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

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.

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.

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.

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.


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

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

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.

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.

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.

Clinical Use and Efficacy of Levetiracetam for Absence Epilepsies

Levetiracetam is prescribed for a broad spectrum of seizure types but does not have a specific indication for absence epilepsy. Researchers hypothesized that levetiracetam is commonly prescribed for children with absence epilepsies and evaluated the efficacy of this medication for absence epilepsy treatment in clinical practice. They also hypothesized that electroencephalographic (EEG) findings could help predict levetiracetam efficacy.

This study reviews the charts of all patients treated for new-onset absence epilepsies at our pediatric neurology clinic between January 2011 and January 2016. Among 158 children diagnosed with absence epilepsies, 72 were treated with levetiracetam.

Levetiracetam was discontinued in 74% (n = 53/72) because of incomplete seizure control (59%, n = 35/72) and/or intolerable side effects (41%, n = 24/72) after a median 8.5 months (interquartile range 2, 17 months). Among patients for whom levetiracetam was effective, 44% (n = 8/18) had polyspikes on their initial EEG, versus 27% (n = 14/52) of patients for whom levetiracetam was discontinued ( P = .17). The maximal prescribed dose was lower for children in whom levetiracetam was effective (29 ± 13 mg/kg/d) than those for whom levetiracetam failed (42 ± 20 mg/kg/d; P = .005).

In routine clinical practice, levetiracetam is often chosen for patients with absence seizures. However, only about one-quarter of children with absence epilepsy in this study became seizure free with levetiracetam. When effective, levetiracetam can control absence epilepsy at a relatively low dose. Lack of seizure control requiring continued dose escalation should prompt early consideration of a therapeutic medication transition.

Dr. Steven Petrou

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

Featuring the work of CURE Grantee Dr. Steven Petrou

[A reporter] sits down to chat with Florey Institute Director Professor Steven Petrou, who leads research that creates organoids to mimic the behavior of the brains of children with rare, debilitating forms of epilepsy.

The researchers take skin cells from the children, turn them into pluripotent stem cells that can form almost any tissue in the body, then direct them to become neurons. Through a microscope you can clearly see the slender bodies of those brain cells afloat in a watery matrix. Hook them up to electrodes and you get something mind-bending. These guys are talking to each other – the computer shows spikes of electrical activity as the neurons fire.

But for the kids Petrou is trying to help, the chatter is out of whack. Some have a mutation in a gene called SCN2A that controls the passage of sodium in and out of the neuron.

“This is a gain of function of excitation, so this channel works too hard and produces epilepsy,” says Petrou.

Replicating that glitch in a dish has allowed the researchers to tailor a treatment right there on the bench; Petrou is on the verge of announcing a clinical trial of a gene therapy to treat one variant of the disorder. And it won’t just aim to stop the seizures.

“The idea with precision medicine in this application is if you can fix the fundamental disorder far enough back in the pathological chain, you should fix all the problems,” says Petrou.

If the treatment works, these kids could be spared the intellectual disability and movement disorders that go hand-in-glove with constant seizures.