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This longitudinal study aims to describe the trajectory of language development in children with CHD aged 12-24 months assessed through an early monitoring and individualized intervention program. We also sought to determine whether early language performances, at 12 months of age, predict 24-month language abilities. We conducted developmental assessments of 49 children with CHD using the Bayley Scales of Infant and Toddler Developmental, third edition (Bayley-III) at 12 and 24 months, and the MacArthur-Bates Communicative Development Inventories (MBCDI) at 12, 18 and 24 months. Compared to normative populations, CHD patients showed significantly lower mean scores in both receptive and expressive language scales of the Bayley-III and the MBCDI at 12 months, whereas at 18 and 24 months only expressive language scores were reduced. No differences were found in the cognitive scale. Communicative gestures at 12 months were significantly predictive of language skills at 24 months of age. Our findings indicate specific vulnerability of language outcome, especially in expressive skills, rather than a global cognitive impairment in our patients with CHD. We recommend using communicative gestures as an early marker of language development to improve our ability to detect language delays in this population.

Purpose: This retrospective study aims to describe the gross motor development of children aged 4 to 24 months with congenital heart disease (CHD) enrolled in a systematic developmental follow-up program and to describe the frequency of physical therapy sessions they received between 4 and 8 months of age. Methods: Twenty-nine infants with CHD underwent motor evaluations using the AIMS at 4 months, and the Bayley-III at 12 and 24 months. Results: Based on AIMS, 79% of 4-month-old infants had a gross motor delay and required physical therapy. Among these, 56.5% received one to two physical therapy sessions, and 43.5% received three to six sessions. Infants who benefited from regular interventions tended to show a better improvement in motor scores from 12 to 24 months. Conclusion: This study highlights the importance of early motor screening in infants with CHD and suggests a potential benefit of early physical therapy in at-risk children. Abbreviations: CHD: Congenital heart disease; AIMS: Alberta Infant Motor Scales; Bayley-III: Bayley Scales of Infant and Toddler Development, Third edition; Bayley-III/GM: Gross Motor section of the Bayley Scales of Infant and Toddler Development, Third edition.

Parents' understanding/expectations regarding genetic testing for children with developmental disorders were explored. Within a month of testing, interviews were conducted with 57 parents. Many (74%) could not recall the nature of testing. Parents expected genetic testing to have positive impacts for the child (93%) and the family (98%), mainly to find the etiology and/or an intervention. Many parents (40%) reported not knowing their child's clinical diagnosis. They expected genetic testing would establish the diagnosis. Parents anticipated potential negative impacts of testing for children (78%) and families (87%), mainly finding another illness or not finding potential interventions. Abnormal results explaining the disorder were found in 9% of children. In summary, genetic results for developmental disorders are unlikely to meet parental expectations.

Infants with congenital heart disease are at risk of impaired neurodevelopment, which frequently manifests as motor delay during their first years of life. This delay is multifactorial in origin and environmental factors, such as a limited experience in prone, may play a role. In this study, we evaluated the motor development of a prospective cohort of 71 infants (37 males) with congenital heart disease at 4 months of age using the Alberta Infant Motor Scales (AIMS). We used regression analyses to determine whether the 4-month AIMS scores predict the ability to walk by 18 months. The influence of demographic and clinical variables was also assessed. Fifty-one infants (71.8%) were able to maintain the prone prop position (AIMS score of ≥3 in prone) at 4 months. Of those, 47 (92.2%) were able to walk by 18 months compared to only 12/20 (60%) of those who did not maintain the position. Higher AIMS scores were predictive of a greater likelihood of walking by 18 months ( P < .001), with the scores in prone having a higher predictive ability compared to those in other positions (Exp(B) 15.2 vs 4.0). Shorter hospital stays and female gender were also associated with an earlier onset of walking. In conclusion, our study demonstrates that early ventral performance in infants with congenital heart disease impacts the age of acquisition of walking and could be used to guide referral to rehabilitation.

Levetiracetam (LEV), and its newer selective analog brivaracetam (BRV), are two seizure medications that share an innovative mechanism of action targeting the Synaptic Vesicle Protein 2A (SV2A), altering neurotransmitter release and decreasing seizure frequency. Behavioral changes are the most significant adverse effects reported by patients taking LEV. We hypothesize that BRV, the more potent SV2A analog, could exert less behavioral side effects, as it requires lower doses than LEV. Using Kainic Acid (KA)-treated and control rats, we measured adverse behavioral effect profiles of LEV, BRV, or Saline, on social and nonsocial behaviors. Our data indicate that both tested drugs had no effect on locomotion, anxiety levels, fear learning, depression-like behavior, and memory retention in rats. However, when considering social interactions, we first confirmed the epilepsy-induced strong increase in aggressive behaviors and specific hippocampal neuronal loss. We furthermore observed, in Sham rats, that LEV-treated animals were 2 times faster to attack at first encounter, had 5 times more aggressive behaviors, and had significantly less social behaviors than control rats. In all circumstances, BRV rats behaved like Saline rats, suggesting that BRV treatment in rats leads to significantly less aggressive behaviors than LEV treatment at the doses used, while there are limited differential effects between these two drugs on other types of behaviors. Since increased aggressiveness has been reported in patients well controlled on LEV, this study indicates based on our findings, that BRV could represent an effective alternative to LEV to limit aggressiveness problems due to this antiepileptic drug (AED) therapy.

Objective Prenatal exposure to stress and fever are factors lowering seizure threshold in animal models. The fever effect on seizure threshold is well documented in human infants, however the associations between maternal perinatal stress and infants’ susceptibility to seizures is unknown. This is the first study in humans to investigate longitudinally, whether in humans, the effect of maternal perinatal emotional symptoms such as stress, anxiety and depression that may trigger a biological stress response on age at first seizure occurrence. Method The study sample is a subgroup drawn from a longitudinal follow up cohort (3D cohort study: Design, Develop, Discover, N = 2366 mother-infant dyads). Twenty-nine otherwise healthy infants who had a febrile seizure (FS) episode before the last follow-up visit (around 24 months of age) were studied. Mothers completed questionnaires regarding their emotional health at each pregnancy trimester and at three months postpartum. The link between maternal emotional symptoms and infant age at first FS was assessed through correlations and multiple regressions. Results We found that maternal anxiety symptoms during the second trimester of pregnancy are linked to the age at first FS (r(23) = −0.459, p = 0.021) and explain 21.1% of its variance. Postnatal maternal depression symptoms at 3 months postpartum were also associated with the age at first FS (r(23) = −0.587, p = 0.002) and explained an additional 17.6% of variance. Together, the variables explained 38.7% of the variance in age at first FS. Maternal perceived stress symptoms at 3 months postpartum were also linked to the age at first FS (r(23) = −0.418, p = 0.038), however, stress did not significantly contribute to the variance of age at first FS.. Significance Our results suggest a link between increased perinatal maternal emotional symptoms and the age at first FS. An earlier age at first FS may be the manifestation of a lower seizure threshold. Early first seizure occurrence is a risk factor for compromised neurological and cognitive development. Further studies should address the mechanisms by which perinatal maternal emotional symptoms may have an impact on seizure threshold in humans.

SummaryObjective To describe the developmental trajectories of quality of life (QoL) in a large cohort of children with epilepsy, and to assess the relative contribution of clinical, psychosocial, and sociodemographic variables on QoL trajectories. Methods Five assessments during a 28-month prospective cohort study were used to model trajectories of QoL. Participants were recruited with their parents from six Canadian tertiary centers. A convenience sample of 506 children aged 8–14 years with epilepsy and without intellectual disability or autism spectrum disorder were enrolled. A total of 894 children were eligible and 330 refused participation. Participating children were, on average, 11.4 years of age, and 49% were female. Nearly one third (32%) had partial seizures. At baseline, 479 and 503 child- and parent-reported questionnaires were completed. In total, 354 children (74%) and 366 parents (73%) completed the 28-month follow-up. QoL was measured using the child- and parent-reported version of the Childhood Epilepsy QoL scale (CHEQOL-25). Results Child-reported QoL was fitted best by a six-class model and parent-reported QoL by a five-class model. In both models, trajectories remained either stable or improved over 28 months. Of these children, 62% rated their QoL as high or moderately high, defined as at least one standard deviation above the average CHEQOL-25 score. Greater family, classmate, and peer social support, fewer symptoms of child and parent depression, and higher receptive vocabulary were identified as the most robust predictors of better QoL (all p < 0.001). Significance Most children with epilepsy and their parents reported relatively good QoL in this first joint self- and proxy-reported trajectory study. Findings confirm the heterogeneous QoL outcomes for children with epilepsy and the primary importance of psychosocial factors rather than seizure and AED-specific factors in influencing QoL. These predictors that are potentially amenable to change should now be the focus of specific intervention studies.

Seizures are common in critically ill neonates. Both seizures and antiepileptic treatments may lead to short term complications and worsen the outcomes. Predicting the risks of seizure reoccurrence could enable individual treatment regimens and better outcomes. We aimed to identify EEG signatures of seizure reoccurrence by investigating periictal electrographic features and spectral power characteristics in hypothermic neonates with hypoxic-ischemic encephalopathy (HIE) with or without reoccurrence of seizures on rewarming.We recruited five consecutive HIE neonates, submitted to continuous EEG monitoring, with high seizure burden (20% per hour) while undergoing therapeutic hypothermia. Two of them had reoccurrence of seizures on rewarming. We performed quantitative analysis of fifteen artifact-free consecutive seizures to appreciate spectral power changes between the interictal, preictal and ictal periods, separately for each patient. Visual analysis allowed description of electrographic features associated with ictal events.Every patient demonstrated a significant increase in overall spectral power from the interictal to preictal and ictal periods (p0.01). Alpha power increase was more pronounced in the two patients with reoccurrence of seizures on rewarming and significant when comparing both interictal-to-preictal and interictal-to-ictal periods. This alpha activity increase could be also appreciated using visual analysis and distinguished neonates with and without seizure reoccurrence.This distinct alpha activity preceding ictal onset could represent a biomarker of propensity for seizure reoccurrence in neonates. Future studies should be performed to confirm whether quantitative periictal characteristics and electrographic features allow predicting the risks of seizure reoccurrence in HIE neonates and other critically ill patients.

International audience; We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Background Seizures are one of the most common symptoms of pediatric brain tumors. The purpose of this study was to define seizures related to primary central nervous system tumors and to identify risk factors predictive of seizure occurrence and recurrence. Methods We reviewed the records of children treated from January 1, 2004, to January 1, 2018 and collected data including age, gender, tumor location, histology, extent of initial resection, seizure characteristics, treatment modalities, recurrence, and seizure control. A binomial logistic regression was performed to determine the risk factors of seizure occurrence. Results During the observation period, 348 children were diagnosed with a primary brain tumor. The median age at diagnosis was 7.8 years, and the median follow-up interval was 3.9 years. There were 196 boys (56.3%). In our cohort, a total of 70 children (20.1%) experienced seizures. Most of them (64.3%) had cortical tumors. All patients with dysembryoplastic neuroepithelial tumors and 81.8% of patients with glioneuronal tumors presented seizures. Risk factors associated with an increased risk for seizures included cortical location, tumor recurrence, and age at diagnosis. Thirty-nine (86.7%) patients with seizures at diagnosis were seizure free at last follow-up (Engel 1). Significantly more patients (69.6%) with a gross total resection were withdrawn from their antiepileptic drugs when compared with those with subtotal resection (27.3%, P = 0.007). Conclusions Our study is the largest cohort in children with tumor-related seizures and brings new insight in terms of seizure risk according to tumor types and evolution following treatment.

Purpose Children with complex congenital heart disease (CHD) experience high incidence of perioperative seizures. Population-based studies also report high epilepsy co-morbidity in CHD. Given the increasing survival of patients with CHD and the interference of seizures and epilepsy with the long-term outcomes, characterizing them in this population is of high relevance. This study investigated the incidence and risk factors of perioperative clinical seizures (CS) and epilepsy in a prospective cohort of children with complex CHD who underwent cardiac surgery. Methods We included 128 consecutive children with CHD, followed for at least two years at the neurocardiac clinic of Montreal’s Sainte-Justine University Hospital Center. We collected perinatal, surgical, critical care and clinical follow-up information and performed logistic regression to reveal risk factors of CS and epilepsy. Results Ten patients (7.8%) experienced perioperative CS. Four of them (40%) developed epilepsy. The incidence of epilepsy was therefore 3.1%. Higher surgical complexity scores, delayed sternal closure, extracorporeal membrane oxygenation (ECMO) use, longer intensive care and hospital stay were associated with CS. ECMO use and hospital stay were also associated with epilepsy. Nine (90%) patients with CS had brain injuries: five strokes, one white matter and three hypoxic-ischemic injury (HII). All patients with HII developed epilepsy, which became intractable in one of them. Conclusion Our study reports high incidence, surgical risk factors and brain injury patterns underlying CS and epilepsy in CHD. Further studies are needed to investigate how epilepsy interferes with neurodevelopment and quality of life in CHD.

Summary Introduction Children with benign epilepsy with centro-temporal spikes (BECTS) often have language problems. Abnormal epileptic activity is found in central and temporal brain regions, which are involved in reading and semantic and syntactic comprehension. Using functional magnetic resonance imaging (fMRI), we examined reading networks in BECTS children with a new sentence reading comprehension task involving semantic and syntactic processing. Method Fifteen children with BECTS (age=11y 1m±16 m; 12 boys) and 18 healthy controls (age=11 y 8m±20 m; 11 boys) performed an fMRI reading comprehension task in which they read a pair of syntactically complex sentences and decided whether the target sentence (the second sentence in the pair) was true or false with respect to the first sentence. All children also underwent an exhaustive neuropsychological assessment. Results We demonstrated weaknesses in several cognitive domains in BECTS children. During the sentence reading fMRI task, left inferior frontal regions and bilateral temporal areas were activated in BECTS children and healthy controls. However, additional brain regions such as the left hippocampus and precuneus were activated in BECTS children. Moreover, specific activation was found in the left caudate and putamen in BECTS children but not in healthy controls. Cognitive results and accuracy during the fMRI task were associated with specific brain activation patterns. Conclusion BECTS children recruited a wider network to perform the fMRI sentence reading comprehension task, with specific activation in the left dorsal striatum. BECTS cognitive performance differently predicted functional activation in frontal and temporal regions compared to controls, suggesting differences in brain network organisation that contribute to reading comprehension.

Background— Arrhythmias associated with QT prolongation on the ECG often lead to sudden unexpected death in epilepsy. The mechanism causing a prolongation of the QT interval during epilepsy remains unknown. Based on observations showing an upregulation of neuronal sodium channels in the brain during epilepsy, we tested the hypothesis that a similar phenomenon occurs in the heart and contributes to QT prolongation by altering cardiac sodium current properties (I Na ). Methods and Results— We used the patch clamp technique to assess the effects of epilepsy on the cardiac action potential and I Na in rat ventricular myocytes. Consistent with QT prolongation, epileptic rats had longer ventricular action potential durations attributable to a sustained component of I Na (I NaL ). The increase in I NaL was because of a larger contribution of neuronal Na channels characterized by their high sensitivity to tetrodotoxin. As in the brain, epilepsy was associated with an enhanced expression of the neuronal isoform Na V 1.1 in cardiomyocyte. Epilepsy was also associated with a lower I Na activation threshold resulting in increased cell excitability. Conclusions— This is the first study correlating increased expression of neuronal sodium channels within the heart to epilepsy-related cardiac arrhythmias. This represents a new paradigm in our understanding of cardiac complications related to epilepsy.

Unilateral hippocampal atrophy (HA) is considered as a precursor of mesial temporal sclerosis (MTS) in some patients with temporal lobe epilepsy. However, in other cases, it has been suggested that HA without MTS may constitute a distinct epileptic entity. Hippocampal atrophy without MTS was defined as HA without T2-weighted hyperintensity, loss of internal architecture, or associated lesion seen on the MRI data. To date, no study has focused on the cognitive pattern of children with epilepsy with HA without MTS. The objectives of the present study were to characterize the cognitive profile of these children and to investigate the presence (or the absence) of material-specific memory deficits in these young patients, as found in patients with MTS. Toward this end, 16 young patients with epilepsy with either left or right HA without MTS completed a set of neuropsychological tests, assessing overall intelligence, verbal memory and nonverbal memory, and some aspects of attention and executive functions. Results showed normal intellectual functioning without specific memory deficits in these patients. Furthermore, comparison between patients with left HA and patients with right HA failed to reveal a material-specific lateralized memory pattern. Instead, attention and executive functions were found to be impaired in most patients. These results suggest that HA may constitute a distinct epileptic entity, and this information may help health-care providers initiate appropriate and timely interventions.

Summary Background Epilepsy is currently conceptualized as a disturbance of neuronal networks with altered connectivity that persists into the interictal phase. Febrile seizures are sometimes a precursor in childhood of lifelong epilepsy. We investigated whether studying functional connectivity in children with febrile seizures could help understand the mechanisms underlying their long-term seizure susceptibility. Methods EEG was recorded during rest and intermittent photic stimulation (IPS) in 12 FS patients, 5 siblings and 15 control children between 6 and 36 months of age. Original EEG data were transformed into source space using a multiple regional source model. Source coherence values were calculated for the interfrontal, interoccipital and occipito-frontal connections for the delta, theta, alpha, beta and gamma frequency bands. Results Our results suggest enhanced delta and theta frequency EEG source coherence in patients with FSs compared to siblings and control children, both under resting conditions and during IPS, more consistent for the theta band and the occipito-frontal connections. Conclusions Enhanced connectivity in patients with FSs could indicate a seizure-prone state and interfere with the maturation of cerebral networks. Further prospective studies are needed to assess whether hyperconnectivity is a risk factor for epileptogenesis and neurodevelopmental disorders.

Rasmussen's encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-γ- and granzyme B-expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of α4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn's disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics.

Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAStatistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAFunctionally relevant variants in genes encoding GABAEuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Background Orbitofrontal epilepsy (OFE) is less known and is poorly characterized in comparison with temporal lobe epilepsy, partly because it is rare and possibly because it is unrecognized and therefore underestimated. Objective This paper aimed to better characterize seizure semiology, presurgical findings, and surgical outcomes in patients with OFE. Methods We retrospectively reviewed all confidently established OFE cases from six Canadian epilepsy monitoring units between 1988 and 2014, and in the literature between 1972 and 2017. Inclusion criteria were identification of an epileptogenic lesion localized in the OFC or if the patient was seizure-free after surgical removal of the OFC in nonlesional cases. Results Sixteen cases were identified from our databases. Fifty percent had predominantly sleep-related seizures; 56% had no aura (the remaining had nonspecific or vegetative auras), and 62.5% featured hypermotor (mostly hyperkinetic) behaviors. Interictal epileptiform discharges over frontal and temporal derivations always allowed lateralization. Magnetic resonance imaging (MRI) identified an orbitofrontal lesion in 8/16, positron emission tomography (PET) identified a hypometabolism extending outside the orbital cortex in 4/9, ictal single-photon emission computed tomography (SPECT) identified an orbital hyperperfusion in 1/5, magnetoencephalography (MEG) identified lateral orbital sources in 2/4, and intracranial electroencephalography (EEG) identified an orbitofrontal onset in 9/10. Fourteen patients underwent surgery, all reaching a favorable outcome (71.4% Engel 1; 28.6% Engel 2; mean FU = 5.6 years). Pre- and postoperative neuropsychological assessments revealed heterogeneous findings. Our review of literature identified 71 possible cases of OFE, 32 with confident focus localization. Extracted data from these cumulated cases supported observations made from our case series. Conclusions Orbitofrontal epilepsy should be suspected with sleep-related, hyperkinetic seizures with no specific aura, and frontotemporal interictal discharges. Several patients have nonmotor seizures with or without auras which may resemble temporal lobe seizures. Postoperative seizure outcome was favorable, but there is inherent bias as we only included patients with a seizure-free outcome if the MRI was negative. A larger study is required to address identified gaps in knowledge such as identifying discriminative features between medial and lateral OFE, evaluating the value of more recent diagnostic tools, and assessing the neuropsychological outcome of orbital epilepsy surgery.

Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy.In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22).Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively.VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.

The aim of this study was to develop a fast and efficient electrophysiological protocol to examine the visual field's integrity, which would be useful in pediatric testing.Steady-state visual-evoked potentials (ssVEPs) to field-specific radial checkerboards flickering at two cycle frequencies (7.5 and 6 Hz for central and peripheral stimulations, respectively) recorded at Oz were collected from 22 participants from 5 to 34 years old and from 5 visually impaired adolescents (12-16 years old). Responses from additional leads (POz, O1, O2), and the impact of gaze deviation on the signals, were also investigated in a subgroup of participants.Steady-state visual-evoked potentials responses were similar at all electrode sites, although the signal from the central stimulation was significantly higher at Oz and was highly sensitive in detecting gaze deviation. No effect of age or sex was found, indicating similar ssVEP responses between adults and healthy children. Visual acuity was related to the central signal when comparing healthy participants with four central visual impaired adolescents. Clinical validation of our electrophysiological protocol was also achieved in a 15-year-old adolescent with a severe peripheral visual deficit, as assessed with Goldmann perimetry.A single electrode over Oz is sufficient to gather both central and peripheral visual signals and also to control for gaze deviation. Our method presents several advantages in evaluating visual fields integrity, as it is fast, reliable, and efficient, and applicable in children as young as 5 years old. However, a larger sample of healthy children should be tested to establish clinical norms.

Purpose In Mali, epilepsy affects 15 individuals per thousand. Perceptions and attitudes have not seemingly evolved with advancing medical knowledge. The objective of this study was to assess parental beliefs and attitudes in families with and without affected children. Methods We enrolled 720 pediatric patients, half of whom had epilepsy, at Mali's largest hospital. We conducted semistructured interviews with the accompanying parent. Control families with unaffected patients and also had affected children were excluded. Results In total, 67% and 24% of families with and without epilepsy, respectively, lived in rural environments. Interviewees were mostly mothers in their 30s; 80% had not completed high school. About 22% of parents without an affected child had witnessed a seizure. During a seizure, 94% of parents with an affected child and 49% of parents without an affected child, respectively, would intervene; 7.5% and 21%, respectively, would wet the patient's face with cool water. Although parents with an affected child had more intimate knowledge of seizures, misconceptions prevailed, perhaps more so than in families without epilepsy: 79% and 66% of parents, respectively, considered epilepsy contagious; 43% vs. 69% thought that it inevitably led to psychosis; and 53% vs. 29% attributed epilepsy to supernatural causes. Finally, 63% of parents with an affected child reported consulting a traditional healer as first-line management for epilepsy. Conclusions Our study demonstrates widespread misconceptions in Mali regarding epilepsy. Our findings argue for more education initiatives focused on the entire population, including traditional healers, to provide knowledge, reduce stigma, and improve quality of life for individuals living with epilepsy.

Background: The impact of childhood epilepsy can only be appreciated by understanding that epilepsy comprises a set of complex neurobehavioral conditions with significant social consequences, and not simply disorders of recurrent seizures. Our objective is to describe the hypotheses and methodology behind a large prospective longitudinal study that is based on a conceptual framework for understanding health outcomes. The study will quantify the specific influences—direct, mediating or moderating—that various epilepsy, comorbid, child, and family variables exert on health over the early life course. Methods: The target population is 8- to 14-year-old children with epilepsy and their caregivers from across Canada. Children, caregivers, and health professionals are completing 17 measures at five visits over a 28-month period. We have selected measures based on content, the source of the items, psychometric properties, and provisions for child self-report. Our cross-sectional and longitudinal design includes a relational model for structural equation modeling of specific biomedical and psychosocial variables with hierarchical direction of influence. To measure change over time, we will use hierarchical linear modeling. Significance: This article reports the framework for interpreting future data. We believe that it will help researchers consider their methodology and encourage them to plan and execute longitudinal studies. Furthermore, the article will help clinical readers identify what to look for when evaluating outcomes research. It is our belief that the next generation of research to understand life-course effect in the lives of children and youth with chronic conditions and their families must occur over real time.

Atypical febrile seizures (FSs) are considered a risk factor for the onset of epilepsy in later life as well as for potential cognitive impairment. However, distinctive characteristics defining the group of children at risk for negative outcomes are not well established. In the following study, children from 6 to 59 months with a history of atypical FSs were investigated using steady state visual evoked potentials (ssVEP), a brain response known to increase with age. Abnormally, low theta and alpha ssVEP brain responses were found in children with a history of atypical FSs.

The SCN1A gene has been implicated in the etiology of various forms of epilepsy. New research has linked this gene to specific types of epilepsy, all of which present in infancy or early childhood. This study examines the time course and pathology of pediatric patients who have a mutation in the SCN1A gene in order to open a discussion regarding the key trends of this form of epilepsy as well as important clinical considerations in management for patients who present with symptoms relating to the SCN1A mutations. We retrospectively examined 20 patients who presented to the clinic with focal seizures, as well as were positive for an SCN1A genetic mutation. Despite the small sample size, we were able to find important trends in the time course of the disorder as well as important areas of clinical practice that must be taken into consideration for these patients.

Background We assessed central and peripheral visual field processing in children with epilepsy who were exposed to vigabatrin during infancy. Methods Steady-state visual evoked potentials and pattern electroretinograms to field-specific radial checkerboards flickering at two cycle frequencies (7.5 and 6 Hz for central and peripheral stimulations, respectively) were recorded from Oz and at the eye in seven school-age children (10.1 ± 3.5 years) exposed to vigabatrin early in life, compared with children early exposed to other antiepileptic drugs (n = 9) and healthy children (n = 8). The stimulation was made of two concentric circles (0 to 5 and 30 to 60 degrees of angle) and presented at four contrast levels (96%, 64%, 32%, and 16%). Results Ocular responses were similar in all groups for central but not for the peripheral stimulations, which were significantly lower in the vigabatrin-exposed group at high contrast level. This peripheral retinal response was negatively correlated to vigabatrin exposure duration. Cortical responses to central stimulations, including contrast response functions in the children with epilepsy in both groups, were lower than those in normally developing children. Conclusions Alteration of ocular processing was found only in the vigabatrin-exposed children. Central cortical processing, however, was impaired in both epileptic groups, with more pronounced effects in vigabatrin-exposed children. Our study suggests that asymptomatic long-term visual toxicity may still be present at school age, even several years after discontinuation of drug therapy.

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. Decrease of Syngap1 in mice has been previously shown to cause cognitive deficits at least in part by inducing alterations in glutamatergic neurotransmission and premature maturation of excitatory connections. Whether Syngap1 plays a role in the development of cortical GABAergic connectivity and function remains unclear. Here, we show that Syngap1 haploinsufficiency significantly reduces the formation of perisomatic innervations by parvalbumin-positive basket cells, a major population of GABAergic neurons, in a cell-autonomous manner. We further show that Syngap1 haploinsufficiency in GABAergic cells derived from the medial ganglionic eminence impairs their connectivity, reduces inhibitory synaptic activity and cortical gamma oscillation power, and causes cognitive deficits. Our results indicate that Syngap1 plays a critical role in GABAergic circuit function and further suggest that Syngap1 haploinsufficiency in GABAergic circuits may contribute to cognitive deficits., Glutamatergic signalling regulation by Syngap1 has been linked to intellectual disabilities. Here, the authors find Syngap1 also regulates cortical GABAergic synaptic signalling development and that this reduced inhibitory signalling contributes to cognitive deficits in a mouse model.

Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits.

We investigated the development of the magnitude and phase alignment of steady-state visual evoked potentials induced by 5 Hz intermittent photic stimulation in 46 children (3 to 16 years) and 8 adults, as a function of age. We found that, over the occipital region, magnitude values were the highest in 8-11-year old children, but decreased with age over all other cerebral regions. Phase alignment values increased with age over the occipital, parietal and frontal cerebral regions. We interpret these findings in terms of the development of functional interactions between different cortical areas involved in the processing of visual stimuli.

Purpose The goals of this study are to evaluate the efficacy and tolerability of levetiracetam (LEV) as add-on therapy in children with refractory epilepsies and to determine the value of LEV blood level monitoring in this population. Methods Sixty-nine children (39 males and 30 females) treated with LEV between 2006 and 2007 were selected. Their medical files were reviewed for LEV efficacy and tolerability. In a subgroup of children currently taking LEV, plasma concentrations were determined by high performance liquid chromatography by ultraviolet detection (HPLC-UV) method and correlated with the given dose per kilo as well as clinical response. Results Fifty-one patients (74%) had a more than 50% reduction in seizure frequency with 16 patients (23%) becoming seizure free on LEV. Eighteen (26%) patients had a less than 50% reduction in seizure frequency. Adverse events due to LEV ranged from mild to moderate in only 18 patients (26%). The most frequently observed were drowsiness, behavioral difficulties, increase in seizure frequency and headaches. The majority (60.5%) of the responders received doses between 10 and 50mg/kg/day and had a plasma concentration (PC) between 5 and 40μg/ml. However, we found no clear correlation between PC and efficacy. Conclusion Levetiracetam given twice a day in children with refractory epilepsy reduces seizure frequency in all types of epilepsy. In children, LEV is a broad spectrum anticonvulsant with a favourable safety profile.

Summary Objective: To determine the clinical characteristics, surgical challenges, and outcome in children younger than 3 years of age undergoing epilepsy surgery in Canada. Methods: Retrospective data on patients younger than age 3 years who underwent epilepsy surgery at multiple centers across Canada from January 1987 to September 2005 were collected and analyzed. Results: There were 116 patients from eight centers. Seizure onset was in the first year of life in 82%, and mean age at first surgery was 15.8 months (1–35 months). Second surgeries were done in 27 patients, and a third surgery in 6. Etiologies were malformations of cortical development (57), tumor (22), Sturge-Weber syndrome (19), infarct (8), and other (10). Surgeries comprised 40 hemispheric operations, 33 cortical resections, 35 lesionectomies, 7 temporal lobectomies, and one callosotomy. There was one surgical mortality. The most common surgical complications (151 operations in 116 patients) were infection (17) and aseptic meningitis in 13. Of 107 patients with seizure outcome assessed more than one year postoperatively, 72 (67.3%) were seizure free (Engel I), 15(14%) had >90% improvement (Engel II), 12 had >50% improvement (Engel III), and 8 did not benefit from surgery (Engel IV). Development improved in 55.3% after surgery. Conclusion: Epilepsy surgery in children younger than 3 years of age is relatively safe and is effective in controlling seizures. Very young age is not a contraindication to surgery in children with refractory epilepsy, and early surgery may impact development positively.

Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients. In contrast, we observed no de novo or truncating mutations in SYNGAP1 in samples from 142 subjects with autism spectrum disorders, 143 subjects with schizophrenia, and 190 control subjects. These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.

Gamma band electroencephalography (EEG) abnormalities have been reported in patients with epilepsy. We aimed to investigate whether patients with febrile seizures (FS) show abnormalities of the gamma frequency steady-state visual evoked potential (SSVEP) components evoked by intermittent photic stimulation (IPS). We analyzed the magnitude and phase alignment of the 50-100 Hz SSVEP components elicited by IPS from 12 FS patients, 5 siblings of FS patients, and 15 control children between 6 and 36 months of age. Patients with FS showed significantly higher SSVEP magnitude and phase alignment values when compared to both the siblings and control groups. Detected abnormalities could either represent the direct consequence of seizures or indicate a preexisting tendency to hypersynchrony in FS patients. Future prospective studies could assess whether SSVEP abnormalities are associated with complex rather than simple FS, or have a prognostic value for the development of epilepsy following FS.

Lacosamide is an antiepileptic drug approved for the treatment of focal epilepsy in adult patients. The aim of this observational study was to review our centre's experience with lacosamide and to characterize its effectiveness and tolerability as an adjunctive antiepileptic drug in a retrospective cohort of children with refractory focal epilepsy.We retrospectively reviewed the medical records of 22 patients who received lacosamide from November 2009 to April 2014 at the CHU Ste-Justine, University of Montreal. Treatment responders were defined as children with a ≥50% reduction in seizure frequency compared to baseline, and this was determined three months after the initiation of treatment and at the last follow-up visit.We included 14 boys and eight girls with a mean age of 12.9 years (SD: 5.2; range: 5.2-20.7 years) at the initiation of treatment. The average length of follow-up was 11.9 months. Patients had previously received an average of 7.5 antiepileptic drugs. The mean number of concomitant antiepileptic drugs was 2.3. The mean initial and maintenance doses were 2.9 and 8.4 mg/kg/d, respectively. Thirteen (59%) and ten (45%) patients were responders after three months of treatment and at the last follow-up visit, respectively. One became seizure-free. Adverse effects were reported in 11 patients and none were severe. Responders and non-responders were identical with respect to all studied parameters except gender, with the proportion of responders being greater in girls than in boys (75% vs 29%; p=0.035).Our study adds evidence that lacosamide appears to be a safe and effective adjunctive therapy for children with refractory focal epilepsy.

Objective To investigate how rewarming impacts the evolution of EEG background in neonates with hypoxic–ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Methods We recruited a retrospective cohort of 15 consecutive newborns with moderate (9) and severe (6) HIE monitored with a continuous EEG during TH and at least 12 h after its end. EEG background was analyzed using conventional visual and quantitative EEG analysis methods including EEG discontinuity, absolute and relative spectral magnitudes. One patient with seizures on rewarming was excluded from analyses. Results Visual and quantitative analyses demonstrated significant changes in EEG background from pre- to post-rewarming, characterized by an increased EEG discontinuity, more pronounced in newborns with severe compared to moderate HIE. Neonates with moderate HIE also had an increase in the relative magnitude of slower delta and a decrease in higher frequency theta and alpha waves with rewarming. Conclusions Rewarming affects EEG background in HIE newborns undergoing TH, which may represent a transient adaptive response or reflect an evolving brain injury. Significance EEG background impairment induced by rewarming may represent a biomarker of evolving encephalopathy in HIE newborns undergoing TH and underscores the importance of continuously monitoring the brain health in critically ill neonates.

SummaryObjective Infantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. Methods Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule—Generic (ADOS-G). Results Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). Significance ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome.

Objective The high-fat ketogenic diet has long been used to treat refractory childhood seizures, but whether there is a relation between the degree of ketosis and effectiveness of seizure control remains unclear. Frequent measurements of plasma ketones are difficult in children so the goal was to determine the utility of breath acetone as a marker of systemic ketosis and seizure control in children given the ketogenic diet because of seizures refractory to medication. Methods In experiment I, breath acetone and plasma ketones were assessed every 2 h during an 8-h test day in seven children. In experiment II, a preliminary assessment of the possible relation between breath acetone and seizure frequency was made over 14 d in five children and one adolescent on the ketogenic diet. Results Breath acetone was positively and curvilinearly related to plasma acetone (r2 = 0.99, P < 0.0001), plasma acetoacetate (r2 = 0.89, P < 0.0001), and plasma β-hydroxybutyrate (r2 = 0.94, P < 0.0001). No significant relation was found between breath acetone and seizure frequency or change in seizure frequency. Conclusions Breath acetone is indicative of systemic ketosis while on the ketogenic diet. However, owing to the wide range of seizure types and plasma acetone, more subjects will be needed to determine whether there is a clear link between breath acetone and seizure frequency or decreased seizure frequency while on the high-fat ketogenic diet.

Summary Purpose To assess the influence of the family history (FH) of epilepsy or febrile seizures (FSs) on the clinical presentation of FSs and on their outcome. Methods We reviewed the charts of 482 children admitted to the Ste-Justine Hospital with FSs between 3 months and 6 years of age and followed for at least 5 years. Results Children with a positive FH of epilepsy (n=67) showed significantly more focal and recurrent FSs than those without such a FH. The risk of developing partial epilepsy (n=17) or generalized epilepsy (n=19) was significantly greater in children with focal or recurrent FSs, respectively. In children with focal FSs, only two out of 30 (6.7%) children with a negative FH of epilepsy developed partial epilepsy compared with four out of nine (44.4%) children with a positive FH. In children with recurrent FSs, as much as seven out of 34 (20.6%) children with a positive FH of epilepsy developed generalized epilepsy compared to only eight out of 161 (0.05%) of those with a negative FH. Nevertheless, when not taking into account the clinical presentation of FSs, the positive FH of epilepsy constituted a risk factor for developing generalized but not partial epilepsy. Finally, children with a positive FH of FSs (n=120) exhibited significantly more recurrent FSs than those without such a FH, but this did not modify the risk of epilepsy. Conclusion The FH of FSs and/or epilepsy should be taken into account when evaluating the risk of FSs recurrence and of epilepsy.

Objective . The goal of this study was to investigate the potential protective effects of nimodipine (ND), a calcium channel blocker, on the acute manifestations and long-term behavioral sequalae of experimental status epilepticus (SE). Methods . Three groups of Postnatal Day (P) 35 rats undergoing kainic acid (KA)-induced SE were injected with phenobarbital (PB) and/or ND, and were subsequently compared with rats injected with KA alone and normal control rats. Behavioral parameters were assessed by the Morris water maze, open field, and handling tests at P125–P135. Acute seizures and spontaneous recurrent seizures (SRS) were assessed by videotape techniques. Results . PB reduced the severity of SE acutely, and protected completely against subsequent long-term SRS, memory impairment, and hyperactivity, and partially against aggressivity. ND alone had no effect on acute seizure activity, but did protect against subsequent SRS and memory impairment, and partially against aggressivity. When administered together, PB and ND had effects similar to those seen with PB alone. However, in addition, and unlike the PB- and ND-alone groups, the PB–ND group was completely protected against KA-induced increased aggressivity. Conclusions . Activation of L-type calcium channels contributes to the long-term behavioral sequalae of KA-induced SE, but is not essential for the development and maintenance of SE. ND has protective effects in SE when given alone or in conjunction with a traditional antiepileptic drug. Calcium channel blockers should be further investigated as add-on protective agents in models of SE and possibly in clinical trials.

Epilepsy is a common brain disorder which is characterised by recurring seizures. In addition to suffering from the constant stress of living with this neurological condition, patients also frequently experience comorbid psychiatric and cognitive disorders which significantly impact their quality of life. There is growing appreciation that stress, in particular occurring in early life, can negatively impact brain development, creating an enduring vulnerability to develop epilepsy. This aligns with the solid connections between early life environments and the development of psychiatric conditions, promoting the possibility that adverse early life events could represent a common risk factor for the later development of both epilepsy and comorbid psychiatric disorders. The influence of sex has been little studied, but recent research points to potential important interactions, particularly with regard to effects mediated by HPA axis programming. Understanding these interactions, and the underlying molecular mechanisms, will provide important new insights into the causation of both epilepsy and of psychiatric disorders, and potentially open up novel avenues for treatment.

Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ∼40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole-exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.

Whether febrile seizures lead to hippocampal necrosis is a question of paramount clinical importance. This study attempted to simulate a complex febrile seizure, compared with hyperthermia (HYP) alone and prolonged seizure alone (produced by continuous hippocampal stimulation (CHS)). Four groups of rats were studied at each of two ages, immature (postnatal day, P20) and adult (P60). Group 1 was subjected to 45 min of HYP (body temperature 40 degrees C) plus CHS, Group 2 received 45 min of HYP alone, Group 3 got 45 min of CHS alone, and Group 4 was sham-handled control rats. Baseline and post-session EEGs were recorded in all groups. Subsequently, brains were examined histologically for evidence of hippocampal damage. Both CHS-treated groups (with and without HYP) exhibited behavioral and EEG seizures while the group undergoing HYP alone did not have seizures. There were no gross histological lesions in any group. Cell counts in regions CA1, CA3, dentate gyrus and dentate hilus did not differ in rats under any condition of hyperthermia and CHS, in either P20 or P60 rats compared to age-matched controls. These results indicate that both immature and mature rodents are resistant to hyperthermic brain damage and raises the question of whether febrile seizures play a role in the genesis of mesial temporal sclerosis.

Glutamate-mediated regulation of intracellular Ca2+ levels was examined in different populations of CA1 interneurons, using confocal microscopy and the Ca2+ indicator fluo 3-AM in rat hippocampal slices. Interneurons in basal [stratum oriens/alveus (OA)] and apical [strata radiatum and lacunosum-moleculare (R/LM)] dendritic layers responded heterogeneously to glutamate. In control medium, OA interneurons responded mostly with oscillatory Ca2+ responses, which consisted of a large Ca2+ transient and successive smaller elevations. R/LM interneurons responded mostly with biphasic responses, characterized by an initial large transient and a secondary prolonged elevation. Other interneurons in both R/LM and OA responded with transient elevations in Ca2+ levels. Ionotropic glutamate receptor antagonists (+/-)2-amino-5-phosphonopentanoic acid and 6-cyano-7-nitro-quinoxaline-2,3-dione reduced peak Ca2+ responses in OA and R/LM cells, and blocked biphasic responses in R/LM interneurons. The metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-carboxyphenylglycine reduced peak Ca2+ responses only in OA interneurons, and prevented oscillatory responses. In low Ca2+ medium, peak responses were reduced in R/LM but not in OA interneurons, and oscillatory responses were absent. Combination of ionotropic and metabotropic receptor antagonists blocked all glutamate-evoked Ca2+ responses. Activation of different types of glutamate receptors may thus produce heterogeneous Ca2+ signals in subpopulations of CA1 interneurons. Ionotropic receptors may generate biphasic responses in interneurons in apical dendritic layers, whereas combined activation of metabotropic and ionotropic receptors may trigger oscillatory responses in interneurons of basal dendritic layers. These heterogeneous Ca2+ responses indicate that glutamate-mediated Ca2+ processes and second messenger systems differ in subpopulations of hippocampal interneurons and suggest possible postsynaptic functional specialization of interneurons.

Infantile spasms constitute a severe epileptic encephalopathy of infancy with poor long-term developmental outcome. Many diverse etiologies have been associated with infantile spasms, but the pathophysiological process is still not fully understood. We describe 2 cases of previously healthy 1- and 3-month-old infants who suffered a nonaccidental head injury with extensive cerebral lesions. Both presented with acute focal seizures rapidly controlled with phenobarbital. Nevertheless, they developed infantile spasms after a latency period of 3-4 months. Spasms were rapidly controlled with vigabatrin. Both children manifested with developmental delay, either exacerbated (case 1) or elicited (case 2) by infantile spasms. Our report highlights nonaccidental head injury as a risk factor for developing infantile spasms following a seizure-free latency period. A better understanding of the pathophysiology linking accidental brain trauma with infantile spasms could lead to more effective neuroprotective strategies. In the meantime, increased awareness and follow-up are warranted.

De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause nonsyndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity-dependent phosphorylated extracellular signal-regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.

Study design The authors have developed technique of using anterior neck derivations to record posterior tibial nerve N28 during operative somatosensory-evoked potential monitoring. Objective This prospective study of 10 patients compared the ease of application of electrodes and stability of waveforms with "traditional" posterior neck recordings. Summary of background data Somatosensory-evoked potential monitoring has been used in children since the 1980s. A number of important factors, patient related and technical, are unique to this age group, which can cause difficulty with execution and interpretation. A major patient-related problem is unreliability of the cortical response in somatosensory-evoked potential monitoring because of the effect of inhalation anesthesia. This has been described as occurring more often in the pediatric group, perhaps because of the continuing maturation of the complex somatosensory system. Thus, the authors have relied heavily on the cervical potential to monitor spinal cord integrity. Recording the cervical response using the traditional "posterior" montage may be technically impossible if the electrodes lie within the operative field. Methods Posterior tibial somatosensory-evoked potentials were performed according to the guidelines of the American Electroencephalographic Society. Additional recordings were obtained from two anterior neck sites. Multiple reference electrodes were used to evaluate which montage rendered the most reliable waveform. Results Optimal montage for recording an anterior neck potential was cricoid cartilage-Cz'. There were no significant differences in the onset latency or peak amplitudes between the anterior and posterior cervical recordings. Conclusions The anterior neck derivation was found to be an acceptable adjunct to posterior montages, being stable, of comparable latency, and of stable amplitude. Electrodes are easier to apply, less invasive than nasopharyngeal or esophageal electrodes. This technique allows one to examine patients who previously could not be monitored.

Summary Purpose: To investigate spatial and metabolic changes associated with frontal lobe seizures. Methods: Functional near-infrared spectroscopy combined with electroencephalography (EEG-fNIRS) recordings of patients with confirmed nonlesional refractory frontal lobe epilepsy (FLE). Key Findings: Eighteen seizures from nine patients (seven male, mean age 27 years, range 13–46 years) with drug-refractory FLE were captured during EEG-fNIRS recordings. All seizures were coupled with significant hemodynamic variations that were greater with electroclinical than with electrical seizures. fNIRS helped in the identification of seizures in three patients with more subtle ictal EEG abnormalities. Hemodynamic changes consisted of local increases in oxygenated (HbO) and total hemoglobin (HbT) but heterogeneous deoxygenated hemoglobin (HbR) behavior. Furthermore, rapid hemodynamic alterations were observed in the homologous contralateral region, even in the absence of obvious propagated epileptic activity. The extent of HbO activation adequately lateralized the epileptogenic side in the majority of patients. Significance: EEG-fNIRS reveals complex spatial and metabolic changes during focal frontal lobe seizures. Further characterization of these changes could improve seizure detection, localization, and understanding of the impact of focal seizures.

Cognitive impairment is observed commonly in children with a history of infantile spasms (IS). The goal of this study was to prospectively examine the effect on cognitive outcome of a neuroprotective agent used as adjunctive therapy during treatment of the spasms.In a randomized controlled trial, patients received a standardized therapy plus flunarizine or placebo. The standardized treatment consisted of vigabatrin as first-line therapy. Nonresponders were switched to intramuscular synthetic adrenocorticotropic hormone (sACTH depot) after 2 weeks and, if necessary, to topiramate after two additional weeks. The Vineland Adaptive Behavior Scale (VABS) and Bayley Scales of Infant Development (BSID) were used as outcome measures 24 months after the intervention.Sixty-eight of 101 children diagnosed over 3 years in seven centers in Canada received either adjunctive flunarizine or placebo. Sixty-five of the 68 children (96%) became spasm-free within 8 weeks and no late relapse occurred. Bayley and Vineland results were available at baseline and at 24 months in 45 children. There was no significant difference in the BSID developmental quotient between the flunarizine- and placebo-treated children at baseline (44.3 ± 35.5 vs. 30.9 ± 29.8; p = 0.18) or 24 months later (56.9 ± 33.3 vs. 46 ± 34.2; p = 0.29). However, the 10 flunarizine-treated children with no identified etiology had a better outcome than the eight controls at 24 months on both the Vineland Scale (84.1 ± 11.3 vs. 72.3 ± 9.8; p = 0.03) and the Bayley Scale (87.6 ± 14.7 vs. 69.9 ± 25.3; p = 0.07).Our study failed to demonstrate a protective effect of flunarizine on cognitive outcome in a cohort of children with IS. An analysis of subgroups suggested that flunarizine may further improve cognitive outcome in children with no identified etiology.

Thirty children (2 to 17 years of age) with refractory partial seizures received open-label felbamate as an add-on medication to their background antiepileptic drugs. The dose was increased up to a maximum of 45 mg/kg. Compared with baseline seizure activity, there was a 53% decrease in seizure frequency during felbamate therapy; 50% of the patients had more than a 50% decrease in seizure frequency. Patients older than 10 years of age were more likely to have a favorable response. Age correlated positively with felbamate concentrations and negatively with apparent felbamate clearance. Transient weight loss occurred in 57% of the patients; the weight loss was maximal after 12 weeks of initiation of felbamate, and subsided after the twentieth week of treatment. Anorexia and insomnia were reported in 20% and 16% of the patients, respectively. Adverse effects were generally tolerable; felbamate therapy was discontinued because of side effects in only one patient, because of a rash. We conclude that felbamate can be a useful and well-tolerated medication in the treatment of refractory partial epilepsy in children. However, increased apparent clearance of this drug in younger children should be considered in treatment of this age group.

Objective: We measured the activity of S-adenosylmethionine decarboxylase, a key regulatory enzyme of polyamine biosynthesis, in the temporal cortex of patients with epilepsy. Design: Cortical surgical specimens were obtained following anterior temporal lobe resection for intractable epilepsy. Enzyme activity was compared in nonepileptogenic (n=16) and epileptogenic (spontaneously discharging; n=19) regions. Results: Mean enzyme activity was increased by 44% in samples from epileptogenic cortex compared with samples from nonepileptic regions. The S -adenosylmethionine decarboxylase activity in regions of focal epileptogenic discharges was also increased in five patients compared with paired samples from the nonepileptogenic portion of the same gyrus (+ 55%). Conclusions: Elevated activity of S -adenosylmethionine decarboxylase in regions of active epileptogenic cortical discharges suggests that a disturbance of the polyamine system may be involved in the maintenance of hypersynchronous discharges, perhaps through a modulatory action at the excitatory N -methyl-D-aspartate—preferring glutamate receptor.