Is Targeting of Compensatory Ion Channel Gene Expression a Viable Therapeutic Strategy for Dravet Syndrome?

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, researchers show enhanced excitability in thalamic inhibitory neurons that promotes the nonconvulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels.

The authors claim that this study supports a mechanism in which loss of potassium SK channel activity causes the reticular thalamic neurons to become hyperexcitable and promote nonconvulsive seizures in DS. They propose that reduced excitability of inhibitory neurons is not global in Dravet syndrome and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

Purified CBD Reduces Seizures in Rare Form of Childhood Epilepsy by Almost 50%, Study Finds

Highly purified cannabidiol (CBD) at a dose of 10mg/kg/day can reduce convulsive seizures in children with Dravet syndrome by almost 50%, a study published in Neurology has found.

Dravet syndrome is a rare, severe form of childhood epilepsy and current medicines are unable to provide complete seizure control.

The study investigated 199 patients with Dravet syndrome who were already taking a median of three anti-epileptic drugs. The patients, who had a mean age of 9 years, were randomized to receive either highly purified CBD at 20mg/kg/day (CBD20), highly purified CBD at 10mg/kg/day (CBD10) or placebo.

The researchers then examined the change in convulsive seizure frequency over a 14-week treatment period by comparing it to the 4 weeks before treatment.

They found that in the group taking CBD20, the number of convulsive seizures was reduced by 46%, while in the CBD10 group the number of seizures was reduced by 49%. In the placebo group, the number of seizures reduced by 27%.

“It’s exciting to be able to offer another alternative for children with this debilitating form of epilepsy, and their families,” said study author Ian Miller, a neurologist at Nicklaus Children’s Hospital in Florida.

“The children in this study had already tried an average of four epilepsy drugs with no success, and [when the study was conducted] were taking an average of three additional drugs, so to have this measure of success with cannabidiol is a major victory.”

Are Febrile Seizures Associated With Increased Sudden Death Risk in Young Children?

Children with febrile seizures (FS) have a small yet elevated risk for death. Recent data suggest that FS may contribute to sudden unexplained death in childhood (SUDC) among cases of sudden explained death in childhood (SEDC). This is according to findings published in JAMA Network Open from one of the largest studies of its kind exploring the role of FS and other risk factors in SUDC.

A total of 622 consecutive cases of sudden child death that occurred from 2001 to 2017 were included in the review. Data were collected from voluntary records of family members who were registered with the SUDC Foundation. The final cause of death resulted in cases categorized as either SEDC or SUDC. The main outcome measure included the certified manner of death as accident, natural, or undetermined.

Alternative Treatment for Epileptic Seizures in Children Identified

A new study published in The Lancet, involving researchers from the University of Liverpool and Alder Hey Children’s Hospital Trust, has identified a ‘user friendly’ treatment for the most common life-threatening neurological emergency in children.

Convulsive status epilepticus (CSE) is the situation when a tonic-clonic seizure doesn’t stop either on its own or with anticonvulsants. It is the most common life-threatening neurological emergency in children.

Currently, CSE is treated using an algorithm which incorporates 10 min intervals between treatments. Second-line treatment is given when CSE persists either after two doses of the first-line treatment, which is an anticonvulsant called a benzodiazepine, or the child’s personalized emergency (rescue) treatment.

The anticonvulsant medication phenytoin has been used as the usual second-line treatment of CSE for several decades and is known to have rare but potentially dangerous side effects. However, some evidence suggests that another medication, levetiracetam could be an effective and safer alternative. To ascertain which treatment was safest and most effective the EcLiPSE Team, made up of doctors from Alder Hey and Bristol Children’s Hospitals together with research teams from the Universities of Liverpool and the West of England, conducted a trial to compare the efficacy and safety of both drugs for second-line management of CSE.

“Our results suggest that levetiracetam could be considered as an alternative treatment to phenytoin for second-line management of pediatric CSE. Possible benefits of levetiracetam over phenytoin include its ease of preparation and administration, minimal interaction with antiepilepsy and other drugs, and easy conversion to oral maintenance therapy. Further randomised clinical trial and meta-analysis data could help to confirm our results and might lead to levetiracetam being the preferred second-line anticonvulsant in children with benzodiazepine-resistant convulsive status epilepticus.

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.