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Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is a rare syndrome associated with cognitive and behavioural regression. On the basis of mostly small observational and retrospective studies, corticosteroids and clobazam are often considered the most effective treatments for this syndrome. We aimed to compare cognitive outcomes of children with EE-SWAS 6 months after starting treatment with either corticosteroids or clobazam. We did a multicentre, randomised controlled trial at eight tertiary referral centres for rare epilepsies in seven European countries. Children were eligible to participate if they were aged 2–12 years, were diagnosed with EE-SWAS within 6 months before inclusion, and had not been treated with corticosteroids or clobazam previously. Participants were randomly assigned (1:1) to treatment with corticosteroids (either continuous treatment with 1–2 mg/kg per day of prednisolone orally or pulse treatment with 20 mg/kg per day of methylprednisolone intravenously for 3 days every 4 weeks) or clobazam (0·5–1·2 mg/kg per day orally). The primary outcome was cognitive functioning after 6 months of treatment, which was assessed by either the intelligence quotient (IQ) responder rate (defined as improvement of ≥11·25 IQ points) or the cognitive sum score responder rate (defined as improvement of ≥0·75 points). Safety was assessed by number of adverse events and serious adverse events. Data were analysed in the intention-to-treat population, which included all children as randomised who had primary outcome data available at 6 months. The trial is registered with the Dutch Trial Register, Toetsingonline, NL43510.041.13, and the ISRCTN registry, ISRCTN42686094. The trial was terminated prematurely because enrolment of the predefined number of 130 participants was deemed not feasible. Between July 22, 2014, and Sept 3, 2022, 45 children were randomly assigned to either corticosteroids (n=22) or clobazam (n=23); two children assigned clobazam dropped out before 6 months and were excluded from the intention-to-treat analysis. At the 6-month assessment, an improvement of 11·25 IQ points or greater was reported for five (25%) of 20 children assigned corticosteroids versus zero (0%) of 18 assigned clobazam (risk ratio [RR] 10·0, 95% CI 1·2–1310·4; p=0·025). An improvement of 0·75 points or more in the cognitive sum score was recorded for one (5%) of 22 children assigned corticosteroids versus one (5%) of 21 children assigned clobazam (RR 1·0, 95% CI 0·1–11·7, p=0·97). Adverse events occurred in ten (45%) of 22 children who received corticosteroids, most frequently weight gain, and in 11 (52%) of 21 children who received clobazam, most often fatigue and behavioural disturbances. Occurrence of adverse events did not differ between groups (RR 0·8, 95% CI 0·4–1·4; p=0·65). Serious adverse events occurred in one child in the corticosteroid group (hospitalisation due to laryngitis) and in two children in the clobazam group (hospitalisation due to seizure aggravation, and respiratory tract infection). No deaths were reported. The trial was terminated prematurely, and the target sample size was not met, so our findings must be interpreted with caution. Our data indicated an improvement in IQ outcomes with corticosteroids compared with clobazam treatment, but no difference was seen in cognitive sum score. Our findings strengthen those from previous uncontrolled studies that support the early use of corticosteroids for children with EE-SWAS. EpilepsieNL, WKZ fund, European Clinical Research Infrastructure Network, and Ming fund.

Behavioral evidence shows that sleep is crucial for the consolidation of declarative memories in children as in adults. However, the underlying cerebral mechanisms remain virtually unexplored. Using magnetoencephalography, we investigated in children (8.0–12.5years) the impact of sleep (90-minute nap) on the neurophysiological processes underlying the creation and consolidation of novel associations between unknown objects and their functions. Learning-dependent changes in brain activity were observed within hippocampal and parahippocampal regions, followed by sleep-dependent changes in the prefrontal cortex, whereas no equivalent change was observed after a similar period of wakeful rest. Hence, our results show that in school-age children a 90-minute daytime nap after learning is sufficient to trigger the reorganization of memory-related brain activity toward prefrontal areas, where it incorporates into pre-existing semantic knowledge. This functional reorganization process in children is similar to that observed in adults but occurs at a much faster rate, which may contribute to the development of the impressive learning skills that characterize childhood. •Sleep triggers a rapid reorganization of new verbal memories in children.•Learning-related changes are initially centered over the (para)hippocampal region.•Sleep-dependent changes in the prefrontal cortex subtend delayed memory retrieval.•No equivalent change is observed after a similar period of wakeful rest.•Effects are specific to the learning of new verbal representations, not to repeated exposure.

•Changes of slow waves in overnight EEGs are thought to reflect synaptic plasticity.•Synaptic plasticity is strongly dependent on intact NMDAR function.•Antibody-mediated NMDAR deficiency occurs in patients with anti-NMDAR encephalitis.•In this human model of NMDAR deficiency, we found altered slow wave changes.•Sleep EEG measures may mark NMDAR-related impairments of synaptic plasticity. Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3–20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor ‘hour’) for patients and controls (factor ‘group’). There was a significant interaction between ‘hour’ and ‘group’ (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Maternal obesity is associated with an increase in maternal, foetal and neonatal morbidity and mortality. The aim of our study was to evaluate the relationships between maternal pre-pregnancy body mass index and (1) neonatal outcome in preterm infants, and (2) neurodevelopmental outcome at 2 years of corrected age. We conducted a single-centre cohort study. Infants born between 24+0 and 33+6 weeks of gestation between January 2009 and December 2013, hospitalised in the neonatal intensive care unit of Angers University Hospital, and with available data regarding maternal pre-pregnancy body mass index were eligible. Three groups were defined according to maternal body mass index: normal (n = 418), overweight (n = 136) and obese (n = 89). The primary outcome was neurodevelopment at 2 years of corrected age. Children with a non-optimal neuromotor and/or psychomotor assessment and/or a sensory disability were regarded as having a \"non-optimal neurodevelopmental outcome\". Neuromotor function was regarded as non-optimal when cerebral palsy was present or when the clinical examination revealed neurological signs of abnormal muscular tone. Psychomotor assessment was regarded as non-optimal if the revised Brunet-Lézine test was < 85 or when the overall score in the parental Ages and Stages Questionnaire (ASQ) was < 185. Finally, sensory disabilities such as blindness and children who required a hearing aid were taken into account. The secondary outcome was the composite criteria of neonatal complications. Multivariable analysis included the following variables: mother's age, gestational age, smoking during pregnancy, magnesium sulphate and steroid treatment during pregnancy, twin status, gender, socioeconomic status and social security benefits for those with low incomes. The study population was composed of 643 preterm infants. Among them, 520 were assessed at 2 years. There was no difference in the proportion of infants with non-optimal neurodevelopmental outcomes between the three groups (16.6% for obese, 13.5% for overweight, 16.9% for normal body mass index mothers; p = 0.73). According to multivariable analysis, being born from an overweight or obese mother was not associated with an increased risk of non-optimal neuro-development at 2 years (adjusted OR = 0.84 [0.40-1.76] for obese, adjusted OR = 0.83 [0.43-1.59] for overweight mothers). There was no difference in the proportion of preterm infants with a non-optimal composite criterion of neonatal complications between the three groups. In the multivariable analysis, being born from an overweight or obese mother was not associated with an increased risk of non-optimal neonatal outcomes (adjusted OR = 0.95 [0.49-1.83] for obese, adjusted OR = 1.18 [0.69-2.01] for overweight mothers). In this large prospective cohort of preterm infants born before 34 weeks of gestation, we found no relationship between maternal body mass index and neurodevelopmental outcomes at 2 years of corrected age and no relationship between maternal body mass index and neonatal outcomes. Other prematurity-related factors may be more relevant for neurodevelopmental outcome than the mother's pre-pregnancy BMI.

We present a novel method, corticokinematic coherence (CKC), for functional mapping of the motor cortex by computing coherence between cortical magnetoencephalographic (MEG) signals and the kinematics of voluntary movements. Ten subjects performed self-paced flexion–extensions of the right-hand fingers at about 3Hz, with a three-axis accelerometer attached to the index finger. Cross-correlogram and coherence spectra were computed between 306 MEG channels and the accelerometer signals. In all subjects, accelerometer and coherence spectra showed peaks around 3–5Hz and 6–10Hz, corresponding to the movement frequencies. The coherence was statistically significant (P<0.05) in all subjects, with sources at the hand area of the primary motor cortex contralateral to the movement. CKC appears to be a promising and robust method for reliable and convenient functional mapping of the human motor cortex. ► New corticokinematic coherence method. ► Magnetoencephalographic singals are coherent with hand kinematics. ► Coherence frequency corresponds to hand movement frequency. ► M1 cortex can be localized using this coherence phenomenon.

ObjectiveThis prospective, bicentre, blinded, intention to treat study assessed the clinical added value of magnetic source imaging (MSI) in the presurgical evaluation of patients with refractory focal epilepsy (RFE).Methods70 consecutive patients with RFE (42 men; mean age 31.5 years, range 3–63) from two Belgian centres were prospectively included. All patients underwent conventional non-invasive presurgical evaluation (CNIPE) and a whole head magnetoencephalography recording (Elekta Neuromag). Equivalent current dipoles corresponding to interictal epileptiform discharges (IED) were fitted in the patients' spherical head model and coregistered on their MRI to produce MSI results. Results of CNIPE were first discussed blinded to the MSI results in respective multidisciplinary epilepsy surgery meetings to determine the presumed localisation of the epileptogenic zone and to set surgical or additional presurgical plans. MSI results were then discussed multidisciplinarily. MSI influence on the initial management plan was assessed.ResultsBased on CNIPE, 21 patients had presumed extratemporal epilepsy, 38 had presumed temporal epilepsy and 11 had undetermined localisation epilepsy. MSI showed IED in 52 patients (74.5%) and changed the initial management in 15 patients (21%). MSI related changes were significantly more frequent in patients with presumed extratemporal or undetermined localisation epilepsy compared with patients with presumed temporal epilepsy (p≤0.001). These changes had a clear impact on clinical management in 13% of all patients.ConclusionMSI is a clinically relevant, non-invasive neuroimaging technique for the presurgical evaluation of patients with refractory focal epilepsy and, particularly, in patients with presumed extratemporal and undetermined localisation epilepsy.

Motor information conveyed by viewing the kinematics of an agent's action helps to predict how the action will unfold. Still, how observed movement kinematics is processed in the brain remains to be clarified. Here, we used magnetoencephalography (MEG) to determine at which frequency and where in the brain, the neural activity is coupled with the kinematics of executed and observed motor actions. Whole-scalp MEG signals were recorded from 11 right-handed healthy adults while they were executing (Self) or observing (Other) similar goal-directed hand actions performed by an actor placed in front of them. Actions consisted of pinching with the right hand green foam-made pieces mixed in a heap with pieces of other colors placed on a table, and put them in a plastic pot on the right side of the heap. Subjects' and actor's forefinger movements were monitored with an accelerometer. The coherence between movement acceleration and MEG signals was computed at the sensor level. Then, cortical sources coherent with movement acceleration were identified with Dynamic Imaging of Coherent Sources. Statistically significant sensor-level coherence peaked at the movement frequency (F0) and its first harmonic (F1) in both movement conditions. Apart from visual cortices, statistically significant local maxima of coherence were observed in the right posterior superior temporal gyrus (F0), bilateral superior parietal lobule (F0 or F1) and primary sensorimotor cortex (F0 or F1) in both movement conditions. These results suggest that observing others' actions engages the viewer's brain in a similar kinematic-related manner as during own action execution. These findings bring new insights into how human brain activity covaries with essential features of observed movements of others. •Mirroring of kinematic processing in executed and observed goal-directed actions.•Mirroring occured in the right posterior superior temporal gyrus.•Mirroring occured in bilateral superior parietal lobule.•Mirroring occured in bilateral primary sensorimotor cortex.•Mirroring of kinematic might help humans to understand how observed actions unfold.

The potassium channel tetramerization domain-containing protein 7 (KCTD7) was named after the structural homology of its predicted N-terminal broad complex, tramtrack and bric à brac/poxvirus and zinc finger domain with the T1 domain of the Kv potassium channel, but its expression profile and cellular function are still largely unknown. We have recently reported a homozygous nonsense mutation of KCTD7 in patients with a novel form of autosomal recessive progressive myoclonic epilepsy. Here, we show that KCTD7 expression hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. We found the expression of KCTD7 in the hippocampal and Purkinje cells of the murine brain, an expression profile consistent with our patients’ phenotype. The effect on the plasma membrane resting potential is possibly mediated by Cullin-3, as we demonstrated direct molecular interaction of KCTD7 with Cullin-3 in co-immunoprecipitation assays. Our data link progressive myoclonic epilepsy to an inherited defect of the neuron plasma membrane’s resting potential in the brain.

To investigate epilepsy-induced changes in effective connectivity between the non-epileptic amygdalo-hippocampal complex (AHC) and the rest of the brain in patients with unilateral mesiotemporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS). Thirty-three patients with unilateral MTLE associated with HS (20 females, mean age: 36 years, 19 left HS) and 33 adult controls matched for age and gender underwent (18)F-Fluorodeoxyglucose positron emission tomography (FDG-PET). Right-HS patients' FDG-PET data were flipped to obtain a left-epileptic-focus-lateralized group of patients. Voxels of interest (VOI) were selected within the cytoarchitectonic probabilistic maps of the non-epileptic AHC (probability level  = 100%, SPM8 Anatomy toolbox v1.7). Patients and controls were compared using VOI metabolic activity as covariate of interest to search for epilepsy-induced changes in the contribution of the non-epileptic AHC to the level of metabolic activity in other brain areas. Age, gender, duration of epilepsy, seizure type and frequency were used as covariates of no-interest for connectivity analyses. Significant decrease in effective connectivity was found between the non-epileptic AHC and ventral prefrontal cortical areas bilaterally, as well as with the temporal pole and the posterior cingulate cortex contralateral to HS. Significant increase in connectivity was found between the non-epileptic AHC and midline structures, such as the anterior cingulate and dorsal medial prefrontal cortices, as well as the temporo-parietal junction bilaterally. Connectivity analyses also revealed a preserved positive connectivity between the non-epileptic and the epileptic AHC in the patients' group. This study evidences epilepsy-induced changes in connectivity between the non-epileptic AHC and some limbic and default mode network areas. These changes in connectivity probably account for emotional, cognitive and decision-making impairments frequently observed in MTLE patients. The preserved neurometabolic connectivity between the non-epileptic and the epileptic AHC in MTLE patients is pivotal to explain the epilepsy-induced changes found in this study.

[This corrects the article on p. e67053 in vol. 8.].