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.

Efficacy of Levetiracetam for Reducing Rolandic Discharges in Comparison with Carbamazepine and Valproate Sodium in Rolandic Epilepsy

PURPOSE: The main purpose of this study was to compare the efficacy of levetiracetam (LEV) with the older antiepileptic drugs (AEDs) for preventing atypical evolution in children with Rolandic epilepsy (RE). Accordingly, the present study compared the efficacy of older AEDs (carbamazepine (CBZ) and valproate sodium (VPA)) with LEV in reducing rolandic discharges (RDs) on interictal electroencephalogram (EEG) in children with RE.

METHODS: Patients in this heterogenous study were subdivided into CBZ, VPA and LEV groups in accordance with the initial monotherapy. The CBZ and VPA groups were studied retrospectively, but the LEV group was studied prospectively. Appearances of discharges were counted and these rates were computed. In comparison with the baseline RD frequency, EEG response to AED treatment was classified such as complete disappearance and response (?50% reduction in RD frequency). The time taken to attain complete disappearance or response in EEG responders was assessed for each AED treatment group.

RESULTS: Responders comprised 10 (11.2%) of the 89 patients treated with CBZ, 41 (56.2%) of the 73 patients with VPA, and 25 (71.4%) of the 35 patients with LEV. Mean interval to achievement of EEG response in the CBZ, VPA, and LEV groups were 36.3, 23.1, and 14.7 months, respectively. EEG response was achieved significantly more rapidly with LEV than with CBZ (p?<?0.001) or VPA (p?<?0.005). Seizure control was not significantly different in all 3 investigated drugs.

CONCLUSIONS: Levetiracetam seems to be superior to carbamazepine and valproate sodium in its ability to suppress rolandic discharges in children with rolandic epilepsy.

Risk Factors for Seizures Among Young Children Monitored With Continuous Electroencephalography in Intensive Care Unit: A Retrospective Study

Objective: cEEG is an emerging technology for which there are no clear guidelines for patient selection or length of monitoring. The purpose of this study was to identify subgroups of pediatric patients with high incidence of seizures.

Study Design: Researchers conducted a retrospective study on 517 children monitored by cEEG in the intensive care unit (ICU) of a children’s hospital. The children were stratified using an age threshold selection method. Using regression modeling, we analyzed significant risk factors for increased seizure risk in younger and older children. Using two alternative correction procedures, we also considered a relevant comparison group to mitigate selection bias and to provide a perspective for our findings.

Results: Researchers discovered an approximate risk threshold of 14 months: below this threshold, the seizure risk increases dramatically. The older children had an overall seizure rate of 18%, and previous seizures were the only significant risk factor. In contrast, the younger children had an overall seizure rate of 45%, and the seizures were significantly associated with hypoxic-ischemic encephalopathy (HIE; p = 0.007), intracranial hemorrhage (ICH; p = 0.005), and central nervous system (CNS) infection (p = 0.02). Children with HIE, ICH, or CNS infection accounted for 61% of all seizure patients diagnosed through cEEG under 14 months.

Conclusions: An extremely high incidence of seizures prevails among critically ill children under 14 months, particularly those with HIE, ICH, or CNS infection.

A Novel GABAergic Dysfunction in Human Dravet Syndrome Suggests GABAA Receptors Could Be the Target of Therapy

OBJECTIVE: Dravet syndrome is a rare neurodevelopmental disease, characterized by general cognitive impairment and severe refractory seizures. The majority of patients carry the gene mutation SCN1A, leading to a defective sodium channel that contributes to pathogenic brain excitability. A ?-aminobutyric acid (GABAergic) impairment, as in other neurodevelopmental diseases, has been proposed as an additional mechanism, suggesting that seizures could be alleviated by GABAergic therapies. However, up to now the physiological mechanisms underlying the GABAergic dysfunction in Dravet syndrome are still unknown due to the scarce availability of this brain tissue. Here researchers studied, for the first time, human GABAA -evoked currents using cortical brain tissue from Dravet syndrome patients.

METHODS: Researchers transplanted in Xenopus oocytes cell membranes obtained from brain tissues of autopsies of Dravet syndrome patients, tuberous sclerosis complex patients as a pathological comparison, and age-matched controls. Additionally, experiments were performed on oocytes expressing human ?1?2?2 and ?1?2 GABAA receptors. GABAA currents were recorded using the two-microelectrodes voltage-clamp technique. Quantitative real-time polymerase chain reaction, immunohistochemistry, and double-labeling techniques were carried out on the same tissue samples.

RESULTS: We found (1) a decrease in GABA sensitivity in Dravet syndrome compared to controls, which was related to an increase in ?4- relative to ?1-containing GABAA receptors; (2) a shift of the GABA reversal potential toward more depolarizing values in Dravet syndrome, and a parallel increase of the chloride transporters NKCC1/KCC2 expression ratio; (3) an increase of GABAA currents induced by low doses of cannabidiol both in Dravet syndrome and tuberous sclerosis complex comparable to that induced by a classical benzodiazepine, flunitrazepam, that still persists in ?-less GABAA receptors.

SIGNIFICANCE: This study indicates that a dysfunction of the GABAergic system, considered as a feature of brain immaturity, together with defective sodium channels, can contribute to a general reduction of inhibitory efficacy in Dravet brain, suggesting that GABAA receptors could be a target for new therapies.