Breakthrough for Children with Serious Epileptic Seizures

Emergency medicine doctors now have a better way to treat severe epileptic seizures in children, thanks to a New Zealand-Australian study.

Prolonged epileptic seizures are the most common neurological emergency in children seen by hospitals. The seizures are potentially fatal: up to five percent of affected children die, and a third suffer long-term complications from brain damage. Crucially, the longer the seizure, the greater the chance of long-term complications.

The study – which will change management of this condition internationally – was published in the prestigious medical journal The Lancet. It was led by Professor Stuart Dalziel from the Faculty of Medical and Health Sciences at the University of Auckland and Starship Children’s Hospital, and the senior author was Professor Franz Babl at Melbourne’s Murdoch Children’s Research Institute.

Ketogenic Diet May Reduce Sudden Unexpected Deaths in Epilepsy, Mouse Study Suggests

Sudden Unexpected Death in Epilepsy (SUDEP) occurs more frequently during early evening and is significantly prevented by prolonged use of the ketogenic diet, research in a mouse model of Dravet syndrome (DS) suggests.

The reasons why this happens are unclear, and should be examined in more depth by future studies, but these findings may be useful to understand why most SUDEP episodes happen at night and how certain diets can benefit epileptics, especially those with Dravet syndrome, researchers say.

Their study, “Time of Day and a Ketogenic Diet Influence Susceptibility to SUDEP in Scn1aR1407X/+ Mice,” was published in the journal Frontiers in Neurology.

Using an established mouse model of Dravet syndrome, the researchers investigated if the time of the day influences the chances of sudden death. They also sought to determine if a ketogenic diet — a high-fat, low-carbohydrate (low-sugar) diet which helps to control seizures in some epileptic patients — can change the frequency of seizures and the rate of mortality.

Mice were continuously recorded on video to monitor for spontaneous seizures and sudden deaths. The recordings showed that SUDEP and spontaneous seizures happened more often during the early evening.

Paving the Way for Innovative Treatment of Epilepsy

A drug commonly used to treat multiple sclerosis may, after necessary modifications, one day be used to treat patients with epilepsy, researchers in Prof. Inna Slutsky’s lab at the Sackler Faculty of Medicine and Sagol School of Neuroscience at Tel Aviv University have discovered.

This is good news for patients with Dravet syndrome, one of the most dangerous forms of childhood epilepsy, for which there is currently no effective treatment.

According to a new study published on April 29 in Neuron, Tel Aviv University researchers uncovered a piece of a puzzle that has eluded scientists for 100 years of studying homeostasis: What is the mechanism that maintains activity set points in neural circuits?

While it is well-understood that the brain functions in a narrow range of activity between status epilepticus and coma, how neural circuits maintain stable activity in a constantly changing environment has remained unknown.

“The concept of homeostasis has a long history in physiology, starting from the work of Claude Bernard in the middle of 19th century on the stability of the milieu interior. In the middle of 20th century, James Hardy proposed a model in which homeostatic mechanisms maintain physiological variables with an acceptable range around a ‘set point’ value. However, the research of neuronal homeostasis began only 25 years ago, and we still don’t understand how it works,” explains Prof. Slutsky. “What we have found is a homeostatic mechanism that acts as a sort of a thermostat of the neural circuits, which ensures the return to a set point after each event that increases or decreases brain activity.

“Our findings may serve as a basis for the development of drugs for a range of neurological and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, which, like epilepsy, are characterized by instability of brain activity.”

Seizure Burden in Severe Early-Life Epilepsy: Perspectives from Parents

Objectives: Seizure burden is typically measured by seizure frequency yet it entails more than seizure counts, especially for people with severe epilepsies and their caregivers. This study aimed to characterize the multi-faceted nature of seizure burden in young people and their parents who are living with severe early-life epilepsies.

Methods: A one-day workshop and a series of teleconferences were held with parents of children with severe, refractory epilepsy of early-life origin and providers for children with epilepsy. The workshop sessions were structured as focus groups and aimed to identify components of seizure burden and their impact from the perspective of parents and providers. Data were gathered, organized, and refined during the workshop using an iterative 4-step process that drew upon grounded theory.

Results: Three primary components of seizure burden were identified: frequency, severity, and unpredictability, which was as important if not more important at times than frequency and severity. Caregivers noted that the impacts of seizures were experienced as acute-immediate consequences, longer-term consequences, and as chronic effects that develop and evolve over time. The severity of the child’s neurological and medical status as well as where in the disease journey a family was represented additional contextual factors that influenced the experience of seizure burden.

Significance: Patient-reported and patient-centered outcomes are increasingly incorporated into the evaluation of treatment effectiveness. Without understanding how the disease creates burden for the patient (or family), it is difficult to know how to assess the impact of treatment. Preliminary findings indicate seizure burden is a complex construct and unpredictability can be as important as frequency and severity.

Seizure Control in Juvenile Myoclonic Epilepsy is Linked to Seizure Type

Objective: The aim of this study was to evaluate the clinical features and treatment outcomes of patients with juvenile myoclonic epilepsy (JME) in western China.

Method: The team continuously reviewed 105 outpatients with JME who were diagnosed and treated at the Epilepsy Registration Center of West China Hospital between October 2012 and July 2014. Seizure control stratified into different seizure types and by antiepileptic drugs (AEDs) was prospectively evaluated every 3-6 months.

Results: Among 105 patients with JME, 85 patients (81%) received monotherapy including valproate (VPA, 47%) and levetiracetam (LEV, 43%) treatment. The rates of seizure freedom 1, 3, and 5 years after the initiation of AED treatment were 64.8% (68/105), 29.5% (31/105), and 14.6% (12/82) in JME patients, respectively. Patients with myoclonic seizure (MS) and absence seizure (AS) were less frequently seizure free than those with MS and generalized tonic-clonic seizure (GTCS) (P = 0.012). Patients on VPA monotherapy had better control of GTCS than patients on LEV monotherapy (P = 0.036). There is a trend of lower rates of seizure freedom in patients treated with LEV than in those treated with VPA after the first-year treatment period.

Significance: The data suggests that in juvenile myoclonic epilepsy (JME), seizure control is linked to seizure type, possibly allowing a more individualized approach when counselling JME patients.

Novel Variants and Phenotypes Widen the Phenotypic Spectrum of GABRG2-Related Disorders

PURPOSE: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier – novel variants are discovered and new phenotypes described. Variants in the same gene – even the same variant – can cause different types of epilepsy and neurodevelopmental disorders. The aim of this study was to identify the genetic causes of epileptic encephalopathies in pediatric patients with complex phenotypes.

METHODS: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. Researchers searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features.

RESULTS: Researchers identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies.

CONCLUSION: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants.

Highly Reproducible Pattern of Brain Activity in Children with Refractory Epilepsy Sheds Light on Epilepsy Network Mechanisms

OBJECTIVE: Interictal spikes are a characteristic feature of invasive electroencephalography (EEG) recordings in children with refractory epilepsy. Spikes frequently co-occur across multiple brain regions with discernable latencies, suggesting that spikes can propagate through distributed neural networks. The purpose of this study was to examine the long-term reproducibility of spike propagation patterns over hours to days of interictal recording.

METHODS: Twelve children (mean age 13.1 years) were retrospectively studied. A mean ± standard deviation (SD) of 47.2 ± 40.1 hours of interictal EEG recordings were examined per patient (range 17.5-166.5 hours). Interictal recordings were divided into 30-minute segments. Networks were extracted based on the frequency of spike coactivation between pairs of electrodes. For each 30-minute segment, electrodes were assigned a “Degree Preference (DP)” based on the tendency to appear upstream or downstream within propagation sequences. The consistency of DPs across segments (“DP-Stability”) was quantified using the Spearman rank correlation.

RESULTS: Regions exhibited highly stable preferences to appear upstream, intermediate, or downstream in spike propagation sequences. Across networks, the mean ± SD DP-Stability was 0.88 ± 0.07, indicating that propagation patterns observed in 30-minute segments were representative of the patterns observed in the full interictal window. At the group level, regions involved in seizure generation appeared more upstream in spike propagation sequences.

SIGNIFICANCE: Interictal spike propagation is a highly reproducible output of epileptic networks. These findings shed new light on the spatiotemporal dynamics that may constrain the network mechanisms of refractory epilepsy.

Parents Reassured Febrile Seizures Following Vaccination Not Dangerous

New research from the University of Sydney has found the severity of febrile seizures following vaccination is no different to febrile seizures from another cause, such as from a virus, and that the majority of seizures are short-lived, self-resolving and don’t require ongoing treatment.

While each Australian child would have received 13 vaccinations by the time they reach two years of age, febrile seizures following vaccination accounted only for 6 per cent of all first febrile seizure presentations to hospital.

Published today in Paediatrics, this is the first prospective study to directly compare the differences in severity and outcomes between febrile seizures following vaccination to other febrile seizures.

“Febrile seizures are not known to cause long-lasting effects, but they are understandably frightening to parents and carers,” said Dr. Lucy Deng, lead author and Ph.D. student from University of Sydney and the National Centre for Immunisation Research and Surveillance (NCIRS).

Scientists Discover Trigger Region for Absence Epileptic Seizures

Scientists have discovered a neurological origin for absence seizures–a type of seizure characterized by very short periods of lost consciousness in which people appear to stare blankly at nothing. Using a mouse model of childhood epilepsy, a team led by Kazuhiro Yamakawa at the RIKEN Center for Brain Science (CBS) in Japan showed that absence epilepsy can be triggered by impaired communication between two brain regions: the cortex and the striatum.

Epileptic seizures come in several varieties. Most are familiar with tonic-clonic seizures, which are characterized by large convulsions. However, several kinds of childhood epilepsy are characterized absence seizures in which children experience widespread erratic brain activity that leaves them unconscious for a number of seconds, but without any convulsions. Absence seizures are associated with spike-wave discharges (SWDs)–irregular brain activity that can be recorded on electrocorticograms. While some medications are available, a clearer understanding of how these types of seizures begin in the brain will lead to the development of better therapies.

Children with Convulsive Status Epilepticus Show Lower Full-Scale Intelligence Quotient and Global Memory Scores 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.

Results: Children with convulsive status epilepticus who undertook formal testing (N = 94) were shown to have significantly lower full-scale intelligence quotients (p = 0.001) and global memory scores (p = 0.025) from controls; the prolonged febrile seizures group (N = 34) had lower full-scale intelligence quotients (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-prolonged febrile seizures group. The relationship between ICV and outcomes was absent in the prolonged febrile seizures group despite its presence in the control and non-prolonged febrile seizures groups. Post-convulsive status epilepticus, survivors reveal significant intelligence and memory impairments, but prognosis differs by convulsive status epilepticus type; memory scores are uncompromised in the prolonged febrile seizures group despite evidence of their lower full-scale intelligence quotients whereas both are compromised in the non-prolonged febrile seizures group. Correlations between brain volumes and outcomes differ in the prolonged febrile seizures, non-prolonged febrile seizures, and control groups and require further investigation.