Partial-onset Seizures In Children Research Articles

Clinical effects and outcomes of perampanel overdoses reported to U.S. poison centers

Introduction Perampanel is indicated for partial onset seizures in children and adults. The mechanism is unique among antiepileptic agents as it inhibits glutamate activity on AMPA receptors. Currently, there are few published case reports describing overdose. Methods This is a retrospective observational study of all single substance perampanel ingestions from January 2014 to December 2019 reported to the national poison data system (NPDS). The primary outcome is to describe the clinical effects of perampanel exposures. Secondary outcomes include evaluation of management and investigation of a dose–effect relationship for the purpose of triaging acute unintentional exposures. Results A total of 138 exposures were reported to NPDS since the release of the agent. Median age was 20 years (IQR 10–38) with 68 (49.3%) males. The reason for exposure was most commonly therapeutic error (80, 58.0%), followed by exploratory ingestion (24, 17.4%), and suicidal ingestion (14, 10.1%). A total of six (4.3%) patients developed major effects, 20 (14.5%) moderate, 32 (23.2%) minor effects and 22 (15.9%) no effect. An additional 54 (39.1%) cases were not followed. Almost half of cases were managed at home. Of those that were in a healthcare facility (HCF) (n = 72), most were treated/evaluated and released (31, 43.1%), followed by admission to a non-critical care unit (20, 27.8%), and critical care unit (13, 18.1%). Most frequently reported symptoms were drowsiness (27, 19.6%), agitation (20, 14.5%), ataxia (13, 9.4%), and confusion (12, 8.7%). The most common therapies provided in a HCF were intravenous fluids (22,30.6%), followed by benzodiazepines (14, 19.4%), then other types of sedation (9, 12.5%). There were too few cases to determine a dose cut off for triaging. Conclusions While drowsiness, agitation, ataxia, and confusion were the most often reported symptoms, close to 19% developed moderate/major effects and almost 4% of patients received potentially life-saving interventions.

Ethical Issues in Pediatric Regulatory Studies Involving Placebo Treatment

AbstractSeparate pediatric studies for antiepileptic drugs (AEDs) emerged with general separate drug approval in children and were defined by the U.S. Food and Drug Administration (FDA) as <17 years and by the European Union (EU) as <18 years. These administrative age limits are necessary in pediatrics, but they correspond variably with the physiological maturity of young patients and are not helpful for therapeutic decisions or as study inclusion criteria. AEDs are often effective for partial onset seizures (POS) in 2 to 17-year-olds as well as in ≥18-year-olds, if dosed correctly. Separate pediatric AED studies assume no difference between the legal and the physiological meaning of the word “child.” While the FDA now accepts efficacy of AEDs in POS in children ≥2 years, the EU still requires separate “pediatric” studies. For retigabine it waived all pediatric studies after having required 20 such studies over several years. We feel the current regulation creates a situation where many studies in children are done unnecessarily; we question the ethics of such an approach, which in our view, is morally wrong. Critical publications contributed to the FDA's shift of opinion for AEDs in POS but did not address the blur of different meanings of the word “child.”

PND43 THE BURDEN OF PEDIATRIC PARTIAL ONSET SEIZURES: A REVIEW OF THE LITERATURE

To better understand the burden of epilepsy among 2- to 12-year-olds, we conducted a targeted literature review summarizing incidence, prevalence, healthcare costs, utilization, and quality of life (QOL). We searched PubMed for English-language publications reporting on children 2-12 years with either partial onset seizures (POS) or primary generalized tonic-clonic seizures, published in the United States since 2008. Data on incidence, prevalence, healthcare costs, utilization, and QOL outcomes were extracted. Findings on POS are presented here. 3,020 studies were found; 48 were included in this review. Incidence of POS was 23.2-47.1 per 100,000 children per year; prevalence was 2.0 per 1,000 children, and ranged from 1.6 to 2.6 per 1,000 in patients of any age. Annual total healthcare costs among patients of any age with POS ranged from $18,369-38,549, and were approximately two times higher in refractory POS. First-year total healthcare costs for children with POS were $19,883. Patients of any age with POS had about 10 outpatient visits, 24 procedures, 2 hospitalization days (less than 1 epilepsy-related) and 30 medication dispensing events (7 epilepsy-related) per year. Eight studies reported on QOL burden; 6 on cognitive difficulties (language, visuospatial, and memory development delays) and 4 on behavioral disorders (anxiety, depression, and attention-deficit disorder). Children with POS scored below average on cognitive assessments, and up to 42%, 16%, and 19% had depression, anxiety, and attention-deficit disorder, respectively. Incidence and prevalence of POS in children are high, similar to that of childhood type 1 diabetes; further, healthcare cost, utilization, and QOL burdens facing patients with POS are significant, especially among the group with refractory seizures. Most studies did not report outcomes aggregated by age groups or did not stratify by POS, which was true for utilization. Future studies focused exclusively on children with POS would be useful to more precisely describe the burden.

Pharmacotherapy of Focal Epilepsy in Children: A Systematic Review of Approved Agents

Partial-onset seizures contribute the bulk of seizure burden in childhood epilepsy. The therapeutic decision making involves consideration of factors specific to drug, patient and socioeconomic situation. This paper systematically reviews the available efficacy/effectiveness evidence for various anti-epileptic drugs (AED) as monotherapy and adjunctive therapy for partial-onset seizures in children. Relevant randomized clinical trials (RCTs) were identified by a structured PubMed search, supplemented by an additional hand search of reference lists and authors' files. Eligible studies were reviewed and data extracted into tables. Included RCTs were classified based on accepted published criteria. Only efficacy and effectiveness outcome measures were evaluated since there is little scientifically rigorous comprehensive AED adverse effects data. Oxcarbazepine is the only AED with Class I evidence for efficacy/effectiveness as initial monotherapy for partial-onset seizures in children. Carbamazepine, clobazam, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, vigabatrin and zonisamide have, at best, Class III efficacy/effectiveness evidence for monotherapy of partial-onset seizures in children. For adjunctive therapy, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and topiramate have Class I efficacy/effectiveness evidence for treatment of pediatric partial-onset seizures. This efficacy/effectiveness analysis must not be used in isolation when selecting therapy. AED selection for a specific child needs to integrate a drug's efficacy/effectiveness data with its safety and tolerability profile, pharmacokinetic properties, available formulations, and patient specific characteristics. It is critical that physicians and patients incorporate all these relevant variables when choosing AED therapy.

Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age

Epilepsy is a common neurological disorder in the pediatric population, affecting up to one percent of children, and for which the mainstay of treatment is anticonvulsant medication. Despite the frequent use of anticonvulsant drugs, remarkably little is known about the safety and efficacy of most of these medications in the pediatric epilepsy population. Of 34 anticonvulsants currently approved for use by the US Food and Drug Administration (FDA), only 13 have been approved for use in children. Although infants and young children are disproportionately affected by epilepsy, there are currently only three anticonvulsant medications that have been specifically evaluated and approved for use in children younger than 2 years of age. In 2012, the FDA approved levetiracetam as an adjunctive treatment for partial onset seizures in infants and children from one month of age. Here we review the available data on levetiracetam in the pediatric epilepsy population. We first discuss the pharmacological profile of levetiracetam, including its mechanism of action, formulations and dosing, and pharmacokinetics in children. We then review the available efficacy, safety, and tolerability data in children from one month of age with partial onset seizures. We conclude that the current data leading to the approval of levetiracetam for use in infants and children with partial onset seizures is encouraging, although more work needs to be done before definitive conclusions can be drawn about the efficacy of levetiracetam across different pediatric age groups.

Levetiracetam

Levetiracetam (LEV) is a broad-spectrum antiepileptic drug that is effective against a variety of seizure types. It is a pyrridoline derivative with a very favourable pharmacokinetic profile: excellent bioavailability, linear kinetics, minimal plasma protein binding and quick achievement of steady state concentrations. It is not metabolized through the P450 hepatic cytochrome system, does not induce its own metabolism and has no clinically relevant drug-drug interactions. It is available as film-coated tablets, liquid formulation for oral ingestion and intravenous concentrated solution. Controlled and open-label studies have shown its efficacy and safety as initial monotherapy and add-on treatment for partial-onset seizures in children and adults, and also as add-on therapy in refractory partial and primary generalized seizures. Its rapid onset of action, lack of drug-drug interactions and availability as an intravenous solution make it an optimal drug to treat epilepsy associated with other medical conditions. Preliminary reports also suggest potential efficacy in refractory status epilepticus, although this is not a registered indication. Levetiracetam is generally well tolerated, and no serious idiosyncratic side effects have been reported so far. Behavioral side effects (hostility up to aggressive behaviour) are not uncommon. Small, uncontrolled studies have suggested potential therapeutic potential in difficult-to-treat dyskinesias in Parkinson's disease, tremors of different etiologies, migraine prophylaxis and mood disorders. This needs to be confirmed in larger, controlled studies.

Rufinamide: pharmacology, clinical trials, and role in clinical practice

Rufinamide is a structurally novel compound with anticonvulsant activity that is undergoing evaluation through the European Medicines Agency and the American Food and Drug Administration. Its mechanism of action is thought to be inhibition of sodium-dependent action potentials in neurons, with possible membrane-stabilising effects. Absorption of the drug is significantly enhanced in the fed state. The drug is extensively metabolised by non-CYP450 systems with a half-life of 8-12 h. Most common adverse effects noted are somnolence, fatigue and tremor. Efficacy against partial seizures in adults and adolescents has been demonstrated in three randomised, placebo-controlled trials. Efficacy against seizures of Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single randomised, placebo-controlled trial. Efficacy against partial onset seizures in children has been suggested in an open-label trial. Should rufinamide become commercially available, reserving the drug as a second- or third-line agent should be considered.

Vagus Nerve Stimulation As Treatment for Epileptic Seizures.

Vagus nerve stimulation is a unique therapy for epileptic seizures. Two randomized controlled trials in patients with medically refractory partial seizures have demonstrated efficacy, leading to US Food and Drug Administration approval of vagus nerve stimulation therapy in 1997. Extensive safety testing has not revealed significant effects on cardiac, respiratory, or gastrointestinal function, though recent reports of intraoperative asystole and sleep-related airway obstruction have raised concerns. Vagus nerve stimulation is indicated for adjunctive therapy of partial-onset seizures in children and individuals older than 12 years (Class I evidence). Based on controlled, randomized trials, approximately 30% of these patients can be expected to have at least a 50% decrease in overall seizure frequency. Vagus nerve stimulation efficacy is similar to that of several newer antiepileptic drugs when used in similar populations in controlled, randomized trials. Long-term follow-up studies suggest continued efficacy over more than 1 year (Class III evidence). Case series suggest similar or greater efficacy in younger children, and in patients with refractory generalized seizures, including those associated with the Lennox-Gastaut syndrome (Class III evidence). Vagus nerve stimulation is appropriate therapy for patients with medically refractory epileptic seizures who are not optimal candidates for resective epilepsy surgery.

Oxcarbazepine: a review of its use in children with epilepsy.

Oxcarbazepine (Trileptal, Timox) is structurally related to carbamazepine and has anticonvulsant activity. Studies suggest that the anticonvulsant activity of oxcarbazepine is mediated via the blocking of neuronal ion channels. In patients aged <18 years, the efficacy of oxcarbazepine monotherapy was similar to that of phenytoin in children with partial onset or generalized tonic-clonic seizures in a 48-week trial. Additional supporting findings demonstrated that 43-71% of patients with partial onset, generalized or undetermined epilepsy were seizure free after oxcarbazepine monotherapy (mean dosage 27.7-50 mg/kg/day; duration 1-5 years). In contrast, one small nonblind trial showed more patients treated with oxcarbazepine monotherapy than with carbamazepine monotherapy had recurrent seizures during 16 months of therapy (although the conclusions that can be drawn from this trial are limited). As adjunctive therapy, oxcarbazepine was significantly better than placebo at reducing seizure frequency in children and adolescents with refractory partial onset seizures with or without secondary generalization: the median percentage change in partial onset seizure frequency was 35% vs 9%, respectively, during 16 weeks of therapy. In noncomparative trials of adjunctive oxcarbazepine (mean dosage of 34.5-56.7 mg/kg/day), 7-11% of patients with partial onset or generalized seizures were seizure free during treatment, and 20-54% had seizure reductions of > or=50%. Oxcarbazepine was generally well tolerated during monotherapy and adjunctive therapy; 2.5% and 10% of patients withdrew from well controlled trials of oxcarbazepine monotherapy and adjunctive therapy. Oxcarbazepine monotherapy was better tolerated than phenytoin and events observed in oxcarbazepine-treated patients were transient. Oxcarbazepine metabolism is largely unaffected by induction of the cytochrome (CYP) P450 system. However, oxcarbazepine can inhibit CYP2C19 and induce CYP3A4 and CYP3A5, thereby interfering with the metabolism of other drugs (e.g. phenytoin). In addition, oxcarbazepine decreases plasma levels of oral contraceptives and alternative contraceptive methods should be used. In conclusion, oxcarbazepine (as both monotherapy and adjunctive therapy) has shown efficacy in the treatment of partial onset seizures in children with epilepsy. Nevertheless, the generally favorable tolerability profile and relatively low potential for drug interactions of oxcarbazepine make it a valuable option in the treatment of childhood epilepsy.

Topiramate in refractory partial-onset seizures in children, adolescents and young adults: a multicentric open trial

Purpose: This study was to evaluate the efficacy and safety of topiramate (TPM) in refractory partial epilepsy in children, adolescents and young adults. Methods: We performed a prospective open label add-on study in 55 patients (age 2–30 years, mean 15 years) with refractory partial seizures. Topiramate was added to one or two other baseline drugs and the efficacy was rated according to seizure type and frequency. Results: TPM was initiated at a daily dose of 0.5–1 mg/kg, followed by a 2-week titration at increments of 1–3 mg/kg/24h, up to a maximum daily dose of 12 mg/kg. After 9 months of treatment, 11 patients (20%) had 100% fewer seizures and 25 patients (45%) had a more than 50% seizure reduction. TPM appeared to be effective both in cryptogenic (76.2%) and symptomatic (58.8%) partial epilepsies. Mild to moderate adverse events were present in 25 patients (45.4%), mostly represented by drowsiness, nervousness and hyporexia with or without weight loss. Conclusion: TPM was an overall effective and safe add-on drug both in cryptogenic and symptomatic childhood refractory partial seizures, the adverse reactions being generally mild or moderate.

Topiramate.

Six studies are cited to demonstrate that topiramate is effective as adjunctive therapy for refractory partial-onset seizures in adults. Subsequent studies indicate that topiramate is also effective as monotherapy in adults and as adjunctive therapy for partial-onset seizures in children, tonic-clonic seizures of nonfocal origin in children and adults, and drop attacks in Lennox-Gastaut syndrome. Adverse effects for adults and children included dizziness, fatigue, ataxia, confusion, somnolence, nephrolithiasis, paresthesia, and weight loss. More adverse effects were observed at higher doses. Topiramate exhibits rapid absorption, long duration of action, and minimal interaction with other antiepileptic drugs.

Topiramate use in pediatric patients.

Topiramate (TPM), a new antiepileptic medication, is efficacious as adjunctive therapy in adults with partial onset seizures. Its efficacy as adjunctive therapy in children was evaluated in two randomized double-blind placebo-controlled trials involving childhood epileptic encephalopathy (the Lennox-Gastaut syndrome) and partial onset seizures. In these studies, topiramate adjunctive therapy resulted in a significant reduction in drop attacks (tonic or atonic seizures) in patients with the Lennox Gastaut syndrome and a significant reduction in partial onset seizures in children with refractory partial epilepsy. In both trials, TPM's efficacy improved as the dose escalated from the double-blind phase to the open-label portion. The minimally effective topiramate dose for adjunctive therapy in children with refractory epilepsy appears to be 6 mg/kg/day. Topiramate was well tolerated with mild or moderate side effects, predominantly related to the central nervous system. Practical tips are provided that may increase the chance that topiramate will be effective and well tolerated. The most important advice is a "start low, go slow" approach. An initial TPM dose of 0.5-1 mg/kg/day followed by weekly increments of 0.5-1 mg/kg is usually well tolerated. Based on these studies, topiramate appears to be an important addition to our pediatric AED armamentarium.

Topiramate

Clinical evidence is emerging that topiramate (TPM) may be effective in pediatric epilepsies. Topiramate pharmacokinetics appear to be linear in children when administered in dosages up to 9 mg/kg/d. Mean oral clearance is 44% to 54% higher in children when compared with historical data from adults; steady-state plasma TPM concentrations for the same mg/kg dose are expected to be 33% lower in children. While double-blind, placebo-controlled trials of adjunctive TPM therapy in Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures, and refractory partial-onset seizures in children are ongoing, preliminary results of pilot studies and the open-label extension phases of these double-blind studies suggest TPM may be effective as adjunctive therapy in a broad range of seizure disorders. In the open-label extension phase of a double-blind trial, the proportion of patients with Lennox-Gastaut syndrome experiencing 50% or greater reduction in seizures was 47%. Likewise, seizures were reduced 50% or more with TPM adjunctive therapy in 64% of children with partial-onset seizures and in 67% of patients with primary generalized tonic-clonic seizures treated with open-label during the extension phase of two separate double-blind studies. Preliminary experience suggests that TPM monotherapy can be successfully substituted for another antiepileptic drug in some children. The results of the well-controlled trials are needed to confirm these preliminary observations of TPM effectiveness in pediatric epilepsies.