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.
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.
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 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.
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.
The purpose of this study is to determine the integrity of colour perception, related to photic sensitivity, in patients with juvenile myoclonic epilepsy.
Twenty-four patients with photoparoxysmal response, 27 patients without photoparoxysmal response, and 32 healthy individuals were investigated using the Farnsworth Munsell-100 Hue test to calculate error scores for total color, blue/yellow, and red/green. No significant differences were observed regarding blue/yellow, red/green or total error score between juvenile myoclonic epilepsy patients with or without photoparoxysmal response. However, the data for all three scores were significantly higher in both patient groups compared to the healthy control group. In both patient groups, the blue/yellow error score was significantly higher than the red/green error score. The researchers were unable to identify a relationship between photoparoxysmal response and color vision in patients with juvenile myoclonic epilepsy.
The researchers believe the underlying reason why juvenile myoclonic epilepsy patients had significantly higher blue/yellow, red/green, and total error score compared to the control group not impacted by epilepsy may be due to GABA dysfunction, which is considered to play a role in the pathophysiology of this disease as well as the physiology of color vision.
Children with new recent-onset juvenile myoclonic epilepsy (JME) are more likely to have difficulty with executive, attention, and verbal faculties than their peers without epilepsy and are also more likely to use a greater number of academic services, researchers found. Study findings were reported in Pediatric Neurology.
Children between the ages of 8 and 18 years with recent-onset JME (n=41) and first-degree cousin controls (n=70) were enrolled from pediatric neurology clinics in Midwestern medical centers. All patients underwent a neuropsychological assessment battery that tested attention span; executive, verbal, and perceptual abilities; and speed. Additionally, researchers performed a structured review of participants’ need for supportive academic services and reviewed parent reports of both behavior and executive function (Child Behavior Checklist [CBCL] and Behavior Rating Inventory of Executive Function [BRIEF]). The researchers also performed a structured psychiatric interview and diagnosis (Kiddie Schedule for Affective Disorders and Schizophrenia—Present and Lifetime Version [K-SADS]).
CURE-funded researchers are using a novel technique to discover ways to predict patients at an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Lori Isom, her team, and co-investigator Dr. Jack Parent at the University of Michigan are transforming skin cells from patients with developmental and epileptic encephalopathy (DEE) syndromes into induced pluripotent stem cells (iPSCs). The team then generates cardiac cells from the iPSCs which retain the patients’ exact genetic information. These unique, patient-specific cardiac cells are used as models to understand if DEE-associated genes play a role in causing heart abnormalities which may lead to SUDEP. The team also hopes to develop measurable indicators, known as biomarkers, of SUDEP risk.
Severe DEE syndromes, such as Dravet syndrome, are associated with a high incidence of SUDEP. It is estimated that up to 20% of patients with Dravet syndrome die from SUDEP.1 There is still much to be understood about the mechanisms of SUDEP and how to predict who is at risk for it.
Dravet syndrome and other DEEs are often associated with variants in genes, such as SCN1A, SCN1B, and SCN8A. These genes provide instructions to make sodium ion channels, which are very important proteins that help brain cells transmit electrical signals. The same genes are also expressed in the heart; thus, the team hypothesizes that any variants in these genes that disrupt electrical signaling in the brain would affect normal electrical function of the heart as well. In support of this hypothesis, the investigators’ previous work in mouse models of Dravet syndrome and DEEs showed that these mice exhibited irregular heartbeat, which in some cases preceded SUDEP-like events.2-4
In this CURE-funded project, the investigators expanded upon their previous work by testing their hypothesis in heart muscle cells called cardiac myocytes, generated in the laboratory from skin cells of patients with Dravet syndrome or other DEEs using iPSC technology. This Nobel Prize-winning technology involves obtaining skin or blood cells from patients and converting them to iPSCs. These are stem cells that can be converted into almost any specialized cell type in the body, such as heart, muscle, pancreatic, or neuronal cells. The cells are patient-specific, meaning they retain the unique genetic make-up of the patient they originated from, allowing investigators to study cell types which would otherwise be very difficult or impossible to obtain from a living patient.
Dr. Isom, Dr. Parent, and their colleagues previously used iPSC technology to generate heart muscle cells from four patients with variants in the SCN1A gene and found increased sodium currents and spontaneous contraction rates in these cells, suggesting cardiac electrical dysfunction.5 Cardiac abnormalities were subsequently found in the patient with the highest increase in sodium current.5 These data suggest that iPSC-cardiac cells may be useful models for identifying and developing biomarkers, such as increased sodium current, as indicators of SUDEP risk.
The investigators used the same technique to study variants in the SCN1B and SCN8A genes. The team observed that iPSC-cardiac myocytes derived from a patient with SCN1B Dravet syndrome had increased sodium currents similar to those seen in iPSC-cardiac myocytes from the patient with SCN1A Dravet syndrome, suggesting that variants in these two different genes could cause heart abnormalities through similar mechanisms. Preliminary data in iPSC-cardiac myocytes from patients with DEE caused by variants in SCN8A, suggest that these cells have altered beating rates but no change in sodium current, which is aligned with their observations in a mouse model with a variant in SCN8A.
Taken together, these results reveal mechanisms by which different epilepsy-related genes can affect heart function and SUDEP. Future research will investigate the impact of variants of a specific non-ion channel gene to see if it causes altered cardiac beating. Patient-specific iPSC cardiac myocytes are a very useful model to study SUDEP mechanisms and could be developed as diagnostic biomarkers to identify SUDEP risk in patients.
1 Cooper MS et al. Mortality in Dravet Syndrome. Epilepsy Res. 2016 Dec; 128:43-47. 2 Auerbach DS et al. Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. PLoS One. 2013;8(10). 3 Lopez-Santiago LF et al. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol. 2007;43(5):636-47. 4 Frasier CR et al. Cardiac arrhythmia in a mouse model of SCN8A Epileptic Encephalopathy. Proc Natl Acad Sci U S A. 2016; in press. 5 Frasier CR et al. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient Derived Cardiac Myocytes. Stem Cell Reports. 2018 Sep 11;11(3):626-634.
In this investigation, researchers tested pregabalin as for safety and effectiveness as adjunctive treatment in children (aged 4-16 years) with partial-onset seizures, now called focal onset seizures. Criteria for inclusion was experiencing focal seizures and having a stable 1 to 3 antiepileptic drug regimen. Pregabalin 2.5 mg/kg/d, 10 mg/kg/d or placebo were used in the study, with doses increased to 3.5 or 14 mg/kg/d for subjects weighing <30 kg. Common adverse events included somnolence, increased weight and increased appetite.
According to this double-blind, randomized, placebo-controlled, international study, pregabalin 10 mg/kg/d showed effectiveness in reducing seizure frequency in children with focal seizures vs placebo; both doses of pregabalin were generally safe and well tolerated.
PURPOSE: The aim of the current study was to systematically review the literature to compare the efficacy of levetiracetam (LEV) with that of carbamazepine (CBZ) to control seizures and reduce the burden of interictal epileptiform discharges in children with rolandic epilepsy (RE) and also to compare their tolerability.
METHODS: Researchers searched the electronic database PubMed on January 9, 2019 for original articles that included the following English-language search terms in the title: “Rolandic epilepsy” OR “benign childhood epilepsy with centrotemporal spikes” since 2000. They concentrated the review on three main areas: 1. Neuropsychological impairments in children with RE; 2. Influence of epileptic activity on cognitive performance in RE; 3. Effects of antiepileptic drug (AED) therapies in RE.
RESULTS: The primary search yielded 308 papers. The researchers reviewed the results and removed duplicate articles and all nonoriginal, non-English papers. Finally, after carefully reviewing the full texts, we included 44 original articles to achieve the aims of this review.
CONCLUSION: Physicians taking care of children with rolandic epilepsy (RE) should be aware of the risks for cognitive dysfunctions in these patients and screen their patients for any subtle dysfunction that may affect their academic performance and achievement. If and when the physician decides to prescribe an antiepileptic drug for their patients with RE, levetiracetam is probably a better option compared with carbamazepine to prescribe for these children.