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γ-Aminobutyric acid (GABA)We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAWe gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABAGABA

Approximately 30 % of children with epilepsy develop refractory epilepsy, which has a major impact on neurodevelopmental processes, cognitive functioning, and daily life. Furthermore, children with highly refractory epilepsy are at particular risk of sudden unexpected death. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has shown antiseizure action and was associated with a decreased severity of peri-ictal hypoxemia in adult patients with focal epilepsy. However, therapeutic studies on SSRI use in children are scarce - particularly in epileptic patients. We retrospectively recruited 14 pediatric patients; inclusion criteria were i) refractory epilepsy ii) frequent generalized or focal seizures (more than 1/week) iii) treated with fluoxetine as adjunctive therapy for one month at least. We analyzed their clinical outcome (efficacy and tolerance). The median age at fluoxetine initiation was 9.5 years (2-19), and fluoxetine was combined with a median number of 4 (2-6) anti-seizure medications. The median dose of fluoxetine at the last follow-up was 0.4 mg/kg/day (0.2-0.8). Among the 14 patients, we observed 6 (43 %) good responders. Complete freedom from seizures with cyanosis was reached in 3 (21 %) patients, and only one patient with early-onset epilepsy related to an FHF1 mutation was completely seizure-free. None of the recruited patients experienced seizure worsening, and 8 patients showed no effect on seizure frequency. Fluoxetine as adjunctive therapy in refractory epilepsy could be a beneficial therapeutic option. Future prospective, randomized and controlled studies are needed to study the efficacy of fluoxetine better.

SummaryObjective Perampanel (PER) is a selective noncompetitive antagonist at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, the first of its class approved for the adjunctive treatment of partial onset seizures and generalized seizures. This study explored anti-ictogenic and antiepileptogenic effects of PER in rats at different stages of development. Methods Using a rapid kindling model in postnatal day 14 (P14), P21, P28, and P60 rats, we studied two doses of PER: 1 and 2 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of PER 30 min after the injection. Results PER 2 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas PER at 1 mg/kg increased ADT only in P21 rats. PER 2 mg/kg also shortened the afterdischarge duration in P14 and P28 rats. PER increased the number of stimulations required to achieve a stage 4–5 seizure in a dose-dependent manner in P14 and P21 rats, with almost complete elimination of stage 4–5 seizures. At P28, only PER 2 mg/kg increased the number of stimulations required to develop a stage 4–5 seizure. In contrast, PER had no effect on the number of stage 4–5 seizures at P60. We did not observed any age-dependent significant difference in the serum and brain levels of PER 30 min after the injection. Significance PER exerted anti-ictogenic effects from P14 to P60 independent of brain maturation. PER also exhibited antiepileptogenic effects with a stronger effect in the younger animals.

International audience; Dravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium-adjuvanted vaccine of children with DS to sex-and age-matched heathy children. Using ex vivo cytokine responses of peripheral-blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome.

Summary Purpose After the first positive experimental data in rodents in the early 1970s demonstrating the anticonvulsant effect of stiripentol (STP), in vitro studies showed that STP acts directly on γ-aminobutyric acid A (GABAA) receptors. Chloride influx is higher when these receptors contain an α3 subunit, leading to the hypothesis that STP might exhibit higher efficacy in the immature brain. Methods We explored this issue by studying the efficacy of STP in P21 and P75 rats using the pentylenetetrazol model of acute seizures or the lithium-pilocarpine status epilepticus model. P21 and adult rats received vehicle, 150, 250, or 350 mg/kg of STP, i.p., 1 h before evaluating the anticonvulsant. We also studied the blood and brain levels of STP as well as the expression and the messenger RNA (mRNA) levels of the α3 subunit of the GABAA receptors at both ages. Keys Findings STP exhibited anticonvulsant properties in both models at both ages, but STP was more effective in P21 than in P75 rats. This was shown by the significant suppression of seizure or status epilepticus occurrence in P21 with 350 mg/kg STP, whereas the same dose had no significant effect at P75. The blood level, brain level, and blood/brain ratio of STP did not explain these differences between the two age groups. Moreover, the higher anticonvulsant properties in the immature brain were not explained by the mRNA level or protein expression of the GABAA α3 subunit at either age. Significance Stiripentol exhibits higher anticonvulsant properties in the immature than in the mature brain. These findings require further investigation because it might lead to new clinical developments.

Background Infectious encephalitides are most often associated with acute seizures during the infection period and are risk factors for the development of epilepsy at later times. Mechanisms of viral encephalitis-induced epileptogenesis are poorly understood. Here, we evaluated the contribution of viral encephalitis-associated inflammation to ictogenesis and epileptogenesis using a rapid kindling protocol in rats. In addition, we examined whether minocycline can improve outcomes of viral-like brain inflammation. Methods To produce viral-like inflammation, polyinosinic-polycytidylic acid (PIC), a toll-like receptor 3 (TLR3) agonist, was applied to microglial/macrophage cell cultures and to the hippocampus of postnatal day 13 (P13) and postnatal day 74 (P74) rats. Cell cultures permit the examination of the inflammation induced by PIC, while the in vivo setting better suits the analysis of cytokine production and the effects of inflammation on epileptogenesis. Minocycline (50 mg/kg) was injected intraperitoneally for 3 consecutive days prior to the kindling procedure to evaluate its effects on inflammation and epileptogenesis. Results PIC injection facilitated kindling epileptogenesis, which was evident as an increase in the number of full limbic seizures at both ages. Furthermore, in P14 rats, we observed a faster seizure onset and prolonged retention of the kindling state. PIC administration also led to an increase in interleukin 1β (IL-1β) levels in the hippocampus in P14 and P75 rats. Treatment with minocycline reversed neither the pro-epileptogenic effects of PIC nor the increase of IL-1β in the hippocampus in both P14 and P75 rats. Conclusions Hippocampal injection of PIC facilitates rapid kindling epileptogenesis at both P14 and P75, suggesting that viral–induced inflammation increases epileptogenesis irrespective of brain maturation. Minocycline, however, was unable to reverse the increase of epileptogenesis, which might be linked to its absence of effect on hippocampal IL-1β levels at both ages. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0773-6) contains supplementary material, which is available to authorized users.

Background Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. Methods A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. Results We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. Conclusions These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.

BACKGROUND: Seizures are one of the most common symptoms of pediatric brain tumors. The purpose of this study was to determine seizures frequency and associated risk in pediatric patients with brain tumors. METHODS: A retrospective study was conducted in a single center over a period of 13 years. Data including demographic, tumor location, pathology, extend of resection, seizure characteristics were collected. A logistic regression model was built to determine which predictors are associated with the occurrence of seizures. RESULTS: Among the 329 children with primary brain tumors, 62 (18.8 %) experienced seizures. Children with cortical tumors were higher at risk to present seizures than patients with infratentorial tumors (OR=96.2; 95% CI=28.8-319.2; p

SummaryObjective Brivaracetam (BRV) is a new antiepileptic drug candidate rationally designed for high affinity and selectivity for the synaptic vesicle protein 2A. This study explored anti-ictogenic and antiepileptogenic effects of BRV in rats at different stages of development. Methods Using a rapid kindling model in P14, P21, P28, and P60 rats, we studied two doses of BRV: 10 and 100 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of BRV 30 min after the injection. Results BRV 100 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas BRV at 10 mg/kg increased ADT in P60, P28, and P21 rats. BRV also shortens the afterdischarge duration (ADD), achieving statistical significance with 10 and 100 mg/kg at P60 and with 100 mg/kg at P21. At P60, BRV increases the number of stimulations required to achieve a stage 4–5 seizure in a dose-dependent manner. At P28 and P21, BRV increased the number of stimulations required to develop a stage 4–5 seizure in a dose-dependent manner with almost complete elimination of stage 4–5 seizures. In contrast, at P14, BRV had no effect on the number of stage 4–5 seizures. An age-related decrease in blood and brain concentrations of BRV was observed 30 min after injection of BRV 10 mg/kg, whereas with 100 mg/kg there were no significant age-correlated differences in brain and serum BRV concentrations. Significance BRV exerted dose-dependent anti-ictogenic effects from P60 to P14 independent of brain maturation. BRV also exhibited antiepileptogenic effects at P60, whereas this effect need to be further evaluated at P28 and P21. We did not observe any effect on epileptogenesis at P14 at either dose.

Objective The first seizure in Dravet syndrome is often considered a febrile seizure (FS), but shortly thereafter, both FSs and seizures without fever occur, leading to diagnosis. Fever remains a factor that easily precipitates seizures. We studied the perception and management of fever of parents of children with Dravet syndrome. Methods We conducted this survey using an anonymous, self-administered questionnaire. Results A total of 20 parents returned the questionnaire. Fever remains a trigger of seizures in 90% of patients. All parents have an accurate knowledge of fever and its management. The familial and socioprofessional impact of fever attacks appears to be very strong. Conclusion Fever represents a significant concern of parents of children with Dravet syndrome. The level of parental anxiety is high in case of fever. The anxiety seems related to fear of seizure recurrence leading to significant modification of parental behavior.