Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene.

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3-5 months concomitant with developmental arrest or regression, other seizure types and drug-resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1-related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1-related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity.

Buccal Midazolam Compared With Rectal Diazepam Reduces Seizure Duration in Children in the Outpatient Setting.

BACKGROUND: Seizures are very common in children. They frequently happen in outpatient settings, in the presence of caregivers who are not always trained in their management. First-line rescue therapy is based on benzodiazepine, historically diazepam. Recent studies have investigated the use of other benzodiazepines in the treatment of acute seizures. OBJECTIVES: The aims of this study were to evaluate the management of pediatric seizures carried out by parents or caregivers in an outpatient setting and to evaluate the differences in terms of immediate management and subsequent outcome when comparing the use of rectal diazepam versus buccal midazolam. METHODS: In this retrospective study, medical records of children consulting for seizures at the Robert Debré Pediatric Emergency Department of Paris, France, over 18 months were analyzed to evaluate seizure characteristics, management by caregivers, received treatments, and the admission rate. RESULTS: Five hundred ninety-four patients resulted eligible for the study. The interview was completed for 135 children who presented a further episode of seizure after inclusion. In the subgroup of children receiving buccal midazolam, compared with the subgroup receiving intrarectal diazepam, seizure duration was significantly shorter (10.3 vs 48.4 minutes, P = 0.0004), and the risk of a status epilepticus decreased (1 vs 11, P = 0.0008). The admission rate was not different between the 2 subgroups. CONCLUSIONS: Based on our results, buccal midazolam seems to have some advantages compared with rectal diazepam in terms of feasibility in an outpatient setting and in terms of reduced seizure duration.

Early Sex Differences in the Immune-Inflammatory Responses to Neonatal Ischemic Stroke.

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.

Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke.

Neonatal acute ischemic stroke is a cause of neonatal brain injury that occurs more frequently in males, resulting in associated neurobehavioral disorders. The bases for these sex differences are poorly understood but might include the number, morphology and activation of microglia in the developing brain when subjected to stroke. Interestingly, poly (ADP-ribose) polymerase (PARP) inhibition preferentially protects males against neonatal ischemia. This study aims to examine the effects of PJ34, a PARP inhibitor, on microglial phenotypes at 3 and 8 days and on neurobehavioral disorders in adulthood for both male and female P9 mice subjected to permanent middle cerebral artery occlusion (pMCAo). PJ34 significantly reduced the lesion size by 78% and reduced the density of CX3CR1gfp-labeled microglial cells by 46% when examined 3 days after pMCAo in male but not in female mice. Eight days after pMCAo, the number of Iba1+/Cox-2+ cells did not differ between male and female mice in the cortical peri-infarct region. In the amygdala, Iba1+/Cox-2+ (M1-like) cell numbers were significantly decreased in PJ34-treated males but not in females. Conversely, Iba1+/Arg-1+ (M2-like) and Arg-1+/Cox-2+ (Mtransitional) cell numbers were significantly increased in PJ34-treated females. Regarding neurobehavioral disorders during adulthood, pMCAo induced a motor coordination deficit and a spatial learning deficit in female mice only. PJ34 prevented MBP fibers, motor coordination and learning disorders during adulthood in female mice. Our data show significant sex differences in the effects of PARP inhibition on microglia phenotypes following neonatal ischemia, associated with improved behavior and myelination during adulthood in females only. Our findings suggest that modulating microglial phenotypes may play key roles in behavior disorders and white matter injury following neonatal stroke.

Role of microglia in a mouse model of paediatric traumatic brain injury.

The cognitive and behavioural deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than TBI in the mature brain. Understanding this developmental sensitivity is critical as children under four years of age sustain TBI more frequently than any other age group. Microglia (MG), resident immune cells of the brain that mediate neuroinflammation, are activated following TBI in the immature brain. However, the type and temporal profile of this activation and the consequences of altering it are still largely unknown. In a mouse model of closed head weight drop paediatric brain trauma, we characterized i) the temporal course of total cortical neuroinflammation and the phenotype of ex vivo isolated CD11B-positive microglia/macrophage (MG/MΦ) using a battery of 32 markers, and ii) neuropathological outcome 1 and 5days post-injury. We also assessed the effects of targeting MG/MΦ activation directly, using minocycline a prototypical microglial activation antagonist, on these processes and outcome. TBI induced a moderate increase in both pro- and anti-inflammatory cytokines/chemokines in the ipsilateral hemisphere. Isolated cortical MG/MΦ expressed increased levels of markers of endogenous reparatory/regenerative and immunomodulatory phenotypes compared with shams. Blocking MG/MΦ activation with minocycline at the time of injury and 1 and 2days post-injury had only transient protective effects, reducing ventricular dilatation and cell death 1day post-injury but having no effect on injury severity at 5days. This study demonstrates that, unlike in adults, the role of MG/MΦ in injury mechanisms following TBI in the immature brain may not be negative. An improved understanding of MG/MΦ function in paediatric TBI could support translational efforts to design therapeutic interventions.

Association Between Migraine and Atopic Diseases in Childhood: A Potential Protective Role of Anti-Allergic Drugs.

BACKGROUND: Migraine is a common cause of headache in childhood. Several studies have investigated the association between migraine and atopic diseases, mostly in the adult population. OBJECTIVE: This study aimed to investigate this association in children. METHODS: A case-control study was conducted across 3 European tertiary care hospitals between June 2014 and August 2014. Cases (n = 229) were children aged 6-18 years consulting for a migraine episode. Controls in the same age range (n = 406) were consulting for a minor injury and did not have a history of recurrent headache. Logistic regression analyses tested the effect of atopic diseases and anti-allergic therapies on occurrence of migraine. RESULTS: Children with migraine were more likely to have persistent asthma compared to absence of asthma (odds ratio [OR]: 4.57, 95% confidence interval [CI]: 2.04-10.24) and less likely to have been treated by inhaled or nasal corticosteroid (OR: 0.34, 95% CI: 0.15-0.76) or antihistamine therapy (OR: 0.33, 95% CI: 0.18-0.60). The median number of monthly migraine episodes was higher in children with persistent asthma (3; interquartile [IQR]: 1-4; range: 0.5-10) compared to children with intermittent asthma (2; IQR: 1-3; range: 0.1-4) or non-asthmatic children (2; IQR: 1-3; range: 0.1-12) (P < .01). CONCLUSION: Persistent childhood asthma was associated with increased risk of migraine and higher frequency of migraine attacks. History of anti-asthmatic or anti-allergic therapies was associated with decreased risk of migraine in children and adolescents. The role of these therapies on the pathogenesis and occurrence of migraine needs to be further elucidated because of the huge potential impact in terms of public health.

Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain.

BACKGROUND: Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation. METHODS: Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed. RESULTS: Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2(+) microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals. CONCLUSIONS: Our findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery.

Contribution of mast cells to injury mechanisms in a mouse model of pediatric traumatic brain injury.

The cognitive and behavioral deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than injuries to the adult brain. Understanding this developmental sensitivity is critical because children under 4 years of age of sustain TBI more frequently than any other age group. One of the first events after TBI is the infiltration and degranulation of mast cells (MCs) in the brain, releasing a range of immunomodulatory substances; inhibition of these cells is neuroprotective in other types of neonatal brain injury. This study investigates for the first time the role of MCs in mediating injury in a P7 mouse model of pediatric contusion-induced TBI. We show that various neural cell types express histamine receptors and that histamine exacerbates excitotoxic cell death in primary cultured neurons. Cromoglycate, an inhibitor of MC degranulation, altered the inflammatory phenotype of microglia activated by TBI, reversing several changes but accentuating others, when administered before TBI. However, without regard to the time of cromoglycate administration, inhibiting MC degranulation did not affect cell loss, as evaluated by ventricular dilatation or cleaved caspase-3 labeling, or the density of activated microglia, neurons, or myelin. In double-heterozygous cKit mutant mice lacking MCs, this overall lack of effect was confirmed. These results suggest that the role of MCs in this model of pediatric TBI is restricted to subtle effects and that they are unlikely to be viable neurotherapeutic targets. © 2016 Wiley Periodicals, Inc.

Epilepsy as a Novel Phenotype of BPTF-Related Disorders.

BACKGROUND: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) is associated to BPTF gene haploinsufficiency. Epilepsy was not included in the initial descriptions of NEDDFL, but emerging evidence indicates that epileptic seizures occur in some affected individuals. This study aims to investigate the electroclinical epilepsy features in individuals with NEDDFL. METHODS: We enrolled individuals with BPTF-related seizures or interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Demographic, clinical, genetic, raw EEG, and neuroimaging data as well as response to antiseizure medication were assessed. RESULTS: We studied 11 individuals with a null variant in BPTF, including five previously unpublished ones. Median age at last observation was 9 years (range: 4 to 43 years). Eight individuals had epilepsy, one had a single unprovoked seizure, and two showed IEDs only. Key features included (1) early childhood epilepsy onset (median 4 years, range: 10 months to 7 years), (2) well-organized EEG background (all cases) and brief bursts of spikes and slow waves (50% of individuals), and (3) developmental delay preceding seizure onset. Spectrum of epilepsy severity varied from drug-resistant epilepsy (27%) to isolated IEDs without seizures (18%). Levetiracetam was widely used and reduced seizure frequency in 67% of the cases. CONCLUSIONS: Our study provides the first characterization of BPTF-related epilepsy. Early-childhood-onset epilepsy occurs in 19% of subjects, all presenting with a well-organized EEG background associated with generalized interictal epileptiform abnormalities in half of these cases. Drug resistance is rare.

Association between childhood migraine and history of infantile colic.

IMPORTANCE: Infantile colic is a common cause of inconsolable crying during the first months of life and has been thought to be a pain syndrome. Migraine is a common cause of headache pain in childhood. Whether there is an association between these 2 types of pain in unknown. OBJECTIVE: To investigate a possible association between infantile colic and migraines in childhood. DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 208 consecutive children aged 6 to 18 years presenting to the emergency department and diagnosed as having migraines in 3 European tertiary care hospitals between April 2012 and June 2012. The control group was composed of 471 children in the same age range who visited the emergency department of each participating center for minor trauma during the same period. A structured questionnaire identified personal history of infantile colic for case and control participants, confirmed by health booklets. A second study of 120 children diagnosed with tension-type headaches was done to test the specificity of the association. MAIN OUTCOMES AND MEASURES: Difference in the prevalence of infantile colic between children with and without a diagnosis of migraine. RESULTS: Children with migraine were more likely to have experienced infantile colic than those without migraine (72.6% vs 26.5%; odds ratio [OR], 6.61 [95% CI, 4.38-10.00]; P < .001), either migraine without aura (n = 142; 73.9% vs 26.5%; OR, 7.01 [95% CI, 4.43-11.09]; P < .001), or migraine with aura (n = 66; 69.7% vs 26.5%; OR, 5.73 [95% CI, 3.07-10.73]; P < .001). This association was not found for children with tension-type headache (35% vs 26.5%; OR, 1.46 [95% CI, 0.92-2.32]; P = .10). CONCLUSION AND RELEVANCE: The presence of migraine in children and adolescents aged 6 to 18 years was associated with a history of infantile colic. Additional longitudinal studies are required.

Is vitamin D status known among children living in Northern Italy?

PURPOSE: To assess vitamin D status in children aged 2-220 months in northeastern Italy (latitude 46°). Serum 25-hydroxyvitamin D (25OHD) concentration was assessed in 93 children afferent to the Pediatric Department of the Hospital of Udine. METHODS: Vitamin D status was defined as follows: sufficient with serum 25OHD between 50 and 250 nmol/l (level 4); insufficient between 37.5 and 50 nmol/l (level 3); deficient less than 37.5 nmol/l (level 2); severely deficient if less than 12.5 nmol/l (level 1). We investigated the potential risk factors of vitamin D deficit. RESULTS: We found that six children (6.4%) had level 1, 36 (38.7%) had level 2, 9 (9.7%) had level 3, and only 45.2% had sufficient level of 25OHD. Immigrate children had a higher risk for vitamin D deficiency if compared with Italians: 75% of non-Italian children had an insufficient 25OHD level compared with 47.0% of Italian children (p = 0.0036). There was a marked seasonal effect on 25OHD level: when plasma sample was withdrawn between November and May, only 29.4% of children showed sufficient vitamin D level, while 70.5% was insufficient (p < 0.0001). Among the obese children, 9.0% had sufficient level of 25OHD with 90% being deficient (p = 0.01). We did not find any significant difference in vitamin D status among children in different age groups. CONCLUSION: Vitamin D deficiency is common in children living in northeastern Italy. The risk factors were winter season for blood withdrawal, non-Caucasian race, and obesity. These high-risk groups should be targeted for screening and educated about the need of sunlight exposure.

SCN1A-related epilepsy with recessive inheritance: Two further families.

BACKGROUND: Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. METHODS AND RESULTS: We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. CONCLUSION: This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.

Electroencephalographic Abnormalites in SARS-CoV-2 Patients.

Viral infection with SARS-CoV-2 has a neurological tropism that may induce an encephalopathy. In this context, electroencephalographic exploration (EEG) is indicated as a diagnostic argument correlated with lumbar puncture, biology, and imaging. We performed a retrospective analysis of 42 patients explored by EEG and infected by COVID-19, according to the EEG abnormalities and clinical signs that motivated the examination. Confusion and epileptic seizures were the most common clinical indications, with 64% of the patients displaying these symptoms. The EEG was altered in 85% of the cases of confusion, in 57% of the cases of epileptic symptoms (general or focal seizure or prolonged loss of contact) and 20% of the cases of malaise or brief loss of consciousness. Nine EEG (21%) were in favor of an encephalopathy, two had de novo alterations in persistent consciousness and two had alterations in general states of confusion; one was very agitated and without history of epilepsy and combined eyelids clonia while a second one exhibited unconsciousness with left hemicorpus clonus. Two were being investigated for delayed awakening without sedation for more than 24 h. All of these patients were diagnosed COVID-19, some of them with associated mild to severe respiratory disorders. This work shows the interest of the EEG in exploring COVID-19 patients suffering from neurological or general symptoms looking for cerebral alteration.

Expanding the clinical and EEG spectrum of CNKSR2-related encephalopathy with status epilepticus during slow sleep (ESES).

OBJECTIVE: To investigate the clinical and EEG features of Encephalopathy with Status Epilepticus during slow Sleep (ESES) related to CNKSR2 pathogenic variants. METHODS: Detailed clinical history, repeated wakefulness/overnight sleep EEGs, brain MRI were collected in five patients, including one female, with CNKSR2-related ESES. RESULTS: Neurodevelopment in infancy was normal in two patients, delayed in three. Epilepsy onset (age range: 2-6 years) was associated with appearance or aggravation of cognitive impairment, language regression and/or behavioral disorders. Worsening of epilepsy and of cognitive/behavioral disturbances paralleled by enhancement of non-rapid eye movement (NREM) sleep-related, frontally predominant, EEG epileptic discharges [spike-wave-index (SWI): range 60-96%] was consistent with ESES. In three patients, episodes of absence status epilepticus or aggravation of atypical absences occurred, in this latter case associated with striking increment of awake SWI. Speech/oro-motor dyspraxia was diagnosed in four patients. In two patients, long-term follow-up showed epilepsy remission and persistence of mild/moderate cognitive disorders and behavioral disturbances into adulthood. CONCLUSIONS: Novel findings of our study are occurrence also in females, normal neurodevelopment before epilepsy onset, epilepsy aggravation associated with enhanced awake SWI, mild/moderate evolution in adulthood and language disorder due to speech/oro-motor dyspraxia. SIGNIFICANCE: Our findings expand the phenotypic spectrum of CNKSR2-related ESES.

Glial response to 17ß-estradiol in neonatal rats with excitotoxic brain injury.

White-matter injury is the most common cause of the adverse neurodevelopmental outcomes observed in preterm infants. Only few options exist to prevent perinatal brain injury associated to preterm delivery. 17ß-estradiol (E2) is the predominant estrogen in circulation and has been shown to be neuroprotective in vitro and in vivo. However, while E2 has been found to modulate inflammation in adult models of brain damage, how estrogens influence glial cells response in the developing brain needs further investigations. Using a model of ibotenate-induced brain injury, we have refined the effects of E2 in the developing brain. E2 provides significant neuroprotection both in the cortical plate and the white matter in neonatal rats subjected to excitotoxic insult mimicking white matter and cortical damages frequently observed in very preterm infants. E2 promotes significant changes in microglial phenotypes balance in response to brain injury and the acceleration of oligodendrocyte maturation. Maturational effects of E2 on myelination process were observed both in vivo and in vitro. Altogether, these data demonstrate that response of glial cells to E2 could be responsible for its neuroprotective properties in neonatal excitotoxic brain injury.

Association between functional gastrointestinal disorders and migraine in children and adolescents: a case-control study.

BACKGROUND: Functional gastrointestinal disorders and migraine are both common causes of medical attention. We have previously shown an association between migraine and infant colic. In this case-control study, we aimed to establish whether there is an association between migraine and other functional gastrointestinal disorders in children and adolescents. METHODS: We included children and adolescents aged 6-17 years presenting to the emergency department of four tertiary hospitals in France and Italy. Patients diagnosed with either migraine or tension-type headache by the hospital's paediatric neurologist were enrolled as cases. Patients presenting to the emergency department with minor trauma and no history of recurrent headache were enrolled as controls. Investigators masked to a patient's group allocation diagnosed functional gastrointestinal disorders using the Rome III diagnostic criteria. Univariable and multivariable analyses were done to identify specific disorders and baseline factors associated with migraines and tension-type headache. FINDINGS: Between Nov 1, 2014, and Jan 31, 2015, we enrolled 648 controls and 424 cases (257 patients with migraine and 167 with tension-type headache). 83 (32%) children and adolescents in the migraine group were diagnosed with functional gastrointestinal disorders compared with 118 (18%) in the control group (p<0·0001). Multivariable logistic regression showed a significant association between migraine and three gastrointestinal disorders: functional dyspepsia (odds ratio 10·76, 95% CI 3·52-32·85; p<0·0001), irritable bowel syndrome (3·47, 1·81-6·62; p=0·0002), and abdominal migraine (5·87, 1·95-17·69; p=0·002). By contrast, there was an inverse association between migraine and functional constipation (0·34, 0·14-0·84, p=0·02). 41 (25%) participants with tension-type headache had functional gastrointestinal disorders, which did not significantly differ from the prevalence of these disorders in the control group (p=0·07); no significant association was noted between any functional gastrointestinal disease and tension-type headaches. INTERPRETATION: Three abdominal-pain-related functional gastrointestinal disorders were associated with migraine in children and adolescents. These findings are of value to the diagnosis and management of these common diseases. Future studies should investigate whether antimigraine drugs are of benefit in functional gastrointestinal disorders. FUNDING: None.

Recovery position significantly associated with a reduced admission rate of children with loss of consciousness.

BACKGROUND: Loss of consciousness (LOC) is often seen in children. The response of caregivers to a child with LOC has been poorly investigated. Potential caregivers (parents, teachers) seem to have a poor knowledge of the recovery position (RP)-that is, the position into which an unconscious child should be placed in order to protect the airway. OBJECTIVES: To report the management and diagnoses of LOC in childhood, and to evaluate variables associated with an increased hospital admission rate. METHODS: We conducted a prospective cohort study of consecutive children aged between 0 and 18 years diagnosed with LOC at 11 paediatric emergency departments (PEDs) of 6 European countries. The enrolment period was 3 months. Data were obtained from parental interviews, PED reports and clinical examination. RESULTS: 553 children were enrolled. The most frequent final diagnoses causing LOC were seizures (n=278, 50.3%), and vasovagal syncope (n=124, 22.4%). Caregivers put the child in the RP in 145 cases (26.2%). The RP was independently associated with a significant decrease in the admission rate (aOR=0.28; 95% CI 0.17 to 0.48; p<0.0001). CONCLUSIONS: Our study demonstrates for the first time that the RP may reduce the admission rate of infants with LOC. Caregivers often perform inadequate manoeuvres when a child becomes unconscious. Campaigns aiming at increasing knowledge of the RP should be promoted.

Pathophysiology and neuroprotection of global and focal perinatal brain injury: lessons from animal models.

BACKGROUND: Arterial ischemic stroke occurs more frequently in term newborns than in the elderly, and brain immaturity affects mechanisms of ischemic injury and recovery. The susceptibility to injury of the brain was assumed to be lower in the perinatal period as compared with childhood. This concept was recently challenged by clinical studies showing marked motor disabilities after stroke in neonates, with the severity of motor and cortical sensory deficits similar in both perinatal and childhood ischemic stroke. Our understanding of the triggers and the pathophysiological mechanisms of perinatal stroke has greatly improved in recent years, but many factors remain incompletely understood. METHODS: In this review, we focus on the pathophysiology of perinatal stroke and on therapeutic strategies that can protect the immature brain from the consequences of stroke by targeting inflammation and brain microenvironment. RESULTS: Studies in neonatal rodent models of cerebral ischemia have suggested a potential role for soluble inflammatory molecules as important modulators of injury and recovery. A great effort is underway to investigate neuroprotective molecules based on our increasing understanding of the pathophysiology. CONCLUSION: In this review, we provide a comprehensive summary of new insights concerning pathophysiology of focal and global perinatal brain injury and their implications for new therapeutic approaches.

Blood-brain barrier dysfunction in disorders of the developing brain.

Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data.