GluN2C selective inhibition is a target to develop new antiepileptic compounds.

OBJECTIVE: Many early-onset epilepsies present as developmental and epileptic encephalopathy associated with refractory seizures, altered psychomotor development, and disorganized interictal cortical activity. Abnormal upregulation of specific N-methyl-d-aspartate receptor (NMDA-R) subunits is being disentangled as one of the mechanisms of severe early-onset epilepsies. In tuberous sclerosis complex (TSC), upregulation of the GluN2C subunit of the NMDA-R with slow deactivation kinetic results in increased neuronal excitation and synchronization. METHODS: Starting from an available GluN2C/D antagonist, NMDA-R-modulating compounds were developed and screened using a patch clamp on neuronal culture to select those with the strongest inhibitory effect on glutamatergic NMDA currents. For these selected compounds, blood pharmacokinetics and passage through the blood-brain barrier were studied. We tested the effect of the most promising compounds on epileptic activity in Tsc1+/- mice brain slices with multielectrode array, and then in vivo at postnatal ages P14-P17, comparable with the usual age at epilepsy onset in human TSC. RESULTS: Using a double-electrode voltage clamp on isolated NMDA currents, we identified the most prominent antagonists of the GluN2C subunit with no effect on GluN2A as a means of preventing side effects. The best compound passing through the blood-brain barrier was selected. Applied in vivo in six Tsc1+/- mice at P14-P17, this compound reduced or completely stopped spontaneous seizures in four of them, and decreased the background activity disorganization. Furthermore, ictal-like discharges stopped on a human brain sample from an infant with epilepsy due to TSC. INTERPRETATION: Subunit-selective inhibition is a valuable target for developing drugs for severe epilepsies resulting from an upregulation of NMDA-R subunit-mediated transmission.

Are Epileptic Spasms a Seizure Type for the Insular Region?

Two patients with insular and striatal postnatal scar had epileptic spasms (ES) that were asymmetrical and the only seizure type, whereas none of the usual ictal symptoms of insular seizures occurred. Ictal electroencephalography (EEG) showed the high-amplitude slow-wave characteristic of ES. Vigabatrin remained efficient for over 4 years for one patient and right into the third decade for the other one. Such ES are distinct from infantile and late onset spasms. Furthermore, these observations suggest that in ES insular epilepsy triggers paroxysmal activation of the striatum, and that vigabatrin inhibits the striatal startle motor program, thus interrupting the corticostriatal loop.

Neonatal SCN2A encephalopathy: A peculiar recognizable electroclinical sequence.

INTRODUCTION: Sodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2A encephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early. PATIENTS AND METHODS: We report three new cases with de novo SCN2A mutations - 166237617C>A p.(Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) - diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years. RESULTS: For all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic-clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay. DISCUSSION: All three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression-burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers. CONCLUSION: Neonatal SCN2A encephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers.

Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures.

OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.

New insights in phenomenology and treatment of epilepsy in CDKL5 encephalopathy.

Eight patients, seven girls and one boy, had CDKL5 gene mutation, duplication, or deletion. Epileptic spasms started at a mean age of 3.5 months (range = 4 weeks-8 months). In five cases, tonic seizures preceded spasms at a median age of 6 weeks. In one patient who started at 8 months, spasms had a component of terror on awakening, reminding sleep terror. In two patients, electroencephalogram polygraphy of a so-called tonic seizure revealed that the tonic phase was followed by an overlooked clonic phase and then by a cluster of spasms during which each spasm was preceded by a brief clonic jerk revealed by electromyography. This sequence is rather particular and can be an early diagnostic clue. Progressive transition from this seizure type to epileptic spasms in clusters seems to result from increasing expression of the CDKL5 gene, as the child grows older. Five patients responded to the combination of vigabatrin and zonisamide.

Gene mutations in paediatric epilepsies cause NMDA-pathy, and phasic and tonic GABA-pathy.

The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss-of-function or gain-of-function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N-methyl-d-aspartate (NMDA) transmission activation (NMDA-pathies); (2) abnormal gamma-aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA-pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA-pathies). NMDA-pathies comprise early epileptic encephalopathy with suppression-burst, neonatal/infantile benign seizures, West and Lennox-Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA-pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long-lasting seizures with mild interictal spiking. Tonic GABA-pathies cause epilepsy with myoclonic-atonic seizures and Angelman syndrome, thus major high-amplitude slow-wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. WHAT THIS PAPER ADDS: In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA-pathies, and phasic and tonic GABA-pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

LAS MUTACIONES GENÉTICAS EN LAS EPILEPSIAS PEDIÁTRICAS CAUSAN PATOLOGÍA POR LOS RECEPTORES NMDA Y GABA FÁSICA Y TÓNICA: El objetivo de este estudio fue desentrañar los mecanismos de la epileptogénesis en las epilepsias monogénicas en niños. Revisamos las epilepsias monogénicas pediátricas, excluyendo la malformación cerebral o un error innato del metabolismo, pero incluyendo la función del gen si hay pérdida de función o ganancia de función, la edad en la expresión del gen cuando esté disponible y el síndrome de epilepsia asociado. Se seleccionaron genes para los que se reportaron al menos cinco pacientes con fenotipo de epilepsia similar. La mayoría de las epilepsias monogénicas comparten tres mecanismos: el exceso de activación de la transmisión de N-metil-D-aspartato (NMDA, por sus siglas en inglés); transmisión anormal del ácido gamma-aminobutírico (GABA) con inhibición reducida (patología del GABA fásica); y la activación tónica de receptores de GABAA extrasinápticos por GABA extracelular (tónica GABA-patologías). Las patologías por NMDA comprenden encefalopatía epiléptica temprana con estallido de supresión, convulsiones benignas neonatales / infantiles, síndromes de West y Lennox-Gastaut, y encefalopatía con ondas de pico continuas en el sueño lento, por lo tanto, breves convulsiones con picos interictales importantes. Las patologías fásicas por GABA comprenden en su mayoría epilepsia generalizada con convulsiones febriles más y síndrome de Dravet, por lo tanto, convulsiones de larga duración con picos interictales leves. Las patologías tónicas por GABA causan epilepsia con convulsiones mioclónica-atónicas y el síndrome de Angelman, por lo tanto, una actividad importante de ondas lentas de gran amplitud. Este enfoque fisiopatológico de las epilepsias monogénicas proporciona pistas de diagnóstico y ayuda a guiar la estrategia de tratamiento.

MUTAÇÕES GENÉTICAS EM EPILEPSIAS PEDIÁTRICAS CAUSAM NMDA-PATIA GABA-PATIA TÔNICA E FÁSICA: O objetivo deste estudo foi desvendar mecanismos de epileptogênese em epilepsias monogências em crianças. Revisamos epilepsias pediátricas monogênicas excluindo malformação cerebral e erros inatos do metabolismo, mas incluindo a função do gene se houvesse perda ou ganho função, idade da expressão do gene quando disponível, e síndrome de epilepsia associada. Genes para os quais pelo menos cinco pacientes com fenótipo epiléptico similar haviam sido reportados foram selecionados. Três mecanismos foram compartilhados pela maioria das epilepsias monogênicas: excessiva transmissão ativação de N-methyl-d-aspartato (NMDA) (NMDA-patias); transmissão anormal de ácido gama-amino-butírico (GABA) com reduzida inibição (GABA-patias fásicas); ativação tônica de receptores extrasinápticos de GABAA por GABA extra-celular (GABA-patias tônicas). NMDA-patias incluem encefalopatia epiléptica precoce com padrão de surto-supressão, convulsões neonatais/infantis benignas, síndromes de West e Lennox-Gastaut, e encefalopatia com picos de ondas contínuas no sono lento, portanto convulsões breves com importante pico interictal. GABA-patias fásicas incluem epilepsia mais generalizada com convulsões febris e síndrome de Dravet, portanto convulsões longas com picos interictais menores. GABA-patias tônicas causam epilepsia com convulsões miocônicas-atônicas e síndrome de Angelman, portanto, importante atividade de ondas lentas de alta amplitude. Esta abordagem patofisiológica das epilepsias monogênicas fornece dicas diagnósticas e ajuda a guiar estratégias de tratamento.

Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood?

OBJECTIVE: To evaluate continuing stiripentol treatment in adulthood in Dravet syndrome (DS). METHOD: Longitudinal data were collected from the last visit prior to age 15 years (V15 y ) to the last visit in adulthood (Vadult ) in the 40 DS patients (32 typical, eight atypical) of a French historical cohort (Paris) of subjects who continued stiripentol from childhood or adolescence to adulthood. RESULTS: At Vadult (18-40 years, median = 23 years), all the patients were still receiving stiripentol (exposure = 3-24 years, median = 18 years), associated with clobazam (40/40), valproate (39/40), and topiramate (21/40). Between V15 y and Vadult , stiripentol was interrupted in five patients (two for adverse events) but reintroduced following seizure aggravation. Loss of appetite affected 15 of 40 patients but resolved after reducing the dose of stiripentol or valproate; no other new stiripentol-related adverse events were reported. Mean stiripentol dose was progressively decreased from 39 to 25 mg/kg/d (P = 0.0002), whereas clobazam (0.27 mg/kg/d) and valproate (14 mg/kg/d) remained stable. At Vadult , 37 of 40 patients still had generalized tonic-clonic seizures, but none still had status epilepticus (vs three at V15 y ) and only one had myoclonia. During adulthood, generalized tonic-clonic seizure frequency and duration continued to decrease (P = 0.02, P = 0.008) and 10 patients experienced seizure-free periods ≥ 1 years (up to 5 years). All patients already had intellectual disability at V15 y , but retardation was more severe at Vadult (P = 0.03). Furthermore, neurological/gait condition had declined (two patients became bedridden) and behavior had worsened (P < 0.0002). Nevertheless, the 33 patients on stiripentol from infancy/childhood (<15 years) tended to have better seizure outcome in midadulthood than the seven treated from adolescence (>15 years) and the DS patients treated from adult age or stiripentol-naive subjects reported in the literature. SIGNIFICANCE: The efficacy and safety of the stiripentol/valproate/clobazam combination started at pediatric age are maintained at very long term during adulthood. Such prolonged stiripentol therapy tends to positively impact the late prognosis of epilepsy, especially when initiated before adolescence.

A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy.

PURPOSE: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L). METHODS: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. RESULTS: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. CONCLUSIONS: If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.

Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures.

Progressive microcephaly is a heterogeneous condition with causes including mutations in genes encoding regulators of neuronal survival. Here, we report the identification of mutations in QARS (encoding glutaminyl-tRNA synthetase [QARS]) as the causative variants in two unrelated families affected by progressive microcephaly, severe seizures in infancy, atrophy of the cerebral cortex and cerebellar vermis, and mild atrophy of the cerebellar hemispheres. Whole-exome sequencing of individuals from each family independently identified compound-heterozygous mutations in QARS as the only candidate causative variants. QARS was highly expressed in the developing fetal human cerebral cortex in many cell types. The four QARS mutations altered highly conserved amino acids, and the aminoacylation activity of QARS was significantly impaired in mutant cell lines. Variants p.Gly45Val and p.Tyr57His were located in the N-terminal domain required for QARS interaction with proteins in the multisynthetase complex and potentially with glutamine tRNA, and recombinant QARS proteins bearing either substitution showed an over 10-fold reduction in aminoacylation activity. Conversely, variants p.Arg403Trp and p.Arg515Trp, each occurring in a different family, were located in the catalytic core and completely disrupted QARS aminoacylation activity in vitro. Furthermore, p.Arg403Trp and p.Arg515Trp rendered QARS less soluble, and p.Arg403Trp disrupted QARS-RARS (arginyl-tRNA synthetase 1) interaction. In zebrafish, homozygous qars loss of function caused decreased brain and eye size and extensive cell death in the brain. Our results highlight the importance of QARS during brain development and that epilepsy due to impairment of QARS activity is unusually severe in comparison to other aminoacyl-tRNA synthetase disorders.

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

AIMS: Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (Ctrough ) of MHD (3-35 mg l-1 ). METHODS: A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain Ctrough between 3-35 mg l-1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg-1  day-1 . RESULTS: A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h-1  70 kg-1 , 337 l 70 kg-1 , 60.7 l and 62.5 l h-1 , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h-1  70 kg-1 and 54.8 l 70 kg-1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg-1  day-1 instead of the recommended target maintenance dose (30-45 mg kg-1  day-1 ) to obtain Ctrough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg-1  day-1 instead of the maximum recommended dose of 60 mg kg-1  day-1 . CONCLUSION: This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.

Language plasticity after hemispherotomy of the dominant hemisphere in 3 patients: Implication of non-linguistic networks.

The neural networks involved in language recovery following hemispherotomy of the dominant hemisphere after language acquisition in children remain poorly known. Twelve hemispherotomized children (mean age at surgery: 11.3years) with comparable post-operative neuropsychological patterns underwent multi-task language functional MRI. Three of them had recovered from an initial postoperative aphasia i.e., hemispherotomy was performed on the language-dominant hemisphere. Our main results revealed (1) perisylvian activations in all patients after either left or right hemispherotomy; (2) no differences in activations between groups regarding the side of hemispherotomy; (3) additional activations in pre-frontal (3/3) and hippocampal/parahippocampal and occipito-parietal (2/3) areas, when comparing language activation in each of the three subjects with hemispherotomy of the language-dominant hemisphere to the group of 9 non-dominant hemispherotomized patients. These neural networks support the stronger engagement of learning and memory during language recovery in a hemisphere that was not initially actively subserving language.

Epilepsy in young Tsc1(+/-) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex.

OBJECTIVE: To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC). METHODS: Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin. RESULTS: Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases. SIGNIFICANCE: Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.

Epileptic Phenotype of Two Siblings with Asparagine Synthesis Deficiency Mimics Neonatal Pyridoxine-Dependent Epilepsy.

We report the cases of a brother and a sister of nonconsanguineous parents who developed progressive microcephaly and had tremor, irritability, spasticity, startle reflexes, and permanent erratic myoclonus since birth. Focal clonic seizures, status epilepticus, and infantile spasms appeared later, during the first months of life, while erratic myoclonic jerks persisted. Electroencephalogram initially showed multifocal spikes that evolved into modified hypsarrhythmia and then discontinuous activity, evoking the progressive nature of the condition. Magnetic resonance imaging showed brain atrophy and poor myelination. Plasma and cerebrospinal fluid asparagine levels were normal or moderately reduced on repeat testing. Both infants died at the age of 8 months in status epilepticus. Neuropathology of the brother revealed diffuse neuronal loss and astrocytic gliosis predominating in superficial layers of temporal and frontal lobes and in thalamus with almost absent myelin, as a consequence of the neuronal death. Whole exome sequencing of the siblings and parents revealed compound heterozygous c.1439C > T (p.Ser480Phe) and c.1648C > T (p.Arg550Cys) mutations in the ASNS gene, indicating asparagine synthetase (ASNS) deficiency. Electroclinical epileptic phenotype and neuropathological findings of ASNS deficiency are reminiscent of neonatal pyridoxine-dependent epilepsy, thus suggesting common pathophysiological mechanism possibly related to cytotoxic glutamate accumulation.

The ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies.

Hormonal therapy or ketogenic diet often permits overcoming the challenging periods of many epileptic encephalopathies (West and Lennox-Gastaut syndromes and encephalopathy with continuous spike-waves in slow sleep), but relapse affects over 20% of patients. We report here a monocenter pilot series of 42 consecutive patients in whom we combined oral steroids with the ketogenic diet for corticosteroid-resistant or -dependent epileptic encephalopathy. We retrospectively evaluated the effect on seizure frequency, interictal spike activity, neuropsychological course, and steroid treatment course. Twenty-three patients had West syndrome (WS), 13 had encephalopathy with continuous spike-waves in slow sleep (CSWS), and six others had miscellaneous epileptic encephalopathies. All patients succeeded to reach 0.8 to 1.6g/l ketone bodies in the urine following the usual KD regimen. For at least 6 months, 14/42 responded to the addition of the ketogenic diet: 4/23 with WS, 8/13 with CSWS, and 2/6 with miscellaneous epileptic encephalopathies. The addition of the KD allowed withdrawing steroids in all responders. Among them, 10/15 had been patients with steroid-dependent epileptic encephalopathy and 4/27 patients with steroid-resistant epileptic encephalopathy. Therefore, the ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies. Patients presenting with steroid-dependent CSWS seem to be the best candidates.

Language recovery after left hemispherotomy for Rasmussen encephalitis.

PURPOSE: Hemispherotomy (H) is the gold standard treatment to cure epilepsy in Rasmussen encephalitis (RE). Linguistic prognosis after surgery remains the main issue when the dominant hemisphere is involved. The topic of the present research is to specify the long-term linguistic profile of the right hemisphere after left dominant H for RE. METHODS: We followed 6 children 8.4 to 14.6 years of age who underwent left H for RE. Preoperatively, four children experienced aphasia, but for two, worsening occurred after surgery. Age at H ranged from 4.1 to 8.4 years. The mean duration of epilepsy was 1.2 years and 5.6 years for follow-up. Neuropsychological evaluation included longitudinal follow-up of intellectual efficiency measurement and a long-term outcome of language using various components of receptive and expressive oral speech with computerized tasks. KEY FINDINGS: Preoperatively, verbal comprehension index (VCI) was dramatically decreased in 4/6 patients, and performance reasoning index (PRI) was low in 5/6 participants, demonstrating a global impact of RE itself. Postoperatively, all children recovered sufficiently to attend a regular VCI (above 70) in a mean of 5 years after H, and 5/6 recovered normal or adapted school. There was a dissociation in favor of VCI, while PRI decreased in 5/6 patients. We found a specific linguistic profile for these children recovering language in the right hemisphere: normal verbal comprehension, and weakness of grammatical judgment, word repetition, statement production, semantic verbal fluency and metaphonological abilities. Language recovery scores were statistically correlated with those of Working Memory Index. SIGNIFICANCE: This study emphasizes for the first time the ability of the right hemisphere to functionally reorganize language over a long period of time following left H for RE. Syntactic abilities and phonology remain low and support the hypothesis of an early left hemispheric specialization. Nevertheless, lexico-semantic processes recover in the right hemisphere that could reflect a pre-existing potential of both hemispheres. Our results support a decision to proceed to H in classical left RE disease until the late childhood even if there is no complete aphasia before surgery. These data should be taken in account in the overall postoperative follow-up and rehabilitation strategy.

Seizures and epilepsy in hypoglycaemia caused by inborn errors of metabolism.

AIM: The aim of the study was to characterize seizures and epilepsy related to hypoglycaemia. METHOD: We analyzed the files of 170 consecutive patients referred for hypoglycaemia (onset 1h to 4y) caused by inborn errors of metabolism (glycogen storage disease type I, fatty acid ß-oxidation disorders, and hyperinsulinism). RESULTS: Ninety patients (42 males and 48 females; 38 neonates and 52 infants/children) had brief hypoglycaemic seizures (68%) or status epilepticus (32%). Status epilepticus occurred earlier (mean 1.4d) than brief neonatal seizures (4.3d, p=0.02). Recurrent status epilepticus followed initial status epilepticus and was often triggered by fever. Epilepsy developed in 21 patients. In 18 patients, epilepsy followed hypoglycaemic status epilepticus and began with shorter delay when associated with grey matter lesions (1.9mo, standard error of the mean [SEM] 1mo) than with white matter damage (3.3y [SEM 1y], p=0.003). Three patients with hyperinsulinism developed idiopathic epilepsy following brief neonatal seizures. INTERPRETATION: Brief neonatal hyperinsulinaemic hypoglycaemic seizures have characteristics of idiopathic neonatal seizures. Neonatal status epilepticus should be prevented by the systematic measurement of glucose blood level. Recurrent seizures never consist of status epilepticus when following brief initial seizures. Epilepsy is symptomatic of brain damage with shorter delay in the case of grey rather than white matter lesions, except in a few idiopathic cases in which epilepsy and hyperinsulinism may share a common genetic background.

Children often present with infantile spasms after herpetic encephalitis.

PURPOSE: To determine what epilepsy types occur after herpetic encephalitis and what are the determinant factors for subsequent infantile spasms. METHODS: We analyzed retrospectively the clinical history of 22 patients, referred to Necker and Saint Vincent de Paul Hospitals (Paris) through the French pediatric epilepsy network from March 1986 to April 2010 and who developed epilepsy some months after herpetic encephalitis. We focused on seizure semiology with video-electroencephalography (EEG) recording, and on neuroradiology and epilepsy follow-up. KEY FINDINGS: Fourteen patients developed pharmacoresistant spasms, and eight developed focal epilepsy, but none had both. The patients who developed spasms were more frequently younger than 30 months at age of onset of epilepsy and had herpetic encephalitis earlier (mean 10.6 months of age) than those who developed focal epilepsy (mean 59.7 and 39.6 months, respectively). Epilepsy follow-up was similar in both groups (8.5 and 11 years, respectively). We found 26 affected cerebral areas; none alone was related to the development of epileptic spasms. SIGNIFICANCE: Risk factors to develop epileptic spasms were to have had herpetic encephalitis early (mean 10 months); to be significantly younger at onset of epilepsy (mean 22.1 months); and to have cerebral lesions involving the insula, the hippocampus, and the temporal pole.

Transition and transfer from pediatric to adult health care in epilepsy: a families' survey on Dravet syndrome.

We used a questionnaire to ascertain the perception of transition and transfer from pediatric to adult health-care system in patients with Dravet syndrome and their families. Sixty families received the questionnaire. We had a response rate of 85%. Sixty-one percent of patients experienced a transfer. Factors that positively impacted transfer were the quality of transition preparation (p<.000001), a longer duration of follow-up by the same child neurologist (p<.001), the availability of the child neurology staff (p<.01), a transfer into the adult health-care system after the age of 18 (p<.01), and a stable medical condition before transfer (p<.05). All families reported a positive experience in the pediatric health-care system. Child neurologists were considered as welcoming, available, and helpful. Their experience in the adult health-care system was similar to pediatric care. Almost all patients who experienced "transfer" reported no gap in this process.