Clinical Use and Efficacy of Levetiracetam for Absence Epilepsies

BACKGROUND:
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.

METHODS:
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.

RESULTS:
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).

CONCLUSION:
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.

Parents, Researchers Work to Find Cause of Neonatal Epilepsy

A shared goal to raise awareness and develop better treatments for neonatal-onset epilepsy has brought Baylor College of Medicine researchers together with three U.S. families: Jim and Tina Thompson of Iowa, Carla and Bryan Forbes from Massachusetts, and Jim Johnson and Scotty Sims in Colorado. Each couple has a child who suffered his or her first seizure within hours of birth. Those seizures continued through long stays in local neonatal intensive care units where standard treatments were unsuccessful.

Extensive diagnostic workups did not find answers, and each family waited years before the gene causing their child’s seizures could be identified. The parents subsequently helped found or lead different non-profit organizations supporting research on their children’s illnesses, including a new U.S.-wide study called Early Recognition of Genetic Epilepsy in Neonates (ERGENT).

Along with co-investigators Dr. John J. Millichap of Ann & Robert H. Lurie Children’s Hospital in Chicago and Dr. Tammy Tsuchida of Children’s National Medical Center in Washington, D.C., Dr. Edward C. Cooper and his colleagues have created a program that provides free-of-charge genetic testing to babies who have features suggestive of a genetically-caused epilepsy.

Long-Term Outcome of Resective Epilepsy Surgery in Patients With Lennox-Gastaut Syndrome

OBJECTIVE: Researchers aimed to evaluate the long-term outcome of resective epilepsy surgery in patients with Lennox-Gastaut syndrome (LGS).

METHODS: This study reviews the case reports of 90 patients with LGS who had undergone resective surgery between 2003 and 2014 at the Severance Children’s Hospital and managed them for a minimum period of 2 years.

CONCLUSIONS: Resective surgery is a viable option in some patients to treat seizures that are associated with LGS, with a high probability of seizure control and better adaptive function.

Model Helps Predict Epilepsy Risk After Paroxysmal Events in Children

Clinicians from the Netherlands have developed and validated a model to help determine the risk of epilepsy in children who have one or more paroxysmal events.

Epileptic seizures in children may be under-recognized because of the heterogeneous clinical symptoms and limited sensitivity of the initial interictal EEG, Dr. Eric van Diessen of University Medical Center in Utrecht and colleagues note in Pediatrics, online November 2.

“Our model provides a rational approach to assist clinicians during the diagnostic process by combining routinely available clinical information in a multivariate way,” write Dr. van Diessen and colleagues.

“More specifically, we expect our model to be useful as an ‘independent’ screening tool to assess the likelihood of a possible seizure to be epileptic in origin and to help the clinician decide on the need for ancillary investigations or refer to an epileptologist. We consciously do not propose a single cutoff value for clinical decision-making because this is a decision rather than a diagnostic model,” they add.

CURE Discovery: Improving Sleep

CURE Discovery: Improving Sleep with Small Environmental Changes May Decrease Seizures

Relatively small changes in environmental factors which improve the ‘internal clock’ (otherwise known as the circadian rhythm) and the quality of sleep lead to decreases in seizures in mice with similarities to Dravet syndrome, a severe form of epilepsy. These promising results are the latest findings from the lab of CURE grantee Dr. Franck Kalume of Seattle Children’s Hospital, whose grant is generously supported through the BAND Foundation.

Individuals with Dravet syndrome have problems with their circadian rhythm and with regulating their sleep.1 Upon observing that mice with similarities to Dravet syndrome have similar sleep disturbances,2 Dr. Kalume and his team set out to determine if improving circadian rhythm and sleep patterns in these mice could reduce the occurrence of seizures.

To improve circadian rhythm in the mice, the team confined either meals or exercise to nighttime, when mice are typically active. The team limited these activities during the day, when mice typically sleep. As a result of these simple changes, the team found that the mice became more active at night and less active during the day, an indication of improved circadian rhythm. The mice also showed improvements in the quality of their sleep.

Significantly, restricting these activities to nighttime led to a decrease in the incidence of irregular brain activity that is characteristic of an epileptic brain, an indication that improvements in sleep practices may improve epilepsy.

Dr. Kalume and his team next plan to confine both exercise and meals to nighttime to see if this leads to an even greater reduction of seizures. They also plan to determine the effect of these changes on the risk of sudden death in these mice, as these mice and humans with Dravet syndrome are more susceptible to Sudden Unexpected Death in Epilepsy (SUDEP).

These important results contribute to our understanding of the relationship between sleep and epilepsy and provide hope for the development of new therapies to improve epilepsy outcomes. Dr. Kalume and his team hope these studies will lead to practical steps not involving medication that individuals with epilepsy can take to improve their circadian rhythm and sleep to reduce seizures and the risk of SUDEP.

1 Licheni SH et al. Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev Med Child Neurol 2018; 60(2):192-198.
2 Kalume F et al. Sleep impairment and reduced interneuron excitability in a mouse model of Dravet Syndrome. Neurobiol Dis. 2015; 77: 141-54.

Generic Clobazam Tablets, Oral Suspenion Receives FDA Approval for Lennox-Gastaut Syndrome

The FDA has approved abbreviated new drug applications for several companies including Breckenridge Pharmaceutical, Amneal Pharmaceuticals, and Upsher-Smith to immediately market a generic version of clobazam (Onfi) (Lundbeck) tablets, CIV, 10 mg and 20 mg, and clobazam oral suspension, CIV, 2.5 mg/mL, for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome in patients 2 years of age and older.

Clobazam’s exact mechanism of action is not fully understood, however, it’s thought to involve the potentiation of GABAergic neurotransmission, a result from binding at the benzodiazepine site of the GABAA receptor.

Staring Spells Are Epileptic Seizures Half the Time, Clinic Review Finds

Children with staring spells who were referred to a new-onset seizure (NOS) clinic were found to have epileptic seizures about half the time, according to findings presented here at the Child Neurology Society annual meeting. The results were based on review of data from a clinic at Emory University.

Researchers said the diverging findings for these patients underscore the value of NOS clinics to steer children down the proper path, particularly for the presenting feature of staring spells, which is so commonly seen in children.

“We need to take staring spells seriously. EEG on the same day [as the initial presentation] can expedite care and provide rapid, accurate diagnoses for both epileptic and non-epileptic spells,” Dr. Koh said. The bottom line is that “we should not be dismissive of staring spells.”

New Causative Gene Found in Severe Childhood Epilepsy

A large international research team has discovered a new genetic cause for a severe, difficult-to-treat childhood epilepsy syndrome. Spontaneous mutations in one gene disrupt the flow of calcium in brain cells, resulting in epileptic overactivity. The team’s research in patients also found clues to potential medical treatments for the rare condition.

“Even though variants in this gene were only just discovered to cause disease, we already have a good understanding of how changes in the gene’s associated protein affect brain function–causing neural overactivity in epilepsy,” said first author Katherine L. Helbig, MS, CGC, a research genetic counselor in the Neurogenetics Program in the Division of Neurology at Children’s Hospital of Philadelphia (CHOP). “Furthermore, although much follow-up research remains to be done, we found that there is a possibility that specific anti-seizure medications could reduce this overactivity in some patients.”

The research team focused on disease-causing changes in the CACNAIE gene, long suspected to play a key role in how neurons regulate their electrical activity, but not previously known to cause human disease. This study was the first to link the gene to human epilepsy.

Acetaminophen Can Reduce Recurrence of Febrile Seizures

Acetaminophen can reduce the risk for febrile seizure (FS) recurrence during the same fever episode among infants and children, according to a study published in Pediatrics.

Shinya Murata, M.D., Ph.D., from Hirakata City Hospital in Osaka, Japan, and colleagues conducted a single-center, randomized controlled study involving children and infants (age range, 6 to 60 months) with FSs. To examine the effectiveness of acetaminophen, recurrence rates were compared for patients in whom rectal acetaminophen was administered every six hours until 24 hours after the first convulsion and for patients in whom no antipyretics were administered. FS recurrence during the same fever episode was assessed as the primary outcome measure.