News Topics: Pediatric Epilepsy

IT Startup Launches Software to Encourage Physician-Family Conversations About Epilepsy

Physicians can now be alerted to pediatric patients’ risk of sudden unexpected death in epilepsy, or SUDEP, during routine primary care visits by using software developed and commercialized by a researcher-entrepreneur at the Indiana University School of Medicine.

Digital Health Solutions LLC, founded by Dr. Stephen Downs, has created a module about SUDEP for its Child Health Improvement through Computer Automation, or CHICA, system. Families answer questions on an electronic tablet about several health topics, including epileptic seizures.

“For children who have seizures, CHICA asks follow-up questions about frequency, medication adherence and barriers to accessing care,” said Downs, who is the Jean and Jerry Bepko Professor of Pediatrics at the IU School of Medicine. “The program shares this information with the physician. It also makes a reminder, through the patient’s electronic health record, for the physician to discuss SUDEP with the family. The physician can document discussing SUDEP and provide computer-generated educational materials.”

A Two-Hit Story: Genetic Mutations Increase the Risk of a ‘Second Hit’ to Developing Severe Epilepsy

SCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS.

Researchers used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling.

Therefore, this study claims to demonstrate for their model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.

GNAO1 Genetic Variant Associated with Seizures Beginning in First Three Months of Life

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships.

METHODS: This study evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model.

RESULTS: The 14 patients in the cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. The researchers attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia.

The 13 GNAO1 variants in the patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes.

SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

App Aids in Diagnosing Pediatric Epilepsy

The challenge of providing an early and accurate diagnosis for a child after an initial paroxysmal event with little information to differentiate epilepsy from other possibilities could become easier with a recently released web-based application.

The model predicts a percentage probability of epilepsy from clinical and electroencephalogram (EEG) data that is routinely available at first consultation, in lieu of or prior to further assessment with such measures as prolonged or sleep-deprived EEG and magnetic resonance imaging (MRI).

The model was developed by Eric van Diessen, MD, PhD, Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands, and colleagues, who point out that previous efforts to identify prognostic clinical variables for seizure recurrence have been with studies that have included only children with a definitive diagnosis of epilepsy.

Implementation of Ketogenic Diet in Children with Drug-Resistant Epilepsy in a Medium Resources Setting: Egyptian Experience

BACKGROUND: Even with the extensive use of ketogenic dietary therapies (KD), there still exist many areas of the world that do not provide these treatments. Implementing the ketogenic diet in different countries forms a real challenge in order to match the cultural and economic differences.

AIM: To assess the feasibility of implementing a ketogenic diet plan in a limited resource setting with identification of the compliance, tolerability and side effects in the target population and to assess the efficacy of the ketogenic diet in children with intractable epilepsy.

METHOD OF THE STUDY: The medical records of 28 patients with intractable epilepsy, treated at The Children’s Hospital – Cairo University from December 2012 to March 2014 with ketogenic dietary therapy were reviewed. The non-fasting protocol was followed without hospital admission. All children were started on a standardized classic ketogenic diet with a ratio ranging from 2.5-4:1 (grams of fat to combined carbohydrate and protein). Patients were followed at 1, 3 and 6 months after diet initiation.

RESULTS: The median age was 60 months (range, 30-110). After 1 month from diet initiation, 16 patients (57%) remained on the diet. One of them (6.3%) had more than 90% reduction in seizure frequency, an additional 6 patients (37.5%) had a 50-90% reduction in seizure frequency. In total, seven out of the 16 patients continuing the diet for 1 month (43.8%) had more than 50% improvement in seizure control from the base line. Despite having 50-90% seizure control, three children discontinued the diet after one month. Three months after diet initiation, 6 patients (22%) remained on diet, 4 of them (66.7%) had more than 50% reduction in seizure frequency. At 6 months, only 3 patients remained on diet, 2 of them (66.6%) had 50-90% reduction in seizure frequency, while one patient (33.3%) showed better than 90% decrease in seizure.

CONCLUSION: The current study shows that the ketogenic diet could be implemented in medium resources countries and should be included in the management of children with intractable epilepsy.

Multivariable Clinical Trait Model Predicts Childhood Epilepsy Risk

A multivariable prediction model composed of several different clinical characteristic variables, including sex, medical history, age of first seizure, and event description, in combination with electroencephalogram readings, may be helpful to predict the risk for epilepsy in children, according to study results published in Pediatrics.

Clinical data from 451 children who visited an outpatient pediatric neurology department after 1 or more paroxysmal event were retrospectively analyzed. Only those patients with epilepsy or an unknown diagnosis who had 1-year or greater follow-up data available were included in the study. An external cohort of 187 patients (ie, validation cohort) tested the validity of the multivariable logistic regression model. Presence or absence of epilepsy comprised the primary outcome measure.

Pharmacokinetic evaluation of vigabatrin dose for the treatment of Refractory Focal Seizures in Children Using Adult and Pediatric Data

Vigabatrin is indicated as adjunctive therapy for refractory focal seizures. For children, European recommendations indicate maintenance doses varying from 30 to 100?mg/kg/day for this indication. Since cumulated dose was associated with retinal toxicity, it is essential to administrate the lowest effective dose to patients.

This work was conducted with the purpose to determine the pediatric doses of vigabatrin that allow a similar exposure than effective doses in adults (2-3?g/day) through a pharmacokinetic (PK) study, using both pediatric and adult data.

For this study, we focused on the active S(+) enantiomer of vigabatrin. First, the adult effective exposition range of vigabatrin-S was determined from an adult PK model. Then, this same model was scaled to the pediatric population using allometry and maturation principles to account for growth and development. The ability of the model to predict pediatric data was assessed by comparing population predictions with observed pediatric data. Finally, the extrapolated pediatric model was used to simulate pediatric expositions which were compared to the adult exposition range (36.5-77.9?mg.h/L).

From those simulations, we determined that, for children aged between 3 months and 18 years, doses between 40 and 50?mg/kg/day allow vigabatrin-S expositions similar to those found in adults at the recommended posology. We proposed those doses as optimal maintenance doses that may be increased, if necessary, by slow titration.

Two Possible New Ways to Treat Silent Seizures in Children

As early as 3 months of age, infants with a severe form of epilepsy called Dravet syndrome start having convulsive seizures, during which their arms and legs jerk repeatedly. As they become toddlers, another type of seizure begins to appear. These seizures do not cause obvious convulsions, but disrupt consciousness and can occur more than 50 times every single day. A challenge to detect and difficult to treat, these non-convulsive seizures often go unnoticed by parents and physicians.

A recent study, published in the journal Cell Reports, characterizes these silent seizures in a mouse model of Dravet syndrome and identifies the brain area that could be targeted to stop them.

“We were able to pinpoint the exact spot in the brain that causes the seizures,” said Jeanne Paz, PhD, the senior author of the study, who is an assistant investigator at the Gladstone Institutes. “This discovery allowed us to develop two new strategies to prevent these non-convulsive seizures in mice simulating Dravet syndrome.”

Epilepsy Research Findings: December 2018

Exciting epilepsy research discoveries include two groundbreaking studies. Dr. Steven Petrou created “minibrains” using stem cells to better understand how neurons behave in children with epilepsy. Dr. Harald Sontheimer discovered the previously unknown function of perineuronal nets, which may lead to new treatments for acquired epilepsy. Both Dr. Petrou and Dr. Sontheimer are CURE grantees, and we’re thrilled to see these innovations from them beyond the work they do with us!

In diagnostic news regarding children with epilepsy, scientists are calling for parents to have their children’s genes reviewed at least every two years. This is to ensure their diagnoses and treatments are based on the latest discoveries.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

Diacomit Add-On Therapy More Effective in Children with Dravet Syndrome Who Carry Pathogenic SCN1A Mutations, Study Shows

Diacomit (stiripentol) add-on therapy is more effective in children with Dravet syndrome who have pathogenic (disease-causing) SCN1A mutations than in those with variants of unknown significance and benign SCN1A mutations, a study has found.

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GW Pharmaceuticals Announces Second Positive Phase 3 Pivotal Trial for EPIDIOLEX® (Cannabidiol) Oral Solution CV in Patients with Dravet Syndrome

GW Pharmaceuticals announces positive top-line results of the second randomized, double-blind, placebo-controlled Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) CV in the treatment of seizures associated with Dravet syndrome, a rare and severe form of childhood-onset epilepsy.

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Aquestive Therapeutics Announces FDA Approval for SYMPAZAN™ (clobazam) Oral Film

The FDA approved SYMPAZAN™ (clobazam) oral film for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. SYMPAZAN is the first and only oral film FDA-approved to treat seizures associated with LGS. Previously, clobazam was marketed as ONFI® and offered in two formulations – either tablet or oral suspension.

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Diagnostic Advances

Reanalyzing Gene Tests Prompts New Diagnoses in Kids

A new study from UT Southwestern quantifies for the first time how quickly rapid advancements in genomics may benefit patients. Research published in JAMA Pediatrics includes a five-year review of more than 300 epilepsy cases showing nearly a third of children had a change in diagnosis based on new data.

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Research Discoveries

Could Lab-Grown Human Minibrains Help Treat Alzheimer’s and Epilepsy?

Featuring the work of CURE Grantee Dr. Steven Petrou

Florey Institute Director Dr. Steven Petrou leads research creating organoids to mimic the behavior of children’s brains with rare, debilitating forms of epilepsy. Replicating the way neurons behave in children with epilepsy using stem cells in a dish allowed the researchers to tailor a treatment; Petrou is on the verge of announcing a clinical trial of a gene therapy to treat one variant of the disorder.

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Scientists Solve Century-Old Neuroscience Mystery; Answers May Lead to Epilepsy Treatment

Featuring the work of CURE Grantee Dr. Harald Sontheimer

A research team led by Dr. Harald Sontheimer determined that perineuronal nets, whose function was previously unknown, modulate electrical impulses in the brain. Seizures can occur if the nets are dissolved. This discovery may lead to a potential treatment for acquired epilepsy.

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Epidemiology of Status Epilepticus in Adults: A Population-Based Study on Incidence, Causes, and Outcomes

The first population-based study using the International League Against Epilepsy 2015 definition and classification of status epilepticus found an increase of incidence of 10% compared to previous definitions. The study also provides epidemiologic evidence that different patterns of status evolution and level of consciousness have strong prognostic implications.

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Can Genetic Therapy Help Kids with Angelman Syndrome Overcome Seizures?

Scientists at the UNC School of Medicine found evidence that genetic therapy may prevent the enhanced seizure susceptibility common in children with Angelman Syndrome. The research marks the first time scientists reduced seizure susceptibility in mice by activating a dormant copy of the UBE3A gene, so it could replace the faulty mutant version.

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Also Notable

Parents and Researchers Work to Find Cause of Neonatal Epilepsy

Three US families aim to help researchers develop better treatments for neonatal-onset epilepsy with a US-wide study called Early Recognition of Genetic Epilepsy in Neonates (ERGENT). This study provides free-of-charge genetic testing to babies who have features suggestive of a genetically-caused epilepsy.

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Alzheimer’s and Epilepsy: Intimate Connections

Like people with Alzheimer’s disease, people with epilepsy can experience memory loss or confusion. As part of an aura, they may hear or see things that aren’t there. When older adults display these symptoms, they may be misdiagnosed with Alzheimer’s disease, when in fact they are having (or just had) a seizure.

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Study Highlights Potential Benefits of Continuous EEG Monitoring for Infant Patients

A recent retrospective study evaluating continuous electroencephalography (cEEG) of children in intensive care units (ICUs) found a higher than anticipated number of seizures. The work also identified several conditions closely associated with the seizures, and suggests that cEEG monitoring may be a valuable tool for helping to identify and treat neurological problems in patients who are 14 months old or younger.

EEGs measure electrical activity in the brain, and are often used to detect potential neurological problems. Conventional EEGs usually last less than an hour, but cEEGs allow health care providers to monitor brain activity for hours or days. However, cEEGs are not in widespread use, due to the expense of related hardware and software and costs associated with having the skilled personnel needed to monitor and interpret cEEG data.

“Our main finding is the unexpectedly high prevalence of mostly non-symptomatic seizures in very young children,” says Keskinocak, the William W. George Chair and Professor in Georgia Tech’s Stewart School of Industrial Engineering and the director of the Center for Health and Humanitarian Systems at Georgia Tech. “Non-symptomatic seizures are those that can be detected with an EEG, but that do not present any outward, physical symptoms. Children over the age of 14 months had an overall seizure rate of 18 percent. However, we found that children aged 14 months and younger had an overall seizure rate of 45 percent.”

“In addition, we found that – for these younger patients – seizures were often associated with one of the following conditions: hypoxic-ischemic encephalopathy, intracranial hemorrhage or central nervous system infection,” says Dr. Larry Olson of Children’s Healthcare of Atlanta and Emory University.