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.

The Refractory Epilepsy Screening Tool for Lennox–Gastaut Syndrome (REST-LGS)

Background
The complex clinical presentation and progression of Lennox–Gastaut syndrome (LGS) can complicate the accurate diagnosis of this severe, lifelong, childhood-onset epilepsy, often resulting in suboptimal treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) was developed to improve the identification of patients with LGS.

Methods
Using the Modified Delphi Consensus, a group of experts developed and tested the REST-LGS Case Report Form (CRF) comprising 8 criteria (4 major, 4 minor) considered potentially indicative of LGS. Diagnosis-blinded specialist and nonspecialist raters at 2 epilepsy centers applied the CRF to deidentified patient records, including 1:1 records of patients with drug-resistant epilepsy or confirmed LGS. Interrater reliability was measured by Cohen’s ?. Diagnosis was then unblinded to reveal common criteria for LGS or drug-resistant epilepsy. Cronbach’s ? was used to measure internal consistency between raters for all criteria combined.

Results
Of 200 patients, 81% to 85% met 1 to 3 major criteria. At both sites, moderate (?, 0.41–0.60) to good (?, 0.61–0.80) agreement on most criteria was reached between expert and nonexpert raters. Unblinding revealed that most patients with LGS met 3 major and 2 to 3 minor criteria, while patients with drug-resistant epilepsy met ? 1 major and only 1 to 2 minor criteria. Cronbach’s ? of raters at both sites was 0.64.

Conclusions
The combined number of major/minor criteria on the CRF may be particularly indicative of LGS. Therefore, the REST-LGS may be a valuable clinical tool in identifying patients requiring further diagnostic evaluation for LGS.

HudsonAlpha Scientists Identify “Poisonous” Piece of Genetic Code Causing Infant Seizures

Featuring the Work of CURE Grantee Gemma L. Carvill, PhD

Researchers at the HudsonAlpha Institute for Biotechnology have pinpointed a previously unknown cause of a serious seizure disorder most common in babies, potentially opening the door to new diagnostic and treatment options for infants that show signs of epilepsy.

They found the genetic cause hidden in the SCN1A gene, one of the most heavily studied genes for seizure disorders. The discovery offers an end to the diagnostic odyssey for affected patients, but it also reveals a genetic mechanism for disease that could uncover the cause of other genetic disorders that are not currently well understood.

Scientists in Greg Cooper’s Lab at HudsonAlpha, along with collaborators from across the country, published their findings in the American Journal of Human Genetics. They identified a variant that cues a poisonous piece of genetic code, called a poison exon, to be included in the final instructions for making a crucial protein. When the poison exon is incorporated, it prematurely cancels the protein’s production, which disrupts neural function leading to seizure disorders.

The lab found the mutation on the SCN1A gene after performing whole genome sequencing for a patient that showed symptoms of a disease called Dravet Syndrome, a serious seizure disorder that most commonly appears in infants. This particular variant would not show up on any of the more common genetic tests and it was only identified because the entire genome was sequenced.

Childhood Seizures and Risk of Psychiatric Disorders in Adolescence and Early Adulthood: a Danish Nationwide Cohort Study

Pediatric seizures have been linked to psychiatric disorders in childhood, but there is a paucity of large-scale population-based studies of psychiatric comorbidity in later life. This study aimed to examine the relation between childhood seizures and the risk of psychiatric disorders in adolescence and early adulthood.

Between Jan 1, 1978, and Dec 31, 2002, 1,291,679 individuals were born in Denmark and followed up in the population cohort (approximately 15 million person-years). 43,148 individuals had a history of febrile seizures, 10,355 had epilepsy, and 1,696 had both these disorders.

83,735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest. The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures (hazard ratio [HR] 1·12, 95% CI 1·08–1·17), epilepsy (1·34, 1·25–1·44), or both disorders (1·50, 1·28–1·75). Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders. Associations did not differ between males and females (p=0·30) but increased with a growing number of admissions for febrile seizures (p<0·0001) and with later onset of childhood epilepsy (p<0·0001).

Children with epilepsy and febrile seizures—with and without concomitant epilepsy—are at increased risk of developing a broad range of psychiatric disorders in later life. Clarification of the underlying mechanisms attributable to these associations is needed to identify potential options for prevention.

Ketogenic Diet Prevents Relapse in Infantile Spasms with Structural and Genetic Etiology

In the United States, adrenocorticotropic hormone (ACTH) and vigabatrin are first-line therapies for patients with infantile spasms (IS). However, IS and other seizure types are often refractory to pharmacological and surgical treatments in patients with IS of focal-structural and genetic etiologies. Thus, research has focused on the important task of identifying alternative safe and effective therapeutic options for this population.

Ketogenic diet therapies are evidence based treatments proven to reduce seizures in children and adults with intractable epilepsy, often started alongside other pharmacological treatments for seizures. At our center, all patients with IS are treated according to a standardized clinical pathway with ACTH, vigabatrin, or a combination of both medications followed by the option of the classic ketogenic diet (KD). This study was completed to examine the efficacy of the classic KD in preventing IS relapse and seizure occurrence in patients with IS.

The classic KD is a safe and effective therapy to prevent IS relapse in patients with focal-structural and genetic etiologies. However, the classic KD does not significantly prevent the occurrence of other seizure types in patients with IS with focal-structural and genetic etiology. Thus, although the classic KD may prevent IS relapse, these patients will need to be monitored for other seizure types. The classic KD had no significant impact on preventing relapse or seizure occurrence in patients with IS of unknown etiology. However this population is less likely to have IS relapse or seizure occurrence overall.

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

Researchers investigated the effectiveness of Diacomit add-on therapy to Depacon (valproate) and Onfi in Dravet syndrome patients carrying known pathogenic (disease-causing) mutations in the SCN1A gene.

Among children with pathogenic SCN1A mutations, Diacomit treatment was more effective in those carrying missense (single nucleotide mutation that alters protein composition) mutations (reduction of 87.50% in seizure frequency), compared to those carrying truncation (mutation that makes proteins shorter) mutations (reduction of 70.50% in seizure frequency).

However, Diacomit treatment was not favorable in children carrying mutations in regions between different domains, or between segments of the same domain of the SCN1A gene, or at splicing sites (regions of the gene that are prone to be removed or shifted to generate different proteins).

Despite “the relative smallness of the sample and it being designed as a retrospective review of clinical data, we were able to demonstrate that STP [stiripentol] has better efficacy in DS [Dravet syndrome] patients with definite SCN1A mutations than in DS patients with VOUS [variants of unknown significance] and benign SCN1A mutations,” researchers wrote.