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The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS).We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2.5 to 22 years.Seizure onset ranged from 2 to 9 months (mean 5 months). Treatment started at a mean age of 7 months with valproate (VPA) as first therapy in 83% of patients. STP was prescribed in 96% at an average age of 20 months. At last follow-up (up to 22 years, median 8 years), 96% were still receiving STP, with VPA and clobazam (CLB) in 91%. Additional therapies were prescribed in 72% of patients. Most patients (96%) continued to have clonic or tonic-clonic seizures but they were brief (5min, with last status epilepticus (SE) episode being before 4 years of age). Seizures occurred weekly (3/month) in 38% of patients, monthly (1-3/month) in 40%, and yearly in the remaining patients. None presented with daily seizures. Seizure frequency at last visit was related to the age of treatment initiation, the age of last SE, and SCN1A mutation type.Triple therapy with STP, VPA, and CLB was maintained long-term by 96% of this large DS cohort because the reduced frequency and severity of seizures STP provided when added to CLB and VPA was durable. Nevertheless, only a few patients achieved seizure freedom and persisting seizures remains a concern in the majority of patients.

The aim was to localize the interictal cerebral perfusion abnormalities of focal cortical dysplasia (FCD) in children with Arterial Spin Labeling MRI (ASL) in a retrospective study of nine consecutive children explored with multimodal investigation during interictal periods. We analyzed brain morphology with a 1.5T MRI and a dedicated protocol for epilepsy. Brain perfusion was quantified with pseudo continuous ASL. Brain metabolism was imaged with (18)FDG-PET in six patients. Microvessel histology was studied in five children who underwent epilepsy surgery with CD34 immunostaining on FCD and control samples. Localized decrease of cerebral blood flow (CBF) was found on visual analysis in all patients with ASL. It was co-localized with the structural MRI abnormalities in every case, with PET hypo-metabolism in 5/6 cases, and with histologically proven FCD type IIb in 5/5 cases (all seizure free after surgery). CBF was lower (Kruskal-Wallis test, p=0.001) in FCD than in normal cortex. The total count of CD34+ microvessels was similar in FCD and control cases, but microvasculature showed disorganized architecture. Interictal ASL is a non-invasive method that may help to localize the epileptogenic zone showing hypo-perfusion in FCD. Whether this finding could be generalized to MRI-negative FCD needs to be further studied.

Previous studies investigating cerebral metabolic changes associated with continuous spike-waves during sleep (CSWS) compared the metabolism of children with CSWS with that of healthy adults, precluding any assessment in brain areas showing physiologic age-related metabolic changes. Here, we investigated the metabolic and connectivity changes characterizing the acute phase of CSWS activity by comparing awake brain metabolism of children with CSWS with that of pediatric pseudo-controls. Positron emission tomography using [18F]-fluorodeoxyglucose (FDG-PET) was performed in 17 awake children with cryptogenic CSWS (5 girls, age: 5-11 years). Voxel-based analyses identified significant metabolic changes in CSWS patients compared with 18 pediatric pseudo-controls (12 girls, age: 6-11 years, non-CSWS focal cryptogenic epilepsy with normal FDG-PET). CSWS-induced changes in the contribution of brain areas displaying metabolic changes to the level of metabolic activity in other brain areas were investigated using pathophysiological interaction. Hypermetabolism in perisylvian regions bilaterally and hypometabolism in lateral and mesial prefrontal cortex, precuneus, posterior cingulate cortex and parahippocampal gyri characterized the acute phase of CSWS (p0.05 FWE). No change in thalamic metabolism was disclosed. Altered functional connectivity was found between hyper- and hypometabolic regions in CSWS patients compared with pediatric pseudo-controls. This study demonstrates hypometabolism in key nodes of the default mode network (DMN) in awake patients with CSWS, in relation with a possible phenomenon of sustained remote inhibition from the epileptic foci. This hypometabolism might account for some of the acquired cognitive or behavioral features of CSWS epileptic encephalopathies. This study failed to find any evidence of thalamic metabolic changes, which supports the primary involvement of the cortex in CSWS genesis.

Summary Purpose To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3–9mg/kg/day) and to compare them to adult target ranges. Methods The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations ( C trough s) within the adult ranges. Results TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15L/h (13%) for CL/F without/with EIAEDs, 28.6L (0.2%) for Vd/F and 1.4h −1 (124%) for the absorption rate constant. Mean AUC 0–12h reached with a 2mg/kg/day dosing regimen was within described range. A 6–16mg/kg/day dose depending on age allowed reaching target C trough range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and C trough , respectively. Conclusion TPM dosage of 2/4mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach C trough comparable to adult values.

Summary A puzzling EEG pattern combining frontal slow bi–tri spikes followed or not by slow waves when awake and activated by sleep with 5–10 s discharges of 8–9 Hz spikes in a minority of adolescents with Dravet syndrome (DS) was recorded in the context of stable seizure and cognitive status, and unchanged antiepileptic medication. Tonic seizures were frequently reported in patients with this EEG pattern (3/5). This EEG pattern could suggest that of Lennox–Gastaut syndrome (LGS) but it exhibits clear differences and therefore should not be considered as a change into LGS but as a previously overlooked unusual pattern in the adolescent course of DS.

Vigabatrin has been shown to be efficient in infants with infantile spasms and tuberous sclerosis, in open studies. In order to compare vigabatrin to oral steroids, a prospective randomized multicenter study was implemented using both drugs as monotherapy in newly diagnosed patients with infantile spasms and tuberous sclerosis. Eleven infants received vigabatrin (150 mg/kg per day) and 11 hydrocortisone (15 mg/kg per day) for 1 month. Spasm free patients continued vigabatrin or progressively stopped hydrocortisone in 1 month, non-responders were crossed to the other drug for a new 2 month-period. All vigabatrin patients (11/11) were spasm-free versus 5/11 hydrocortisone infants (P < 0.01). Seven patients were crossed to vigabatrin (six for inefficacy, one for adverse events) and became also totally controlled. Mean time to disappearance of infantile spasms was 3.5 days on vigabatrin versus 13 days on hydrocortisone (P < 0.01). Five patients exhibited side effects on vigabatrin but nine on hydrocortisone (P = 0.006). Vigabatrin should therefore be considered as the first choice treatment for infantile spasms due to tuberous sclerosis.

Purpose To describe the characteristics of a previously overlooked devastating epileptic encephalopathy that presents as intractable bilateral perisylvian epilepsy starting with prolonged status epilepticus (SE) in normally developing school-aged children. Methods Retrospective study over 7 years of all normally developing children admitted in our institution for a prolonged SE following non-specific febrile illness with at least one seizure recorded on EEG. Results Fourteen children were included at a median age of 7.5 years (4–11) (median follow-up of 4 years (1–7)). Intractable SE lasted 4–60 days (median 30). CSF cell count was normal in five cases and moderately increased in the others. During SE, seizures were recorded in 11 patients and involved temporal lobes in 7; the other 4 patients exhibited perisylvian clinical features with secondary generalization. Intractable epilepsy followed SE in all cases without any latent period. Persisting seizures were recorded in 10 patients and involved temporo-perisylvian regions in 8, frontal regions in 2; 3 others had perisylvian ictal semiology. Spiking was bilateral in 10 cases. MRI showed bilateral hippocampal hypersignal and/or atrophy in 10 cases (extended to the neocortex in 3). All children had major cognitive sequelae. When feasible (six patients), detailed neuropsychology suggested fronto-temporal impairment. Conclusions Among so called grey matter encephalitis patients, we identified a recognizable pattern we propose to call Devastating Epileptic encephalopathy in School-age Children (DESC) that begins with prolonged SE triggered by fever of unknown cause, and persists as intractable perisylvian epilepsy with severe cognitive deterioration.

To investigate the impact of treatment lag in infantile spasms (IS) on treatment response, occurrence of later epilepsy, and long-term cognition and behavior in patients with one single etiological entity, we examined 18 patients with Down syndrome (DS) and earlier IS retrospectively (follow-up period of 32-180 months with a mean of 85.1 months), and determined their history and present condition, in terms of previously mentioned items. There was a statistically significant correlation between treatment lag and lag to cessation of spasms (R=0.55, P=0.02), developmental quotient (DQ) (R=-0.75, P=0.003), and score of autistic features (AF) (R=0.57, P=0.04). Moreover we found that the later the response to treatment of IS, the lower was the DQ (R=-0.86, P=0.001) and the higher was the score of autistic features (R=0.5, P=0.06). A long duration of spasms also determined a low DQ (R=-0.93, P0.0001) and a high score of autistic features (R=0.66, P0.01). All patients with persistent epilepsy (n=5) had had a treatment lag of over 2 months. Conversely, for all children treated within 2 months (n=8) spasms ceased within 3 months of treatment and none of them had later epilepsy. This group of patients with a treatment lag of less than 2 months had earlier treatment response (P=0.002), higher DQ (P=0.004) and lower score of autistic features (P=0.006). The data stress the importance of a short treatment lag in view of mental development and prevention of later epilepsy and autistic features, and raise the question of antiepileptogenic effect in this specific condition.

To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.

To describe the poorly known characteristics of epilepsy during infancy in focal cortical dysplasia (FCD), one of the most frequent cause of infantile epilepsy. All 28 patients with FCD referred to two specialized centres were retrospectively studied regarding seizure characteristics, psychomotor evaluation, and response to medical and surgical treatment. All patients presented with early partial seizures. Semiology, but not the age of onset, depended on the topography of the dysplasia, with abnormal eye movements in all cases of posterior FCD. Eleven patients also developed infantile spasms (IS), mainly asymmetrical. IS were easily controlled with Vigabatrin or ACTH, but no partial seizures could be medically controlled except in one patient. All patients except one had abnormal neuropsychological findings. Fifteen patients had surgery, eight became seizure free, and seven were significantly improved regarding psychomotor development. Very early and refractory partial seizures, but easily controlled IS are the main characteristics of FCD in infancy. Only the focal ictal semiology may help differentiate the localization of FCD. Its intrinsic epileptogenicity could sustain this clinical pattern. Since the chances for medical control and normal neurodevelopment are poor, surgical treatment should be considered early in infants with FCD.

Vigabatrin (VGB) has demonstrated high efficacy in infantile spasms (IS) due to tuberous sclerosis. Our first objective was to evaluate the cognitive long term effect outcome of children whose refractory spasms definitely disappeared when VGB was given as an add on drug. Our second objective was to determine the response of generalized epilepsy (infantile spasms) compared to partial epilepsy on cognitive impairment. A non selected series of 13 children underwent psychometric and behavioural evaluation before VGB initiation at a mean of 3 years on VGB treatment. Eight of them could perform detailed neuropsychological tests at follow-up. Seven had infantile spasms (Group I), they all were spasm free before 2 years of age and five remained with rare partial seizures (mean age, 5.5 years). Six others had partial epilepsy without spasms (Group II) and five remained with rare seizures (mean age, 7.5 years). Patients of Group I experienced dramatic changes. Developmental quotient (DQ) significantly rose in six out of seven by ten to more than 45 points (P = 0.03) and autistic behaviour disappeared in five out of the six who presented with. The four tested children had normal verbal level after 5 years and could integrate at school but they remained with marked visuospatial disabilities. By contrast, patients of Group II remained with an unchanged DQ of about 60 so that both groups had similar DQ levels on follow-up. The cessation of spasms with VGB is therefore associated with significant improvement of cognition and behaviour in children with tuberous sclerosis. Controlling secondary generalization induced by infantile spasms seems to be a key factor for mental development.

Controlled studies with new antiepileptic drugs are problematic and limited in children. Withdrawal randomization versus placebo in responders previously recognized in an open phase is a new design reported in adults which allows comparison to placebo without delaying the administration of the active compound. We applied such a design in refractory epileptic children in order to study vigabatrin (VGB) in children. Twenty-eight patients aged 1.5-18.5 years and having partially responded to VGB, prescribed in an open study for refractory epilepsy, were included. Patients were randomized to VGB (continued) or placebo (VGB blindy stopped in 3 weeks) for 2 months and seizure frequency was compared to the prerandomization period. More than 50% increase in seizure frequency induced drop-out. Fifteen patients received VGB, 13 others placebo, with the same clinical characteristics in both groups. The patients remaining in the study (primary efficacy endpoint) were more numerous on VGB (93%) than on placebo (46%) (P < 0.01) and seizure frequency (secondary endpoint) was lower on VGB than placebo (P < 0.05). The same results were observed in a subgroup of partial epilepsies. No status epilepticus was observed when withdrawing VGB and all patients returned to baseline status by reintroducing VGB. Such a randomized withdrawal design is therefore feasible in epileptic children. It provides the first VGB controlled study in this age range and demonstrates efficacy. It could be useful for future designs of drug trials in childhood epilepsy.

Hemimegalencephaly (HME) is a severe unilateral brain malformation the prognosis of which may be improved by hemispherectomy. HME also provides a unique opportunity to compare normal and pathological hemispheric function in the same patient. We performed a serial functional cerebral imaging study in a child suffering from a neuropathologically confirmed left HME. He was hemispherectomized at 11 months because of intractable epilepsy; this led to cessation of seizures and dramatic psychomotor improvement. Regional cerebral blood flow (rCBF) was studied at 1, 7, 10, 12 and 25 months with single photon computed tomography (SPECT) using 133-Xenon and with simultaneous EEG recording. At one month of age SPECT was performed ictally. During left EEG discharges, rCBF was 40% higher on the left hemisphere than on the right, even in occipital and frontal regions, usually immature at this age. A crossed cerebellar hyperperfusion was also found. At 7 and 10 months, SPECT was performed interictally; rCBF was 45% lower in the left hemisphere than in the right. During follow-up, global and regional CBF values showed normal levels and normal maturation in the right hemisphere except for a mild and transient decrease observed one month after hemispherectomy. SPECT provides an additional procedure for studying hemispheric function in vivo. Serial SPECT imaging may be useful for the preoperative and postoperative evaluation in unilateral cerebral malformation.