1 in 5 Pediatric Epilepsy Readmissions Preventable

While 1 in 5 pediatric epilepsy readmissions were scheduled, an additional 20% were judged to be preventable, according to a new report.

An interdisciplinary team from the Cincinnati Children’s Hospital Medical Center was established to review and characterize 30-day readmissions from patients admitted for epilepsy between May 2014 and October 2016. The team was made up of inpatient and outpatient neuroscience nurses, care managers, a quality outcomes manager, and child neurology physicians who individually reviewed the data.

“There was no prior data of this sort, so we were not sure what we were going to find when we started the study,” study author Marissa Vawter-Lee, MD told MD Magazine®. Other studies had found that pediatric epilepsy readmission rates hovered around 6-10% but they did not describe the readmitted patients.

The investigators classified 21.5% of the readmissions as “preventable” and 64.9% as not preventable. The most common preventable causes for readmissions were problems with the discharge care plan or medication management, the study authors said.

A Neuropsychological Model for the Pre-Surgical Evaluation of Children with Focal-Onset Epilepsy: An Integrated Approach

This review explores the complexities of pre-surgical neuropsychological assessment for children with focal-onset epilepsy. A model is proposed outlining a range of factors that potentially influence the neuropsychological formulation. These factors include a developmental, epilepsy, psychological and cognitive dimension, together with family and social context and intrinsic factors. This model is child-centered and recognizes that these factors will be weighted differently for each individual. In some instances the neuropsychological profile might suggest localized and lateralized function, but there are significant limitations to this approach in the context of the contemporary view of epilepsy as a network disorder.

This review recognizes that a range of issues impact on neuropsychological function in children with focal-onset epilepsy, including the connectivity between neural systems and the dynamic nature of development. The aim of this review is to provide a neuropsychological framework to enhance and support clinical decision-making in the pre-surgical evaluation of children with focal-onset epilepsy.

Cannabidiol Reduces Seizures in Patients with Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). This study is an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial.

Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.

Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). 35 patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. 88% of patients/caregivers reported an improvement in the patient’s overall condition per the Subject/Caregiver Global Impression of Change scale.

Significance: In this study, long-term add-on cannabidiol treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Zogenix Submits New Drug Application to FDA and Marketing Authorization Application to European Medicines Agency for FINTEPLA® for the Treatment of Dravet Syndrome

Zogenix, Inc. announced it has completed its rolling submission of a New Drug Application (NDA) to the FDA and submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for FINTEPLA (ZX008, low-dose fenfluramine) for the treatment of seizures associated with Dravet syndrome. Dravet syndrome is an intractable and difficult-to-treat epilepsy that begins in infancy and is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, and cognitive impairment.

Both applications are based on data from two pivotal Phase 3 trials in Dravet syndrome and an interim analysis from an ongoing open-label extension study, which included 232 patients treated for up to 21 months.

Lisuride Shows Promise as Dravet Syndrome Treatment, Zebrafish Study Suggests

Lisuride, an anti-parkinson medicine with demonstrated anti-seizure effects, was able to stop epileptic activity in a model of convulsant Dravet syndrome zebrafish, researchers report. The study with that finding, “Drug repurposing for Dravet syndrome in scn1Lab?/? mutant zebrafish,” was published in Epilepsia.

Recent studies have used a zebrafish model of Dravet syndrome to reveal the role of pharmacologic modulation of the serotonin (5-HT) system in treating drug-resistant seizures. Serotonin is a chemical known as a neurotransmitter (used to transmit messages between nerve cells). It plays a key role in the central nervous system (CNS) and the body’s function in general.

“With the aim to bring novel therapeutics to the market together with reducing the costs associated with traditional de novo drug development, many efforts are underway to repurpose existing drugs,” researchers wrote.

As such, investigators from the University of Leuven in Belgium, preformed a literature search on already marketed medicines that could affect the serotonin system.

They found three compounds that filled these criteria: rizatriptan (a headache medicine, brand name Maxalt), lisuride (antiparkinson medicine, brand names Dopergin, Proclacam, and Revanil) and efavirenz (an anti-HIV medicine, brand name Sustiva, among others).

They then investigated the feasibility of repurposing the above-mentioned marketed medicines as anti-epileptic drugs, particularly in difficult-to-treat epilepsy conditions like Dravet syndrome.

IT Startup Launches Software to Encourage Physician-Family Conversations About Epilepsy

Physicians can now be alerted to pediatric patients’ risk of sudden unexpected death in epilepsy, or SUDEP, during routine primary care visits by using software developed and commercialized by a researcher-entrepreneur at the Indiana University School of Medicine.

Digital Health Solutions LLC, founded by Dr. Stephen Downs, has created a module about SUDEP for its Child Health Improvement through Computer Automation, or CHICA, system. Families answer questions on an electronic tablet about several health topics, including epileptic seizures.

“For children who have seizures, CHICA asks follow-up questions about frequency, medication adherence and barriers to accessing care,” said Downs, who is the Jean and Jerry Bepko Professor of Pediatrics at the IU School of Medicine. “The program shares this information with the physician. It also makes a reminder, through the patient’s electronic health record, for the physician to discuss SUDEP with the family. The physician can document discussing SUDEP and provide computer-generated educational materials.”

A Two-Hit Story: Genetic Mutations Increase the Risk of a ‘Second Hit’ to Developing Severe Epilepsy

SCN1A (NaV1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS.

Researchers used a R1648H knock-in mouse model (Scn1aRH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1aRH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling.

Therefore, this study claims to demonstrate for their model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes.

GNAO1 Genetic Variant Associated with Seizures Beginning in First Three Months of Life

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships.

METHODS: This study evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model.

RESULTS: The 14 patients in the cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. The researchers attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia.

The 13 GNAO1 variants in the patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes.

SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

App Aids in Diagnosing Pediatric Epilepsy

The challenge of providing an early and accurate diagnosis for a child after an initial paroxysmal event with little information to differentiate epilepsy from other possibilities could become easier with a recently released web-based application.

The model predicts a percentage probability of epilepsy from clinical and electroencephalogram (EEG) data that is routinely available at first consultation, in lieu of or prior to further assessment with such measures as prolonged or sleep-deprived EEG and magnetic resonance imaging (MRI).

The model was developed by Eric van Diessen, MD, PhD, Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands, and colleagues, who point out that previous efforts to identify prognostic clinical variables for seizure recurrence have been with studies that have included only children with a definitive diagnosis of epilepsy.

Implementation of Ketogenic Diet in Children with Drug-Resistant Epilepsy in a Medium Resources Setting: Egyptian Experience

BACKGROUND: Even with the extensive use of ketogenic dietary therapies (KD), there still exist many areas of the world that do not provide these treatments. Implementing the ketogenic diet in different countries forms a real challenge in order to match the cultural and economic differences.

AIM: To assess the feasibility of implementing a ketogenic diet plan in a limited resource setting with identification of the compliance, tolerability and side effects in the target population and to assess the efficacy of the ketogenic diet in children with intractable epilepsy.

METHOD OF THE STUDY: The medical records of 28 patients with intractable epilepsy, treated at The Children’s Hospital – Cairo University from December 2012 to March 2014 with ketogenic dietary therapy were reviewed. The non-fasting protocol was followed without hospital admission. All children were started on a standardized classic ketogenic diet with a ratio ranging from 2.5-4:1 (grams of fat to combined carbohydrate and protein). Patients were followed at 1, 3 and 6 months after diet initiation.

RESULTS: The median age was 60 months (range, 30-110). After 1 month from diet initiation, 16 patients (57%) remained on the diet. One of them (6.3%) had more than 90% reduction in seizure frequency, an additional 6 patients (37.5%) had a 50-90% reduction in seizure frequency. In total, seven out of the 16 patients continuing the diet for 1 month (43.8%) had more than 50% improvement in seizure control from the base line. Despite having 50-90% seizure control, three children discontinued the diet after one month. Three months after diet initiation, 6 patients (22%) remained on diet, 4 of them (66.7%) had more than 50% reduction in seizure frequency. At 6 months, only 3 patients remained on diet, 2 of them (66.6%) had 50-90% reduction in seizure frequency, while one patient (33.3%) showed better than 90% decrease in seizure.

CONCLUSION: The current study shows that the ketogenic diet could be implemented in medium resources countries and should be included in the management of children with intractable epilepsy.