Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome.

Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

[Assessment of education needs of adolescents and parents of children with epilepsy]. / Évaluation des besoins en éducation thérapeutique auprès des parents d'enfants et d'adolescents ayant une épilepsie.

INTRODUCTION: Education program for patients (EPP) is now a part of the management of patients with chronic disease. According to WHO, the EPP is designed to help patients to maintain or gain self-care skills and adaptive skills necessary to improve their health and their quality of life. Patient education programs have been developed in recent years in several chronic diseases such as diabetes and asthma. In the field of epilepsy, however, adult and child programs have been developed only recently in France. We evaluate the interests for the establishment of an EPP and the topics that the parents and the adolescents would like to be discussed in such courses. METHODS: We conducted a qualitative survey, based on interviews of parents of epileptic children and adolescents. The survey was conducted between April and November 2010 in pediatric neurology services of four French university hospitals: Amiens, Nancy, Marseille, and in Robert Debré (Paris) hospital. We investigated the following issues: treatment and self-management, and seizure management, psychosocial difficulties related to epilepsy, anatomical and physiological knowledge of epilepsy and lifestyle. RESULTS: Two topics seem to have the greatest interest for parents of children with epilepsy and adolescents: knowledge about seizures and knowledge of anatomy and physiology of the brain. Adolescents involved in this study gave consistently lower scores in all items compare to parents of children. CONCLUSION: The medical management of children and adolescents with epilepsy, and their caregivers, is a comprehensive care including the EPP in order to provide a full management of all issues raised by epilepsy. The survey identified key-points that parents and their children would like to learn in an EPP. These data would be helpful to design an EPP.

Spatiotemporal source analysis in scalp EEG vs. intracerebral EEG and SPECT: a case study in a 2-year-old child.

OBJECTIVE: This case study aims to demonstrate that spatiotemporal spike discrimination and source analysis are effective to monitor the development of sources of epileptic activity in time and space. Therefore, they can provide clinically useful information allowing a better understanding of the pathophysiology of individual seizures with time- and space-resolved characteristics of successive epileptic states, including interictal, preictal, postictal, and ictal states. METHODS: High spatial resolution scalp EEGs (HR-EEG) were acquired from a 2-year-old girl with refractory central epilepsy and single-focus seizures as confirmed by intracerebral EEG recordings and ictal single-photon emission computed tomography (SPECT). Evaluation of HR-EEG consists of the following three global steps: (1) creation of the initial head model, (2) automatic spike and seizure detection, and finally (3) source localization. During the source localization phase, epileptic states are determined to allow state-based spike detection and localization of underlying sources for each spike. In a final cluster analysis, localization results are integrated to determine the possible sources of epileptic activity. The results were compared with the cerebral locations identified by intracerebral EEG recordings and SPECT. RESULTS: The results obtained with this approach were concordant with those of MRI, SPECT and distribution of intracerebral potentials. Dipole cluster centres found for spikes in interictal, preictal, ictal and postictal states were situated an average of 6.3mm from the intracerebral contacts with the highest voltage. Both amplitude and shape of spikes change between states. Dispersion of the dipoles was higher in the preictal state than in the postictal state. Two clusters of spikes were identified. The centres of these clusters changed position periodically during the various epileptic states. CONCLUSION: High-resolution surface EEG evaluated by an advanced algorithmic approach can be used to investigate the spatiotemporal characteristics of sources located in the epileptic focus. The results were validated by standard methods, ensuring good spatial resolution by MRI and SPECT and optimal temporal resolution by intracerebral EEG. Surface EEG can be used to identify different spike clusters and sources of the successive epileptic states. The method that was used in this study will provide physicians with a better understanding of the pathophysiological characteristics of epileptic activities. In particular, this method may be useful for more effective positioning of implantable intracerebral electrodes.

[Experience with levetiracetam in the treatment of childhood refractory epilepsy]. / Utilisation du lévétiracétam (LEV) dans le traitement des épilepsies réfractaires de l'enfant : expérience du service de neuropédiatrie du CHU d'Amiens en France.

INTRODUCTION: In young children presenting drug-resistant epilepsy, the number of approved antiepileptic drugs is limited. Levetiracetam (LEV) is one of the most recent antiepileptic drugs (AED) introduced on the market and data on its effectiveness and tolerance in children are scarce. PATIENTS AND METHODS: The objective of this retrospective study was to report our experience with the use of levetiracetam as an adjuvant therapy in a population of 42 children presenting a drug-resistant epilepsy. The study was conducted over a 5-year-period (from 1 January 2004 to 30 June 2007). RESULTS: The patients' mean age was 10.8 years (range, 2.1-19 years). The mean duration of epilepsy was 6.6 years (range, 1.5-19 years). After the administration of LEV, 10 patients (23.8%) became seizure-free and 16 (38.1%) had more than 50% seizure reduction. A reduction of less than 50% was observed in 13 patients (31%). Three patients (7.1%) presented an increase in seizure frequency. The effectiveness of LEV was similar in partial and generalized epilepsy. LEV was well tolerated by these patients. The main adverse effects were anorexia, asthenia, and behavioral disorders, and drowsiness was encountered in 17% of the patients. All persistent adverse events were noted. In children under 4 years of age, LEV was particularly well tolerated. CONCLUSION: This study confirms the effectiveness and tolerance of LEV used as an adjuvant therapy in children presenting drug-resistant epilepsy, particularly in the very young ones.

[Familial and non-familial benign infantile seizures: A homogeneous entity?]. / Convulsions infantiles bénignes familiales et non familiales : une entité homogène ?

Among the epileptic syndromes occurring during infancy, which are mostly non-idiopathic and associated with a poor prognosis, benign infantile convulsions are characterized by a favourable evolution. This work aims to analyse and compare the clinical, EEG and outcome characteristics of familial benign infantile convulsions (FBIC) and non-familial benign infantile convulsions (NFBIC). This is a retrospective study, conducted between 1988 and 2008, in 40 infants who presented benign infantile seizures during the two first years of life. All of them had no personal history, normal psychomotor development, normal neurological examinations, no abnormalities on biological and radiological investigations and a favourable outcome. In 14 cases, there was a familial history of familial benign infantile convulsions. However, among the 26 cases with non-familial benign infantile convulsions, 11 children had a familial history of other epileptic syndrome. That may suggest a genetic familial susceptibility. In the two groups, the clinical features and the electroencephalography were similar. The seizures had short duration and occurred most often in clusters. Twenty-nine children had secondarily generalized partial seizures and 11 infants had generalized seizures but a focal onset cannot be excluded. The antiepileptic drugs allowed rapid resolution of seizures. One child necessitated a prolonged antiepileptic treatment. In the other cases, seizures cured in the first year without recurrence of seizures after treatment discontinuation. The evolution was characterised in five children by a later occurrence of dystonia. This subgroup was described as infantile convulsion and choreoathetosis syndrome (ICCA). Benign infantile convulsions are probably an underestimated epileptic syndrome. The diagnosis is relatively easy in the familial forms with dominant autosomal transmission. In contrast, in sporadic forms, the diagnosis can be confirmed only by the evolution. The good prognosis must be tempered by the subsequent onset of dystonia consisted in the ICCA syndrome and justifies a prolonged follow-up.

[Infratentorial ischemic stroke in children: Three case reports]. / Accidents vasculaires cérébraux de la fosse postérieure chez l'enfant : à propos de trois cas.

Ischemic stroke is rare in children, most of which occur in the supratentorial brain, and infratentorial infarcts are very rare. Some clinical manifestations may be similar but others such as ataxia and cranial nerve palsy are more specific. Vertebral artery dissection is the most frequent cause of stroke in the vertebrobasilar territory, but the cause most often remains unknown in children. We report three cases of infratentorial stroke in children. The first observation concerns a 4-year-old boy brought to medical attention because left hemicorporal motor deficit associated with ataxia following a minor cranial traumatism. While computed tomography (CT) of the brain was normal, magnetic resonance imaging (MRI) revealed an area of signal alteration on the diffusion-weighted image within the right protuberance. The second observation is a 15-year-old girl who developed sudden-onset ataxia. The CT scan and MRI of the brain revealed an acute bilateral cerebellar stroke. MRI angiography showed an anatomical variant of the left vertebral artery that did not participate in the Willis polygon. In these two observations, no other abnormalities were detected except they were homozygotous for MTHFR mutation in the first observation and minor alpha-thalassemia for the second one. The outcome in these two children was good without sequelae after a 6-month follow-up. The third observation is a 6-year-old girl who suddenly exhibited cephalalgia, ataxia, and left visual impairment. The brain MRI revealed left occipital and cerebellar strokes due to vertebral artery dissection. The authors recommend the systematic search for vertebral artery dissection in cases of infratentorial stroke.

Maturation of response time and attentional control in ADHD: evidence from an attentional capture paradigm.

Inattention and hyperactivity/impulsivity are the core symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). Slowness, although less known, has been also recently reported in children with ADHD and may contribute to their learning difficulties. Slow response time and greater response time variability have been highlighted by several computerized tasks. The goal of the present work was to evaluate the age-related response time in ADHD children and in a group of matched control children during an attentional capture paradigm. The study population included 75 children with ADHD (aged between 6 and 13) and 75 age- and gender-matched typical developing children (Control group). The children with ADHD made more errors than children on the control group. The response times and the response time variability decreased with age in both groups and were significantly greater in ADHD than in controls. The distractor effect was similar in both groups. The maturation of response times and response time variability with age is quite similar in children with ADHD and typical developing children but whatever the age-class, children with ADHD were slower and exhibited greater response time variability than control children that could explain the variation during day-time of attention capacities in ADHD.

Local haemodynamic changes preceding interictal spikes: a simultaneous electrocorticography (ECoG) and near-infrared spectroscopy (NIRS) analysis in rats.

The mechanisms that drive neurons to synchronize in epileptic spikes are still subject to debate. In the present study, we used a combination of electrocorticography and near-infrared spectroscopy (ECoG/NIRS) to evaluate haemodynamic changes before, during and after epileptic spikes induced by administration of bicuculline methiodide (BM) onto the sensorimotor cortex in 8 adult Sprague-Dawley rats. Simultaneous ECoG/NIRS signals were recorded during an initial reference period (to measure spontaneous bioelectrical/metabolic activities) and then again 60 min after BM administration. Spikes in the ECoG were detected by an in-house program based on MatLab 7.0. The appearance times of the P1 peaks were used to determine corresponding time periods in the NIRS for further analysis. We observed a pronounced pre-spike modification in the haemodynamics, which became visible latest 5 s before the spike, achieving after some oscillations its minimum at round about the P1 appearance time. The post-spike period was characterized by an initial increase in oxyhaemoglobin (HbO) and total haemoglobin (HbT) to a maximum at about 2 s after the spike followed by a phase of declining oscillations disappearing after 10 to 15 s after the spike. We discuss the mechanisms underlying the haemodynamic and electrical changes that occur before, during and after epileptiform spikes. The haemodynamic changes observed with NIRS and occurring before the spikes constitute a haemodynamic predictor of electrical synchronization of spikes.

Coupled oxygenation oscillation measured by NIRS and intermittent cerebral activation on EEG in premature infants.

Electroencephalography of premature neonates shows a physiological discontinuity of electrical activity during quiet sleep. Near infrared spectroscopy (NIRS) shows spontaneous oscillations of hemoglobin oxygenation and volume. Similar oscillations are visible in term neonates and adults, with NIRS and other functional imaging techniques (fMRI, Doppler, etc.), but are generally thought to result from vasomotion and to be a physiological artifact of limited interest. The origin and possible relationship to neuronal activity of the baseline changes in the NIRS signal have not been established. We carried out simultaneous EEG-NIRS recordings on six healthy premature neonates and four premature neonates presenting neurological distress, to determine whether changes in the concentration of cerebral oxy- and deoxy- and total hemoglobin were related to the occurrence of spontaneous bursts of cerebral electric activity. Bursts of electroencephalographic activity in neonates during quiet sleep were found to be coupled to a transient stereotyped hemodynamic response involving a decrease in oxy-hemoglobin concentration, sometimes beginning a few seconds before the onset of electroencephalographic activity, followed by an increase, and then a return to baseline. This pattern could be either part of the baseline oscillations or superimposed changes to this baseline, influencing its shape and phase. The temporal patterns of NIRS parameters present an unique configuration, and tend to be different between our healthy and pathological subjects. Studies of physiological activities and of the effects of intrinsic regulation on the NIRS signal should increase our understanding of these patterns and EEG-NIRS studies should facilitate the integration of NIRS into the set of clinical tools used in neurology.