Network-based analysis predicts interacting genetic modifiers from a meta-mapping study of spike-wave discharge in mice.

Absence seizures are characterized by brief lapses in awareness accompanied by a hallmark spike-and-wave discharge (SWD) electroencephalographic pattern and are common to genetic generalized epilepsies (GGEs). While numerous genes have been associated with increased risk, including some Mendelian forms with a single causal allele, most cases of GGE are idiopathic and there are many unknown genetic modifiers of GGE influencing risk and severity. In a previous meta-mapping study, crosses between transgenic C57BL/6 and C3HeB/FeJ strains, each carrying one of three SWD-causing mutations (Gabrg2tm1Spet(R43Q) , Scn8a8j or Gria4spkw1 ), demonstrated an antagonistic epistatic interaction between loci on mouse chromosomes 2 and 7 influencing SWD. These results implicate universal modifiers in the B6 background that mitigate SWD severity through a common pathway, independent of the causal mutation. In this study, we prioritized candidate modifiers in these interacting loci. Our approach integrated human genome-wide association results with gene interaction networks and mouse brain gene expression to prioritize candidate genes and pathways driving variation in SWD outcomes. We considered candidate genes that are functionally associated with human GGE risk genes and genes with evidence for coding or non-coding allele effects between the B6 and C3H backgrounds. Our analyses output a summary ranking of gene pairs, one gene from each locus, as candidates for explaining the epistatic interaction. Our top-ranking gene pairs implicate microtubule function, cytoskeletal stability and cell cycle regulation as novel hypotheses about the source of SWD variation across strain backgrounds, which could clarify underlying mechanisms driving differences in GGE severity in humans.

Biological networks and complexity in early-onset motor neuron diseases.

Motor neuron diseases (MNDs) are neuromuscular disorders where the spinal motor neurons-either the cell bodies themselves or their axons-are the primary cells affected. To date, there are 120 different genes that are lost or mutated in pediatric-onset MNDs. Most of these childhood-onset disorders, aside from spinal muscular atrophy (SMA), lack viable therapeutic options. Previous research on MNDs has focused on understanding the pathobiology of a single, specific gene mutation and targeting therapies to that pathobiology. This reductionist approach has yielded therapeutic options for a specific disorder, in this case SMA. Unfortunately, therapies specific for SMA have not been effective against other pediatric-onset MNDs. Pursuing the same approach for the other defined MNDs would require development of at least 120 independent treatments raising feasibility issues. We propose an alternative to this this type of reductionist approach by conceptualizing MNDs in a complex adaptive systems framework that will allow identification of common molecular and cellular pathways which form biological networks that are adversely affected in early-onset MNDs and thus MNDs with similar phenotypes despite diverse genotypes. This systems biology approach highlights the complexity and self-organization of the motor system as well as the ways in which it can be affected by these genetic disorders. Using this integrated approach to understand early-onset MNDs, we would be better poised to expand the therapeutic repertoire for multiple MNDs.

Seizure outcome determinants in children after surgery for single unilateral lesions on magnetic resonance imaging: Role of preoperative ictal and interictal electroencephalography.

OBJECTIVE: To determine whether an ictal electroencephalographic (EEG) recording as part of presurgical evaluation of children with a demarcated single unilateral magnetic resonance imaging (MRI) lesion is indispensable for surgical decision-making, we investigated the relationship of interictal/ictal EEG and seizure semiology with seizure-free outcome. METHODS: Data were obtained retrospectively from consecutive patients (≤18 years old) undergoing epilepsy surgery with a single unilateral MRI lesion at our institution over a 6-year period. Video-telemetry EEG (VT-EEG) was classified as concordant or nonconcordant/noninformative in relation to the MRI lesion location. The odds of seizure-free outcome associated with nonconcordant versus concordant for semiology, interictal EEG, and ictal EEG were compared separately. Multivariate logistic regression was conducted to correct for confounding variables. RESULTS: After a median follow-up of 26 months (interquartile range = 17-37.5), 73 (69%) of 117 children enrolled were seizure-free. Histopathological diagnoses included low-grade epilepsy-associated tumors, n = 46 (39%); focal cortical dysplasia (FCD), n = 33 (28%); mesial temporal sclerosis (MTS), n = 23 (20%); polymicrogyria, n = 3 (3%); and nondiagnostic findings/gliosis, n = 12 (10%). The odds of seizure freedom were lower with a nonconcordant interictal EEG (odds ratio [OR] = .227, 95% confidence interval [CI] = .079-.646, p = .006) and nonconcordant ictal EEG (OR = .359, 95% CI = .15-.878, p = .035). In the multivariate logistic regression model, factors predicting lower odds for seizure-free outcome were developmental delay/intellectual disability and higher number of antiseizure medications tried, with a nonsignificant trend for "nonconcordant interictal EEG." In the combined subgroup of patients with FCD and tumors (n = 79), there was no significant relationship of VT-EEG factors and seizure outcomes, whereas in children with MTS and acquired lesions (n = 25), a nonconcordant EEG was associated with poorer seizure outcomes (p = .003). SIGNIFICANCE: An ictal EEG may not be mandatory for presurgical evaluation, particularly when a well-defined single unilateral MRI lesion has been identified and the interictal EEG is concordant.

Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures.

Early-life seizures (ELS) are associated with persistent cognitive deficits such as ADHD and memory impairment. These co-morbidities have a dramatic negative impact on the quality of life of patients. Therapies that improve cognitive outcomes have enormous potential to improve patients' quality of life. Our previous work in a rat flurothyl-induction model showed that administration of adrenocorticotropic hormone (ACTH) at time of seizure induction led to improved learning and memory in the animals despite no effect on seizure latency or duration. Administration of dexamethasone (Dex), a corticosteroid, did not have the same positive effect on learning and memory and has even been shown to exacerbate injury in a rat model of temporal lobe epilepsy. We hypothesized that ACTH exerted positive effects on cognitive outcomes through beneficial changes to gene expression and proposed that administration of ACTH at seizure induction would return gene-expression in the brain towards the normal pattern of expression in the Control animals whereas Dex would not. Twenty-six Sprague-Dawley rats were randomized into vehicle- Control, and ACTH-, Dex-, and vehicle- ELS. Rat pups were subjected to 60 flurothyl seizures from P5 to P14. After seizure induction, brains were removed and the hippocampus and PFC were dissected, RNA was extracted and sequenced, and differential expression analysis was performed using generalized estimating equations. Differential expression analysis showed that ACTH pushes gene expression in the brain back to a more normal state of expression through enrichment of pathways involved in supporting homeostatic balance and down-regulating pathways that might contribute to excitotoxic cell-damage post-ELS.

Expedited epilepsy surgery prior to drug resistance in children: a frontier worth crossing?

Epilepsy surgery is an established safe and effective treatment for selected candidates with drug-resistant epilepsy. In this opinion piece, we outline the clinical and experimental evidence for selectively considering epilepsy surgery prior to drug resistance. Our rationale for expedited surgery is based on the observations that (i) a high proportion of patients with lesional epilepsies (e.g. focal cortical dysplasia, epilepsy-associated tumours) will progress to drug resistance; (ii) surgical treatment of these lesions, especially in non-eloquent areas of brain, is safe; and (iii) earlier surgery may be associated with better seizure outcomes. Potential benefits beyond seizure reduction or elimination include less exposure to antiseizure medications, which may lead to improved developmental trajectories in children and optimize long-term neurocognitive outcomes and quality of life. Further, there exists emerging experimental evidence that brain network dysfunction exists at the onset of epilepsy, where continuing dysfunctional activity could exacerbate network perturbations. This in turn could lead to expanded seizure foci and contribution to the comorbidities associated with epilepsy. Taken together, we rationalize that epilepsy surgery, in carefully selected cases, may be considered prior to drug resistance. Last, we outline the path forward, including the challenges associated with developing the evidence base and implementing this paradigm into clinical care.

Mechanisms for Cognitive Impairment in Epilepsy: Moving Beyond Seizures.

There has been a major emphasis on defining the role of seizures in the causation of cognitive impairments like memory deficits in epilepsy. Here we focus on an alternative hypothesis behind these deficits, emphasizing the mechanisms of information processing underlying healthy cognition characterized as rate, temporal and population coding. We discuss the role of the underlying etiology of epilepsy in altering neural networks thereby leading to both the propensity for seizures and the associated cognitive impairments. In addition, we address potential treatments that can recover the network function in the context of a diseased brain, thereby improving both seizure and cognitive outcomes simultaneously. This review shows the importance of moving beyond seizures and approaching the deficits from a system-level perspective with the guidance of network neuroscience.

Drug-resistant focal epilepsy in children is associated with increased modal controllability of the whole brain and epileptogenic regions.

Network control theory provides a framework by which neurophysiological dynamics of the brain can be modelled as a function of the structural connectome constructed from diffusion MRI. Average controllability describes the ability of a region to drive the brain to easy-to-reach neurophysiological states whilst modal controllability describes the ability of a region to drive the brain to difficult-to-reach states. In this study, we identify increases in mean average and modal controllability in children with drug-resistant epilepsy compared to healthy controls. Using simulations, we purport that these changes may be a result of increased thalamocortical connectivity. At the node level, we demonstrate decreased modal controllability in the thalamus and posterior cingulate regions. In those undergoing resective surgery, we also demonstrate increased modal controllability of the resected parcels, a finding specific to patients who were rendered seizure free following surgery. Changes in controllability are a manifestation of brain network dysfunction in epilepsy and may be a useful construct to understand the pathophysiology of this archetypical network disease. Understanding the mechanisms underlying these controllability changes may also facilitate the design of network-focussed interventions that seek to normalise network structure and function.

Brains, complex systems and therapeutic opportunities in epilepsy.

The treatment of epilepsy remains extremely challenging for the thirty percent of people that do not become seizure free. This is despite the introduction of multiple new drugs over that last several decades, highlighting the need for new approaches to identifying novel therapeutic strategies. Conceptualizing the brain as a complex adaptive system and applying the tools that are used in addressing such systems provides an opportunity for expanding the space in which to search for new therapies. Epilepsy has long been considered a network disease at the level of whole brain connectivity, but the application of the concepts to gene and protein expression networks as well as to the dynamic behaviors of microcircuits has been underexplored. These levels of the brain complex adaptive system will be reviewed and a case made for the epilepsy community to embrace these concepts in order to reap to enormous potential rewards.

Fine Spike Timing in Hippocampal-Prefrontal Ensembles Predicts Poor Encoding and Underlies Behavioral Performance in Healthy and Malformed Brains.

Spatial working memory (SWM) is a central cognitive process during which the hippocampus and prefrontal cortex (PFC) encode and maintain spatial information for subsequent decision-making. This occurs in the context of ongoing computations relating to spatial position, recall of long-term memory, attention, among many others. To establish how intermittently presented information is integrated with ongoing computations we recorded single units, simultaneously in hippocampus and PFC, in control rats and those with a brain malformation during performance of an SWM task. Neurons that encode intermittent task parameters are also well modulated in time and incorporated into a functional network across regions. Neurons from animals with cortical malformation are poorly modulated in time, less likely to encode task parameters, and less likely to be integrated into a functional network. Our results implicate a model in which ongoing oscillatory coordination among neurons in the hippocampal-PFC network describes a functional network that is poised to receive sensory inputs that are then integrated and multiplexed as working memory. The background temporal modulation is systematically altered in disease, but the relationship between these dynamics and behaviorally relevant firing is maintained, thereby providing potential targets for stimulation-based therapies.

Current understanding of febrile seizures and their long-term outcomes.

In this paper we reframe febrile seizures, which are viewed as a symptom of an underlying brain disorder. The general observation is that a small cohort of children will develop febrile seizures (2-5% in the West), while the greater majority will not. This suggests that the brain that generates a seizure, in an often-mild febrile context, differs in some ways from the brain that does not. While the underlying brain disorder appears to have no significant adverse implication in the majority of children with febrile seizures, serious long-term outcomes (cognitive and neuropsychiatric) have been recently reported, including sudden death. These adverse events likely reflect the underlying intrinsic brain pathology, as yet undefined, of which febrile seizures are purely a manifestation and not the primary cause. A complex interaction between brain-genetics-epigenetics-early environment is likely at play. In view of this emerging data, it is time to review whether febrile seizures are a single entity, with a new and multidimensional approach needed to help with predicting outcome. WHAT THIS PAPER ADDS: A febrile seizure is due to a brain's aberrant response to high temperature. Problems in a small group of children are now being identified later in life. There is no clear correlation between duration or other characteristics of febrile seizures and subsequent mesial temporal sclerosis.

Subcortical nuclei volumes are associated with cognition in children post-convulsive status epilepticus: Results at nine years follow-up.

PURPOSE: The purpose of the present study was to investigate the relationship between subcortical nuclei volume and cognition in children with post-convulsive status epilepticus (CSE). METHODS: Structural T1-weighted magnetic resonance imaging (MRI) scans (Siemens Avanto, 1.5 T) and neuropsychological assessments (full-scale intelligence quotient (FSIQ) and Global Memory Scores (GMS)) were collected from subjects at a mean 8.5 years post-CSE (prolonged febrile seizures (PFS), n = 30; symptomatic/known, n = 28; and other, n = 12) and from age- and sex-matched healthy controls (HC). Subjects with CSE were stratified into those with lower cognitive ability (LCA) (CSE+, n = 22) and those without (CSE-, n = 48). Quantitative volumetric analysis using Functional MRI of the Brain Software Library (FSL) (Analysis Group, FMRIB, Oxford) provided segmented MRI brain volumes. Univariate analysis of covariance (ANCOVA) was performed to compare subcortical nuclei volumes across subgroups. Multivariable linear regression was performed for each subcortical structure and for total subcortical volume (SCV) to identify significant predictors of LCA (FSIQ <85) while adjusting for etiology, age, socioeconomic status, sex, CSE duration, and intracranial volume (ICV); Bonferroni correction was applied for the analysis of individual subcortical nuclei. RESULTS: Seventy subjects (11.8 ±â€¯3.4 standard deviation (SD) years; 34 males) and 72 controls (12.1 ±â€¯3.0SD years; 29 males) underwent analysis. Significantly smaller volumes of the left thalamus, left caudate, right caudate, and SCV were found in subjects with CSE+ compared with HC, after adjustment for intracranial, gray matter (GM), or cortical/cerebellar volume. When compared with subjects with CSE-, subjects with CSE+ also had smaller volumes of the left thalamus, left pallidum, right pallidum, and SCV. Individual subcortical nuclei were not associated, but SCV was associated with FSIQ (p = 0.005) and GMS (p = 0.014). Intracranial volume and etiology were similarly predictive. CONCLUSIONS: Nine years post-CSE, SCV is significantly lower in children who have LCA compared with those that do not. However, in this cohort, we are unable to determine whether the relationship is independent of ICV or etiology. Future, larger scale studies may help tease this out.

Focal Dorsal Hippocampal Nav1.1 Knock Down Alters Place Cell Temporal Coordination and Spatial Behavior.

Alterations in the voltage-gated sodium channel Nav.1.1 are implicated in various neurological disorders, including epilepsy, Alzheimer's disease, and autism spectrum disorders. Previous studies suggest that the reduction of Nav1.1 expression leads to a decrease of fast spiking activity in inhibitory neurons. Because interneurons (INs) play a critical role in the temporal organization of neuronal discharge, we hypothesize that Nav1.1 dysfunction will negatively impact neuronal coordination in vivo. Using shRNA interference, we induced a focal Nav1.1 knock-down (KD) in the dorsal region of the right hippocampus of adult rats. Focal, unilateral Nav1.1 KD decreases the performance in a spatial novelty recognition task and the firing rate in INs, but not in pyramidal cells. It reduced theta/gamma coupling of hippocampal oscillations and induced a shift in pyramidal cell theta phase preference. Nav1.1 KD degraded spatial accuracy and temporal coding properties of place cells, such as theta phase precession and compression of ongoing sequences. Aken together, these data demonstrate that a deficit in Nav1.1 alters the temporal coordination of neuronal firing in CA1 and impairs behaviors that rely on the integrity of this network. They highlight the potential contribution of local inhibition in neuronal coordination and its impact on behavior in pathological conditions.

Long-term outcomes after childhood convulsive status epilepticus.

PURPOSE OF REVIEW: It is widely accepted that childhood convulsive status epilepticus (CSE) has associated short-term and long-term mortality and morbidity. However, the role of CSE itself on subsequent adverse outcomes is still debated. In addition, whether prolonged seizures cause any long-term hippocampal injury and developmental or memory impairment is uncertain. In this review, we aim to provide an overview of long-term outcomes after childhood CSE, highlighting data from recent literature on this subject. RECENT FINDINGS: Long-term outcome after childhood CSE is favorable in previously normal children, with low incidence of epilepsy, motor and intellectual disability, behavioral impairment and need for special educational provision. Mesial temporal sclerosis is uncommon in children after prolonged febrile seizures. There is substantial morbidity after childhood CSE, but this is seen primarily in children with symptomatic causes and preexisting neurological abnormalities. Cause is the primary determinant of outcomes after childhood CSE and the additional effect of CSE characteristics such as seizure duration seems to be less than previously believed. SUMMARY: Childhood CSE is associated with substantial neurological, cognitive and behavioral morbidity. Early identification of these difficulties and appropriate intervention are likely to have a major positive impact on their quality of life.

Autism, ADHD and parent-reported behavioural difficulties in young children with epilepsy.

PURPOSE: To provide data on the prevalence of Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and parent reported behaviour difficulties in young children with epilepsy, and to compare results with children with neurodisability (neurodevelopmental/neurological difficulties) without epilepsy. METHOD: Children with epilepsy (1-7 years, n = 48) and children with neurodisability (1-7 years, n = 48) matched for gender, chronological and developmental age underwent psychological assessment. Parents completed measures of behaviour including the Strengths and Difficulties Questionnaire (SDQ). DSM-5 diagnoses of ASD and ADHD were made at consensus case conferences. Factors associated with child behaviour were analysed using linear regression. RESULTS: Of the children with epilepsy, 18% met ASD criteria and 40% met ADHD criteria (corresponding figures in the non-epilepsy group were 41% and 27%). A large proportion (76%-78%) in both groups scored in the at-risk range on the SDQ and frequently had difficulties across multiple behavioural domains. Children with epilepsy had more concerns expressed regarding attention and mood. None of the epilepsy factors were significantly associated with scores on the behavioural measures. SIGNIFICANCE: Young children with epilepsy had a very high level of parent reported behavioural difficulties and a high risk for ADHD and ASD highlighting the need for comprehensive multidisciplinary assessment. Behavioural concerns were not greater than for other children with non-epilepsy related neurodisability with the exception of attention and mood. Epilepsy related factors were not associated with child behaviour, suggesting that seizures per se do not confer a unique risk for behavioural difficulties.

Intelligence and memory outcomes within 10 years of childhood convulsive status epilepticus.

Long-term intelligence and memory outcomes of children post convulsive status epilepticus (CSE) have not been systematically investigated despite evidence of short-term impairments in CSE. The present study aimed to describe intelligence and memory outcomes in children within 10 years of CSE and identify potential risk factors for adverse outcomes. In this cohort study, children originally identified by the population-based North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) were prospectively recruited between July 2009 and February 2013 and invited for neuropsychological assessments and magnetic resonance imaging (MRI) scans. Full-scale intelligence quotients (FSIQs) were measured using the Wechsler Abbreviated Scales of Intelligence (WASI), and global memory scores (GMS) was assessed using the Children's Memory Scale (CMS). The cohort was analyzed as a whole and stratified into a prolonged febrile seizures (PFS) and non-PFS group. Their performance was compared with population norms and controls. Regression models were fitted to identify predictors of outcomes. With a mean of 8.9 years post-CSE, 28.5% of eligible participants were unable to undertake testing because of their severe neurodevelopmental deficits. Children with CSE who undertook formal testing (N = 94) were shown to have significantly lower FSIQ (p = 0.001) and GMS (p = 0.025) from controls; the PFS group (N = 34) had lower FSIQs (p = 0.022) but similar memory quotients (p = 0.88) with controls. Intracranial volume (ICV), developmental delay at baseline, and active epilepsy at follow-up were predictive of long-term outcomes in the non-PFS group. The relationship between ICV and outcomes was absent in the PFS group despite its presence in the control and non-PFS groups. Post-CSE, survivors reveal significant intelligence and memory impairments, but prognosis differs by CSE type; memory scores are uncompromised in the PFS group despite evidence of their lower FSIQ whereas both are compromised in the non-PFS group. Correlations between brain volumes and outcomes differ in the PFS, non-PFS, and control groups and require further investigation.

Global development and adaptive behaviour in children with early-onset epilepsy: a population-based case-control study.

AIM: There are limited population-based data on global development and adaptive behaviour in children with early-onset epilepsy. The aims of this study were: (1) to identify the prevalence of deficits in global development and adaptive behaviour experienced by children with early-onset epilepsy; (2) to identify factors associated with such deficits; and (3) to compare the relationship between measures of neurodevelopment in the group with epilepsy to a group without epilepsy who had other neurological or neurodevelopmental difficulties. METHOD: The Sussex Early Epilepsy and Neurobehaviour study is a prospective, community-based study involving children (1-7y) with epilepsy. We undertook comprehensive psychological assessment with participants, including measures of global development and adaptive behaviour. We compared the children with epilepsy with a sex, age, and developmentally-matched group of children without epilepsy who had neurodevelopmental or neurological difficulties using correlation matrices. RESULTS: Forty-eight children (91% of the eligible population) with epilepsy underwent assessment. Seventy-one per cent of children displayed delayed global development (<2SD) and 56% showed significant deficits (<2SD) in adaptive behaviour. Our analysis revealed that non-white ethnicity and use of polytherapy were independently associated with decreased scores on measures of global development and adaptive behaviour. The correlations between measures of developmental functioning were higher in children with epilepsy than in those without. INTERPRETATION: Children with early-onset epilepsy frequently have difficulties with global development and adaptive behaviour. The higher correlations between neurodevelopmental measures in children with epilepsy suggest that the profile in children with epilepsy is different. This may have significant implications for both neuropathology and interventions. WHAT THIS PAPER ADDS: Children with early-onset epilepsy are at significant risk of intellectual disability. Developmental impairment is associated with use of polytherapy but not with any seizure parameters. Developmental profiles in young children with epilepsy differ from other conditions.

Experiences and needs of parents of young children with active epilepsy: A population-based study.

The aim of the study was to gain a comprehensive understanding of the experiences and needs of parents of young children with epilepsy from a total population sample. The parents (mothers (n = 38), fathers (n = 9)) of 40/53 (75% of total population) young children (1-7 years; 23 males, 17 females) with 'active' epilepsy (had a seizure in the last year or taking Anti-epileptic drugs (AEDs)) were interviewed either in person or over the telephone using a semistructured interview schedule. The families were resident in the south of the UK. The interviews were audio-recorded, transcribed, and coded using thematic analysis. Thematic analysis revealed six main themes: diagnostic journey, parental perception of epilepsy management, awareness and impact of associated neurobehavioral difficulties, inconsistent availability of therapeutic and educational supports, impact on family functioning, and need for parental support. Parents reported often having difficulty accessing a professional knowledgeable about epilepsy. While parents were generally satisfied with the initial information they received about seizures and their management, they reported that the association between epilepsy and neurobehavioral issues was often not broached. These developmental/behavioral difficulties often had a bigger impact on child wellbeing and family functioning, but provision of therapeutic and educational supports for the difficulties was often very patchy. Parents noted that early onset epilepsy and associated neurobehavioral difficulties often have a very significant impact on family functioning including increased restrictions on family activities and increased financial burden. Parents would like informational and emotional support to extend beyond the time of epilepsy diagnosis. There is a clear need for comprehensive childhood epilepsy services to include provision for identification and management of child neurobehavioral needs and a focus on family-centered care.

Pathophysiology of convulsive status epilepticus.

PURPOSE: To summarize the pathophysiology of convulsive status epilepticus (SE) with a focus on practical implications for treatment. METHOD: Narrative review of the medical literature on the pathophysiology of convulsive SE. We considered both animal models of SE and clinical studies. RESULTS: Convulsive SE is an emergency in which prolonged convulsive seizures are associated with cardiorespiratory instability, hypoxia, hypoglycemia, and hyperthermia. Supportive treatment helps correct these physiological imbalances. When treatment is delayed, the ability of first line seizure suppressing medications to terminate the seizure can be reduced. Animal studies have suggested that GABAA receptor trafficking may contribute to the failure of the first line therapies and that NMDA receptor antagonists such as ketamine may become more effective as seizures last longer. Potential strategies to take advantage of these changes in pathophysiology include a rapid escalation from benzodiazepines to non-benzodiazepine antiepileptic drugs (AEDs), early polytherapy and use of NMDA antagonists such as ketamine for refractory convulsive SE. Despite the importance of a timely treatment of convulsive SE, major treatment delays are frequent in clinical practice. Policies to improve time to treatment, especially in convulsive SE that starts outside the hospital, may improve response to treatment and convulsive SE outcomes. CONCLUSIONS: Convulsive SE is a time-sensitive emergency in which the underlying pathophysiology may provide targets for improving treatment strategies. A timely transition from benzodiazepines to other AEDs may help reduce treatment resistance in convulsive SE.

Cognitive outcomes following epilepsy in infancy: A longitudinal community-based study.

OBJECTIVE: Onset of epilepsy before 2 years of age is associated with poor cognitive outcome; however, the natural course of the range of epilepsies that occur at this age is unknown. The aim of this prospective community-based study was to investigate the neuropsychological development of infants with newly diagnosed epilepsy longitudinally and to identify the clinical factors that predict long-term impairment. METHODS: Sixty-six infants <24 months of age were enrolled in the baseline phase of this study; 40 were seen again at 1-year follow-up and 40 at 3-year follow-up. Children underwent a neurological and neuropsychological assessment at each time point. RESULTS: More than 55% of children demonstrated impaired cognitive functioning at each assessment, with a similar percentage showing impaired memory and attention at 3-year follow-up. Cognitive scores obtained at each time point were correlated. More than 20 seizures/seizure clusters prior to assessment and an abnormal neurologic examination predicted poor cognitive functioning at baseline, whereas continuing seizures and baseline cognitive score predicted 3-year intelligence quotient (IQ)/cognitive score. SIGNIFICANCE: These findings demonstrate the following: (1) infants who are performing poorly at baseline continue to display impaired development at follow-up, (2) these children are delayed across a range of neuropsychological functions, and (3) a high number of seizures close to initial diagnosis and continuing seizures at follow-up independently predict cognitive impairment. These findings help to identify those infants with new-onset epilepsy who are most at risk for poor developmental outcome and suggest that multimodal interventions should be instituted early in the course of the disorder to improve outcomes.