A critical evaluation of midazolam nasal spray for the treatment of patients with seizure clusters.

Introduction: Patients with epilepsy may experience seizure clusters (SCs), which are considered a medical emergency requiring immediate treatment. Besides seizures and seizure-related injuries, patients with SCs experience impaired quality of life and have a greater need for healthcare resources. Midazolam nasal spray (MDZ-NS) was approved by the United States Food and Drug Administration (FDA) for the treatment of SCs in 2019, and was the first FDA-approved nasally administered formulation for treating SCs.Areas covered: This article provides a critical evaluation of MDZ-NS for the treatment of patients with SCs. It covers the chemistry, pharmacodynamic and pharmacokinetic properties of MDZ-NS, and safety, tolerability, and efficacy data from phase I and phase III trials. SC treatment guidelines in different countries and for alternative therapies are also discussed.Expert opinion: Midazolam is a well-established drug that is familiar to physicians. The newer MDZ-NS formulation offers the benefits of intranasal administration, which allows for outpatient treatment by caregivers and other non-healthcare professionals when an SC occurs, and may be particularly meaningful to patients with limited treatment options because other routes of administration are unsuitable. MDZ-NS is effective and patients are known to return to baseline alertness and psychomotor function within 240 minutes after administration.

Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

BACKGROUND: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. METHODS: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). RESULTS: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). CONCLUSIONS: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02324673).

Managing severe epilepsy syndromes of early childhood.

Managing severe epilepsy syndromes of early childhood is challenging as the seizures are typically resistant to treatment and may cause disabling mental and behavioral problems in later life. A comprehensive treatment plan includes pharmacologic, nonpharmacologic, and surgical options. This article reviews clinical studies examining the efficacies of antiepileptic medications in reducing seizure frequency in Dravet syndrome, Doose syndrome, and Lennox-Gastaut syndrome. The benefits of the ketogenic diet for children with these severe epilepsies, together with the advantages of vagus nerve stimulation and corpus callosotomy in those patients with Lennox-Gastaut syndrome, are also discussed. Special treatment considerations for each syndrome are also highlighted to improve the management of patients with these syndromes.

Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

Combined ketogenic diet and vagus nerve stimulation: rational polytherapy?

OBJECTIVE: The concept of "rational polypharmacy" has been associated with anticonvulsant management for decades, but the term has not been applied to nonpharmacologic therapies. METHODS: We conducted a multicenter, retrospective study of children who received concurrent diet (ketogenic or modified Atkins) and vagus nerve stimulation (VNS) treatment for medically intractable epilepsy. RESULTS: Thirty children in total from six epilepsy centers were treated over a 6-yr period. The median age at the initiation of combination therapy was 10 yr (range, 4-24 yr). Sixteen (53%) received dietary therapy followed by VNS; no differences were noted between centers. After 3 months, 21 (70%) had seizure reduced by >50% over the previous single nonpharmacologic treatment, of whom 13 (62%) had improvement within the first month. A 5-min VNS off-time correlated with >90% seizure reduction (p = 0.02). The median duration of nonpharmacologic polytherapy was 12 months (range, 0.5-96 months); 17 (57%) remain on dual therapy at this time. No side effects were noted. Most patients who discontinued combination therapy did so because of a lack of efficacy rather than restrictiveness. CONCLUSIONS: In this small group, the combined use of diet and VNS appeared synergistic and yielded rapid benefits. It may be more effective with longer VNS off-times. Further prospective studies of this combination in refractory pediatric epilepsy are needed to help guide optimal use.

Vagus nerve stimulation therapy.

Until recently, antiepileptic drugs and traditional epilepsy surgery were the two primary treatment options available to patients with epilepsy. Drug therapy, however, does not always control seizures and can be associated with negative side effects. Additionally, only a minority of patients are candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy, approved by the US FDA in 1997, is now a treatment option that is effective in reducing seizure frequency and severity as well as improving patient quality of life without the pharmacological side effects associated with traditional antiepileptic drugs. Provided here is an overview of VNS therapy and the VNS therapy system, including the history of vagal nerve stimulation, patient selection guidelines and new indications currently under investigation for this novel therapy.

Nonpharmacologic treatment of the catastrophic epilepsies of childhood.

The catastrophic epilepsy syndromes of childhood are initially treated with a pharmacologic intervention in most cases. However, due to the poor response patients often have to pharmacologic interventions, nonpharmacologic treatment options are an important part of a comprehensive treatment plan for this group of children. Additionally, nonpharmacologic therapy may offer a method to minimize associated morbidity and mortality. This article discusses the use of epilepsy surgery, the ketogenic diet, and vagus nerve stimulation in the treatment of patients with infantile spasms, Lennox-Gastaut syndrome, and progressive myoclonic epilepsy. Efficacy of the nonpharmacologic treatment options, as measured by reduction in seizure frequency, as well as by developmental progress or behavioral improvement, varies according to the specific catastrophic epilepsy disorder and the treatment option.

The evolving place of vagus nerve stimulation therapy.

Approximately 40% of patients with epilepsy have seizures that do not adequately respond to medical therapy. Vagus nerve stimulation (VNS) therapy, approved 5 years ago by the Food and Drug Administration, offers a therapeutic option for patients with pharmacoresistant seizures. This supplement updates developments with VNS therapy since its approval and suggests future directions for this still-evolving treatment.

Vagus nerve stimulation therapy in patients younger than 18 years.

Nonpharmacologic treatment options are effective in reducing seizures and improving quality of life without the negative side effects associated with antiepileptic drug (AED) therapy among pediatric epilepsy patients. One such treatment, vagus nerve stimulation (VNS) therapy, appears to be particularly effective among pediatric patients with refractory seizures. Seizure severity and frequency, as well as quality of life, are improved with VNS therapy.

Earlier use of adjunctive vagus nerve stimulation therapy for refractory epilepsy.

Recent studies suggest that epilepsy that is unresponsive to medical therapy is likely to be refractory from the onset. Identifying such patients early and treating them with nonpharmacologic therapies may improve their outcome. We hypothesized that patients who had adjunctive therapy with vagus nerve stimulation (VNS) earlier in the course of their epilepsy would have a better response compared with patients who had VNS therapy instituted later in the course. Patients in the VNS patient outcome registry who were more than 5 years post onset of their seizure disorder at implantation and had seizure frequency data available at both baseline and 3 months comprised the control group (n = 2785). These data were obtained retrospectively. Patients who were implanted between August 15, 2000 and July 31, 2001 who had epilepsy for 5 years or less at implantation or who had tried four or fewer standard antiepileptic drugs (AEDs) before implantation, and who were evaluated at baseline and at 3-month intervals for seizure frequency and quality of life, comprised the early adjunctive registry (EAR group; n = 120). This group was identified prospectively by participating physicians at multiple centers. The data describe patient demographics, medical history, seizure frequency, and physician-graded quality of life measures. The two populations were demographically similar except for statistically significant differences in age, duration of epilepsy, institutionalized patients, and seizure type (partial and generalized). Although the median reduction in seizure frequency for all patients at 3 months was similar between groups (48.2% control versus 50.0% EAR), 15.0% of the patients in the EAR group reported no seizures at 3 months compared with 4.4% of those in the control group (p < 0.001). In addition, significantly more patients in the EAR group (20% versus 8%; p < 0.001) reported no seizures with alteration or loss of consciousness, and 32% of EAR patients reported no complex partial seizures compared with 17% in the control group (p = 0.002). Improvements in all areas of quality of life were reported by both populations, but more patients in the EAR group were reported as "much better/better" for postictal state (p = 0.030) and seizure clustering (p = 0.002). Typically, 5% of patients report having no seizures after 3 months of VNS therapy. The proportion increased threefold, from 5% to 15%, for patients who received VNS therapy earlier in the treatment process. Patients reported even higher rates of no seizures when simple partial seizures were excluded from the analysis or when only complex partial seizures were considered. Although these results are preliminary, they offer promise of success in achieving seizure control among patients with refractory seizures who have been diagnosed with epilepsy for less than 5 years or who have tried four or fewer AEDs. We suggest future prospective studies evaluating VNS therapy versus best medical therapy after the first two to three AEDs have failed, which typically occurs within 2 years of seizure onset.