LACOSAMIDE MODULATES INTERICTAL SPIKING AND HIGH-FREQUENCY OSCILLATIONS IN A MODEL OF MESIAL TEMPORAL LOBE EPILEPSY
Effects of Site-Specific Infusions of Methionine Sulfoximine on the Temporal Progression of Seizures in a Rat Model of Mesial Temporal Lobe Epilepsy
WASHINGTON – The antiepileptic drug perampanel cut the frequency of primary generalized tonic-clonic seizures by 50% versus placebo in patients who were already taking a number of other anti-seizure...
To evaluate the safety, tolerability, and comparative pharmacokinetics (PK) of intravenous and oral carbamazepine.Methods
In this phase 1, open-label study, adult patients with epilepsy on a stable oral carbamazepine dosage (400–2,000 mg/day) were converted to intravenous carbamazepine (administered at 70% of the oral dosage). A 28-day outpatient period preceded an up to 10-day inpatient period and a 30-day follow-up period. Intravenous carbamazepine was administered over 15 or 30 min every 6 h on days 1–7; some patients in the 15-min group were eligible to receive four 2- to 5-min (rapid) infusions on day 8. Patients underwent blood sampling to determine the area under the concentration–time curve (AUC) for carbamazepine and metabolite carbamazepine-10,11-epoxide following oral (day 0) and intravenous carbamazepine administration (days 1, 7, and 8). Bioequivalence was evaluated in patients with normal renal function (creatinine clearance >80 ml/min). Safety assessments were conducted through day 38.Results
Ninety-eight patients enrolled and 77 completed the PK component. The mean daily oral and intravenous carbamazepine dosage for 64 PK-evaluable patients with normal renal function was 962.5 and 675.1 mg (70% of oral dosage), respectively. Steady-state minimum concentration (Cmin) and overall exposure (AUC0–24) for intravenous carbamazepine infused over 30, 15, or 2–5 min were similar to oral carbamazepine. The 90% confidence intervals (CIs) for the ratios of the adjusted means for AUC0–24, maximum concentration (Cmax), and Cmin were within the 80%–125% bioequivalence range for 30-min intravenous infusions versus oral administration, but exceeded the upper limit for Cmax for the 15-min and rapid infusions. All intravenous carbamazepine infusions were well tolerated.Significance
Intravenous carbamazepine infusions (70% of oral daily dose) of 30-, 15-, and 2- to 5-min duration, given every 6 h, maintained patients’ plasma carbamazepine concentrations. Intravenous carbamazepine 30-min infusions were bioequivalent to oral carbamazepine in patients with normal renal function; rapid infusions were well-tolerated in this study.
This study aimed to explore the effects of theory of mind (ToM) and related potential risk factors, including cognitive functions, psychiatric status, and seizure-related clinical variables, on social functioning in patients with temporal lobe epilepsy (TLE).Methods
Sixty-seven patients with intractable TLE who were potential candidates for epilepsy surgery and 30 matched controls were included. All participants completed four tasks measuring different levels of ToM (False Belief, Faux Pas Recognition, Implication Stories, and Visual Cartoon), the Symptom Checklist-90-Revised (SCL-90-R), the Social and Occupational Functioning Scale for Epilepsy (SOFSE), and neuropsychological tests.Results
The patients exhibited impairments in both basic and advanced ToM. Multiple regression analyses revealed the following: (1) the SOFSE total score was significantly predicted by the Faux Pas Recognition (FPR), Global Severity Index (GSI) score of the SCL-90-R, and Full-Scale intelligence quotient (IQ) of the Wechsler Adult Intelligence Scale (WAIS), which accounted for 38%, 11%, and 8% of the variance, respectively; and (2) the FPR was a significant predictor of all SOFSE subscales, whereas the GSI score contributed substantially to the Interpersonal Relationships, Communication, and Occupation subscales of the SOFSE.Significance
Advanced ToM, measured by impaired faux pas recognition, is a relatively strong predictor of poor social functioning in surgical candidates for intractable TLE. Identifying ToM impairment may help plan nonpharmacologic treatment for improving social functions in patients with intractable TLE.
This document provides guidance on the use of valproate in girls and women of childbearing age from a joint Task Force of the Commission on European Affairs of the International League Against Epilepsy (CEA-ILAE) and the European Academy of Neurology (EAN), following strengthened warnings from the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) of the European Medicines Agency (EMA), which highlight the risk of malformations and developmental problems in infants who are exposed to valproate in the womb. To produce these recommendations, the Task Force has considered teratogenic risks associated with use of valproate and treatment alternatives, the importance of seizure control and of patient and fetal risks with seizures, and the effectiveness of valproate and treatment alternatives in the treatment of different epilepsies. The Task Force's recommendations include the following: (1) Where possible, valproate should be avoided in women of childbearing potential. (2) The choice of treatment for girls and women of childbearing potential should be based on a shared decision between clinician and patient, and where appropriate, the patient's representatives. Discussions should include a careful risk–benefit assessment of reasonable treatment options for the patient's seizure or epilepsy type. (3) For seizure (or epilepsy) types where valproate is the most effective treatment, the risks and benefits of valproate and other treatment alternatives should be discussed. (4) Valproate should not be prescribed as a first-line treatment for focal epilepsy. (5) Valproate may be offered as a first-line treatment for epilepsy syndromes where it is the most effective treatment, including idiopathic (genetic) generalized syndromes associated with tonic–clonic seizures. (6) Valproate may be offered as a first-line treatment in situations where pregnancy is highly unlikely (e.g., significant intellectual or physical disability). (7) Women and girls taking valproate require regular follow-up for ongoing consideration of the most appropriate treatment regimen.
We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions.Methods
Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci.Results
Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved.Significance
Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.
Response to “No clinically significant lymphocyte count change in pediatric patients treated with levetiracetam”
Valproic acid (VPA)–induced adverse effects, which are sometimes serious in children, can be associated with alterations in VPA metabolism. VPA-evoked toxicity is attributed to both the parent compound and its unsaturated metabolites, primarily formed by the cytochrome P450 (CYP)2C9 enzyme. Thus, patients’ CYP2C9-status may account for the predisposition to adverse reactions, and testing CYP2C9-status may contribute to the improvement and rationalization of VPA therapy in children.Methods
In the CYPtest group, children's CYP2C9-status was screened before initiating antiepileptic therapy. CYP2C9-status was estimated by the identification of defective CYP2C9 allelic variants (CYP2C9*2, CYP2C9*3) and current CYP2C9 expression in patients’ leukocytes, which reflects hepatic CYP2C9 activities. When the results of CYP2C9 genotyping and CYP2C9 expression were combined, the patients’ VPA-metabolizing capacity was predicted, and VPA dosing was adjusted to the patients’ CYP2C9-status. Clinical and biochemical parameters, such as VPA serum levels, blood cell counts, liver function parameters, and adverse effects in patients of CYPtest group were compared with those of the control group treated with VPA according to conventional clinical practice.Results
CYP2C9-guided treatment significantly reduced VPA misdosing and consequently decreased the ratio of patients out of the range of target VPA blood concentrations. In the CYPtest group of children who received CYP2C9-status adapted dose, serum alkaline phosphatase (ALP) level and the ratio of patients with abnormal ALP levels were substantially lower than in the control group. The incidence of serious side effects, notably hyperammonemia, was reduced in the CYPtest group; however, some other side effects, such as weight changes and somnolence, could not be avoided.Significance
The knowledge of pediatric patients’ CYP2C9-status can contribute to the optimization of VPA dosing and to the avoidance of misdosing-induced side effects.
High quality data to guide recommendations for infants with epilepsy are lacking. This study aimed to develop an understanding of common practice and regional variations in the treatment interventions of infants with epilepsy, and also to identify areas for further study and to highlight where common practice occurs without sound evidence.Method
A survey addressed clinical treatment practice for infants with epilepsy. Alternative interventions were included.Results
The survey found that most regions had similar practice for first-line interventions, except for North America, where more levetiracetam was prescribed. There was a preference for valproate as first-line therapy for generalized seizures, myoclonic seizures, and Dravet syndrome; only Oceania differed for generalized and myoclonic seizures. Phenobarbital was used for generalized and focal seizures in resource-poor and resource-equipped regions. Carbamazepine and oxcarbazepine were the preferred agents for focal seizures from all regions except North America, which uses more levetiracetam. For second- and third-line interventions, the range of choices was diverse, often with little correlation across regions. The ketogenic diet, vagus nerve stimulation, and epilepsy surgery were considered viable choices in most settings, but usually only once seizures were considered medically refractory. The survey highlighted the marked discrepancy in Africa, the one region that consistently confirmed a lack of access to these alternative interventions and to the newer antiepileptic drugs.Significance
More randomized controlled trials in infants with seizures are needed to permit useful recommendations. The survey identified widespread use of levetiracetam in North America, which may be the result of effective marketing or based on good clinical practice. The widespread use of valproate may have safety implications. The lack of access to care in the African region highlighted the need for more sustained resources. Although the survey was not evidence based, the findings could be useful to support additional well-designed studies.
Refractory status epilepticus (RSE) is a medical emergency, with significant morbidity and mortality. The use and effectiveness of clobazam, a unique 1,5-benzodiazepine, in the management of RSE has not been reported before. Over the last 24 months, we identified 17 patients with RSE who were treated with clobazam in our hospital. Eleven of the 17 patients had prior epilepsy. Fifteen patients had focal status epilepticus. Use of clobazam was prompted by a favorable pharmacokinetic profile devoid of drug interactions. Clobazam was introduced after a median duration of 4 days and after a median of three failed antiepileptic drugs. A successful response, defined as termination of RSE within 24 h of administration, without addition or modification of concurrent AED and with successful wean of anesthetic infusions, was seen in 13 patients. Indeterminate response was seen in three patients, whereas clobazam was unsuccessful in one patient. Clobazam averted the need for anesthetic infusions in five patients. Clobazam was well tolerated, and appears to be an effective and promising option as add-on therapy in RSE. Its efficacy, particularly early in the course of SE, should be further investigated in prospective, randomized trials.
Health resource utilization among US veterans with psychogenic nonepileptic seizures: A comparison before and after video-EEG monitoring
Dose-dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship
Examine the efficacy of a competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonist, selurampanel (BGG492), in the human photostimulation model.Methods
Patients with epilepsy and a generalized epileptiform electroencephalography response to intermittent photic stimulation (photoparoxysmal response or PPR; diagnosed ≥6 months prior to initial study dosing) were enrolled in a phase II, multicenter, single-blind, within-subject, placebo-controlled proof-of-concept (PoC) study. PPR was used as a biomarker to assess the efficacy and safety of BGG492 in three cohorts (cohorts I–III received BGG492 50, 100, and 15 mg, respectively). Primary endpoints were to evaluate the efficacy of single oral BGG492 doses in abolishment of PPR or a relevant reduction of the standardized photoparoxysmal response (SPR), and to evaluate time of onset and duration of response. Secondary endpoints were to evaluate maximal SPR reduction, determine the pharmacokinetic profile of BGG492, explore the pharmacokinetic/pharmacodynamic relationship, and evaluate the safety and tolerability of BGG492.Results
Ten patients were enrolled, with three participating twice, that is, in two cohorts (n = 13). Treatment with BGG492 resulted in abolition of PPR in seven of 13 patients in a dose-dependent manner: three, three, and one patient in cohorts I–III, respectively. All patients showed treatment-related reductions of SPR range of at least three steps in at least one eye condition (eye closure, eyes closed, or eyes open). Generally, onset of the suppressive effect appeared to be within 1–2 h post-BGG492 dose and continued in three patients at the 50- and 100-mg doses for 29–33 h. Most common adverse events across the BGG492-treated groups were headache and nasopharyngitis (three patients each), followed by dizziness, fatigue, and diarrhea (two patients each).Significance
The dose-dependent positive effect of BGG492 on the PPR and SPR in patients with photosensitive epilepsy in this proof-of-concept study supports further investigation of AMPA receptor antagonists in large-scale phase III trials.
The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status.Methods
Participants were 105 Australian children aged 6–8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).Results
Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores.Significance
Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.