median of 36 months (maximum 85 months). In accordance with international treatment guidelines, 250 children (65%) received acute anticoagulation with unfractionated heparin or low-molecular weight heparin, followed by secondary anticoagulation prophylaxis with low-molecular weight heparin or warfarin in 165 (43%). Results Of 396 children enrolled, 12 died immediately and 22 (6%) had recurrent VT (13 cerebral; 3%) at a median of 6 months (range 0·1–85). Repeat venous imaging was available in 266 children. Recurrent VT only occurred in children whose first CVT was diagnosed after age 2 years; the underlying medical condition had no effect. In Cox regression analyses, non-administration of anticoagulant before relapse (hazard ratio [HR] 11·2 95% CI 3·4–37·0; p<0·0001), persistent occlusion on repeat venous imaging (4·1, 1·1–14·8; p=0·032), and heterozygosity for the G20210A mutation in factor II (4·3, 1·1–16·2; p=0·034) were independently associated with recurrent VT. Among patients who had recurrent VT, 70% (15) occurred within the 6 months after onset. Conclusion Age at CVT onset, non-administration of anticoagulation, persistent venous occlusion, and presence of G20210A mutation in factor II predict recurrent VT in children. Secondary prophylactic anticoagulation should be given on a patient-to-patient basis in children with newly identified CVT and at high risk of recurrent VT. Factors that affect recanalisation need further research.

Varicella as a risk factor for cerebral infarction in childhood: a case-control study.

The results of this case‐control study show a significant statistical link between idiopathic arterial ischemic strokes in children and varicella‐zoster virus infection. Ann Neurol 1999;45:679–680

Transient Cerebral Arteriopathy: A Disorder Recognized by Serial Angiograms in Children With Stroke

Repeated clinical evaluation and cerebral arteriography during the evolution of ischemic strokes of idiopathic origin allowed us to characterize a transient cerebral arteriopathy. We retrospectively studied the clinical characteristics, course, and neuroimaging features of this disorder in nine children. Of 34 children with ischemic strokes seen consecutively between 1984 and 1995, 9 (26%) were diagnosed as having transient attack of the cerebral arterial wall, termed transient cerebral arteriopathy. All of these patients had previously been in good health. The mean age at the time of the first stroke was 6 years (range, 29/12 years to 134/12 years). All children presented with acute hemiplegia. A recurrence of the stroke took place 3 months at the latest after the initial infarct in three children (mean clinical follow-up 27/12 years). Cerebral imaging in all the patients showed small subcortical infarcts located in basal ganglia or internal capsule. Arteriography revealed multifocal lesions of the arterial wall (focal stenosis or segmental narrowing), mostly located in the initial parts of basal arteries of the carotid system. Longitudinal arteriographic follow-up showed initial worsening of these arterial lesions (n = 5) for a maximum duration of 7 months followed by complete regression (n = 2), improvement (n = 5), or stabilization of the lesions (n = 2). Five patients had a complete clinical recovery. Further studies are necessary to confirm a presumed inflammatory cause of this arteriopathy. (J Child Neurol 1998; 13:27-32).

IL-1 Receptor Antagonist Protects against Placental and Neurodevelopmental Defects Induced by Maternal Inflammation

The precise role of maternal bacterial infection and inflammation occurring at the end of gestation is a controversial matter. Although it is recognized as an independent risk factor for neurodevelopmental diseases such as cerebral palsy, mental deficiency, and autism, it remains unclear whether it is causal or simply associated with the diseases. In this study, we demonstrate that IL-1 plays a key role in mediating severe placental damage and neurodevelopmental anomalies in offspring. Our results show that end of gestation exposure of pregnant rats to systemic microbial product (LPS) triggers placental inflammation and massive cell death, fetal mortality, and both forebrain white matter and motor behavioral alterations in the offspring. All these effects are alleviated by the coadministration of IL-1 receptor antagonist with LPS, suggesting a possible protective treatment against human placental and fetal brain damage.

Cytokines and brain injury: Invited review

The brain reacts to injury or disease by cascades of cellular and molecular responses. Evidence suggests that immune-inflammatory processes are key elements in the physiopathological processes associated with brain injury or damage. Cytokines are among major mediators implicated in these processes. Cytokine responses in the initial phase of brain injury might have a role in aggravating brain damage. However, in later stages, these molecular mediators might contribute to recovery or repair. Hemodynamic stabilization and optimalization of oxygen delivery to the brain remain cornerstones in the management of acute brain injury. New approaches might use anticytokine therapy to limit progression and halt or attenuate secondary brain damage. Progress toward such novel neuroprotection strategies, however, awaits better understanding of the optimal timing and dosing of those neuromodulatory therapies and better knowledge of the numerous interactions of those mediators. This also requires understanding of how and when precisely immune mechanisms shift from noxious to protective or restorative actions.

Magnetic Resonance Angiography in Childhood Arterial Brain Infarcts A Comparative Study With Contrast Angiography

Background and Purpose— Contrast angiography (CA) is the reference examination for the diagnosis of cerebral arterial abnormality, but this procedure is invasive. In childhood, ischemic strokes are being increasingly investigated by means of MRI, including MR angiography (MRA). Very few data are available about the accuracy of MRA compared with CA in the specific context of acute pediatric stroke. We sought to compare the results of MRA with those of CA for the study of cerebral arteries in children with arterial infarction in an arterial distribution. Methods— Twenty-four children presenting with 26 infarcts were studied. All were examined with cerebral MRI and MRA and with CA. The interval between CA and MRA was <3 days for most of the patients. Results— Arterial lesions were detected in all but 2 children. They were located in the major cerebral arteries, predominantly in the anterior circulation (85% of cases). All lesions shown by CA were present on MRA (19 cases). Patients with no lesion on MRA had normal CA (2 cases). Associated distal vascular lesions and degree of arterial stenosis were more accurately detected with CA. Conclusions— MRA is sensitive enough to provide an adequate initial evaluation of arterial brain disease in childhood.

Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: An experimental study

BackgroundPreterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Indeed, hypoxia-ischemia (HI), pathogen exposures, and associated intracerebral increase of pro-inflammatory cytokines have all been linked to perinatal brain damage. However, the developmental effects of potential variations of pro- and anti-inflammatory cytokine ratios remain unknown.MethodsUsing rat models of perinatal brain damage induced by exposures to lipopolysaccharide (LPS) and/or HI at distinct levels of maturity, we compared cytokine expression at stages of cerebral development equivalent to either preterm (postnatal day 1, P1) or term (P12) newborns.ResultsAt P1, expression of anti-inflammatory cytokine within the brain was either not modulated (IL-6, IL-10) or down-regulated (IL-1ra, TGF-β1) by HI, LPS or LPS+HI. In contrast, there was at P12 an up-regulation of all anti-inflammatory cytokines studied in HI or LPS+HI condition, but not after LPS exposure. Interestingly, IL-1β was the main pro-inflammatory cytokine up-regulated moderately at P1, and strongly at P12, with a weak co-expression of TNF-α observed mainly at P12. These age-dependant inflammatory reactions were also accompanied, under HI and LPS+HI conditions, at P12 only, by combined: (i) expression of chemokines CINC-1 and MCP-1, (ii) blood-brain barrier (BBB) leakage, and (iii) intracerebral recruitment of systemic immune cells such as neutrophils. In contrast, sole LPS induced IL-1β responses mainly within white matter at P1 and mainly within gray matter at P12, that were only associated with early MCP-1 (but no CINC-1) induction at both ages, without any recruitment of neutrophils and CD68+ cells.ConclusionHI and LPS+HI induce pro-inflammatory oriented immune responses in both preterm and term like brains, with a maximal inflammatory response triggered by the combination of LPS+HI. The profile of these neuroinflammatory responses presented striking variations according to age: no or down-regulated anti-inflammatory responses associated with mainly IL-1β release in preterm-like brains (P1), in sharp contrast to term-like brains (P12) presenting stronger anti-and pro-inflammatory responses, including both IL-1β and TNF-α releases, and BBB leakage. These developmental-dependant variations of neuroinflammatory response could contribute to the differential pattern of brain lesions observed across gestational ages in humans. This also highlights the necessity to take into consideration the maturation stage, of both brain and immune systems, in order to develop new anti-inflammatory neuroprotective strategies.