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.

Observance of Anticonvulsant Treatments and Quality of Life of Epileptic Children (ObEPI)

There is little epidemiological data in the literature on the therapeutic compliance of epileptic children. Yet it is a fundamental issue in the therapeutic education and balance of this pathology. To obtain more epidemiological precision on the observance of epileptic children and to propose, according to the factors involved, the improvement of practices (therapeutic education). Propose an evaluation of the quality of life of their children by a suitable self-questionnaire.

Eligibility

Ages Eligible for Study: 5 Years to 18 Years (Child, Adult)
Sexes Eligible for Study: All
Sampling Method: Non-Probability Sample

Inclusion Criteria:

  • Child aged 5 to 17
    • Child who has received complete information on the organization of the research and who has not objected to his participation and the exploitation of his data
    • Holder (s) of the parental authority present (s) having received the complete information on the organization of the research and not being opposed to the participation and the exploitation of the data of his child
    • Epileptic child
    • Follow-up at the neuro pediatric department of CHRU Nancy

Exclusion Criteria:

  • Epileptic encephalopathy
  • Multiply handicapped child

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.

In this trial, EPIDIOLEX, when added to the patient’s current treatment, achieved the primary endpoint of reduction in convulsive seizures for both dose levels (10 mg/kg per day and 20 mg/kg per day) with high statistical significance compared to placebo. Both EPIDIOLEX doses also demonstrated statistically significant improvements on all key secondary endpoints.

“The positive results from this trial follow the recent FDA approval, DEA rescheduling and U.S. launch of EPIDIOLEX for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut Syndrome in patients two years and older. These data show an effective dose range in Dravet syndrome that is consistent with our FDA approved label, and which allows for dosing flexibility to address individual patient needs,” stated Justin Gover, GW’s CEO.

Neurocognition in Childhood Epilepsy: Impact on Mortality and Complete Seizure Remission 50 Years Later

Objective:
To study associations of the severity of impairment in childhood neurocognition (NC) with long?term mortality and complete seizure remission.

Methods:
A population-based cohort of 245 subjects with childhood onset epilepsy was followed up for 50 years (median = 45, range = 2?50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, 10th revision (R41.83, F70-F73). The outcome variables, defined as all?cause mortality and 10?year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models.

Results:
Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50?year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2?9.2], 4.2 [1.2?14.2], and 5.5 [2.4?12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment.

Significance:
The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood onset epilepsy.