Different Types Of Epilepsy Research Articles

Understanding the Spectrum of SLC2A1-Associated Disorders.

Investigators from the Danish Epilepsy Center the frequency of SLC2A1 mutations in a cohort of patients with different types of epilepsies.

Autoantibodies to NR2A Peptide of the Glutamate/NMDA Receptor in Patients with Seizure Disorders in Neuropsychiatric Systemic Lupus Erythematosus.

Objective. Seizure disorders are one of the most disabling, life-threatening, and the least understood syndromes associated with neuropsychiatric SLE (NPSLE). N-Methyl-D-aspartate (NMDA) receptors are a subgroup of the glutamate receptor family, whose NR2A subunit was found on neuronal cells (anti-NR2A) in NPSLE patients with different types of epilepsy. The present study was conducted to determine the serum levels of anti-NR2A antibodies in a large group of SLE patients, to investigate the possible correlation between the presence of the NR2A specific antibodies and NPSLE-related seizure disorders. Methods and Results. The study population consisted of 107 SLE patients and 43 age- and sex-matched healthy controls. 73 SLE patients had active disease. 36 of these had NPSLE. NMDA levels were measured by ELISA. Clinical and serological parameters were assessed according to routine procedures. The levels of anti-NR2A antibodies were significantly higher in NPSLE patients, compared with non-NPSLE patients and healthy controls. Furthermore, the levels of NPSLE in patients with seizure disorders were shown to be higher than in those with cognitive dysfunction and other CNS symptoms, however, without significance. Increase in serum anti-NR2A antibodies levels correlated to anti-dsDNA antibody and SLEDAI as well as complement levels. Conclusion. We suggest that anti-NR2A antibodies play a role in the pathogenesis of NPSLE with seizure disorders.

Altered states of consciousness in epilepsy: a DTI study of the brain

Background: A disturbance in the level of consciousness is a classical clinical sign of several seizure types. Recent studies have shown that altered states of consciousness in seizures are associated with structural and functional changes of several brain regions. Prominent among these are the thalamus, the brain stem and the default mode network, which is part of the consciousness system. Our study used diffusion tensor imaging (DTI) to evaluate these brain regions in patients with three different types of epilepsies that are associated with altered consciousness: complex partial seizures (CPS), primary generalized tonic–clonic seizures (PGTCS) or secondary generalized tonic–clonic seizures (SGTCS). Additionally, this study further explores the probable mechanisms underlying impairment of consciousness in seizures. Materials and methods: Conventional MRI and DTI scanning were performed in 51 patients with epilepsy and 51 healthy volunteers. The epilepsy group was in turn subdivided into three subgroups: CPS, PGTCS or SGTCS. Each subgroup comprised 17 patients. Each subject involved in the study underwent a DTI evaluation of the brain to measure the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of nine regions of interest: the postero-superior portion of midbrain, the bilateral dorsal thalamus, the bilateral precuneus/posterior cingulate, the bilateral medial pre-frontal gyri and the bilateral supramarginalgyri. The statistical significance of the measured ADC and FA values between the experimental and control groups was analysed using the paired t-test, and one-way analysis of variance was performed for a comparative analysis between the three subgroups. Results: Statistically significantly higher ADC values ( p < 0.01) were observed in the bilateral dorsal thalamus and postero-superior aspect of the midbrain in the three patient subgroups than in the control group. There were no significant changes in the ADC values ( p > 0.05) in the bilateral precuneus/posterior cingulate, bilateral medial pre-frontal gyri or bilateral supramarginalgyri in the experimental group. Among the three patient subgroups and the ADC values of corresponding brain regions, there were no statistically significant changes. Statistically significantly lower FA values ( p < 0.05) were observed in the bilateral dorsal thalamus of the patients in the three subgroups than in the control group. Significantly lowered FA values from the postero-superior aspect of the mid brain ( p < 0.01) were observed in patients with PGTCS compared with the control group. There were no significant changes in the FA values ( p > 0.05) from the bilateral precuneus/posterior cingulate, bilateral medial frontal gyri or bilateral supramarginalgyri in the experimental group. Among the three patient subgroups and the FA values of the corresponding brain regions, there were no statistically significant changes. Conclusion: In epileptic patients with CPS, PGTCS or SGTCS, there seems to be a long-lasting neuronal dysfunction of the bilateral dorsal thalamus and postero-superior aspect of the midbrain. The thalamus and upper brain stem are likely to play a key role in epileptic patients with impaired consciousness.

H1 histamine receptor densities are increased in brain regions of rats with genetically generalized epilepsies

Genetic animal models for convulsive, non-convulsive and mixed types of generalized epilepsies were used to establish putative histaminergic brain sites involved in the control of different types of epilepsy. Age matched rats of the KM strain (audiogenic seizures, AGS), WAG/Rij strain (absence seizures) and the WAG/Rij-AGS substrain (mixed model) were compared with a control group of Wistar rats on regional binding densities of H1 histamine receptors. Coronal slices of adult brains of the four groups were labeled with 3H pyrilamine, an antagonist of H1 histamine receptor and density of receptors was quantified with image analyses. All three groups of epileptic rats showed an increase in the density of H1 histamine receptor binding in the frontal motor cortex and interposed nucleus of cerebellum compared to the non-epileptic control group. Audiogenic epilepsy was characterized by increased H1 histamine receptor density in the frontal cortical and hippocampal regions, and in two midbrain (interpedunculus and lateral vestibular) nuclei. Absence epilepsy was characterized by a decrease in substantia nigra pars compacta, while the mixed model showed an elevation of H1 histamine receptor binding density in limbic regions such as the shell of the nucleus accumbens and the ventral tegmental area. It can be concluded that common changes in H1 histamine receptors can be found in genetic epilepsy models irrespective of the seizure type, and that each type of generalized epilepsy has its own pattern of H1 histamine receptor changes. It is speculated that H1 histamine receptors play a role in the brain's endogenous epilepsy control system.

Haploinsufficiency of the STX1B gene is associated with myoclonic astatic epilepsy

We describe an 18-year-old male patient with myoclonic astatic epilepsy (MAE), moderate to severe intellectual disability, behavioural problems, several dysmorphisms and a 1.2-Mb de novo deletion on chromosome 16p11.2. This deletion results in haploinsufficiency of STX1B and other genes. Recently, variants in the STX1B gene have been associated with a wide spectrum of fever-related epilepsies ranging from single febrile seizures to severe epileptic encephalopathies. Two previously reported patients with a STX1B missense variant or deletion were diagnosed with MAE. Our observation of a STX1B deletion in a third patient with MAE therefore supports that STX1B gene variants or deletions can be involved in the aetiology of MAE. Furthermore, STX1B encodes for syntaxin-1B, of which interaction with the protein encoded by the STXBP1 gene is essential for the regulation of the synaptic transmission of neurotransmitters. STXBP1 gene variants have been identified in patients with many different types of epilepsy, including Dravet syndrome and epileptic encephalopathies, suggesting STX1B plays a similar role. We recommend that analysis of STX1B should be considered in the diagnostic work-up of individuals with MAE.

Interictal cytokine levels were correlated to seizure severity of epileptic patients: a retrospective study on 1218 epileptic patients.

BackgroundMany aspects on the correlation between epilepsy and cytokine levels were unclear. This study aims to investigate the correlations between cytokine levels and severe epilepsy.MethodsTotally 1218 epileptic patients were grouped by types of epilepsy: TLE (temporal lobe epilepsy, n = 409), XLE (extra-temporal lobe epilepsy, n = 290) and IGE (idiopathic generalized epilepsy, n = 519). Two hundred healthy volunteers were as controls. Clinical findings and levels of 14 serum and CSF cytokines and 6 STAT members were collected, measured and analyzed.ResultsAnalysis showed no differences in interictal cytokine levels among patients from TLE, XLE and IGE groups. Interictal serum levels of IL-1b, IL-1Ra, IL-6, IL-8, IFNγ, IFNλ3 and IL-17a were associated with seizure severity of epileptic patients, measured by seizure frequency, VA score or NHS3. Multivariate regression analysis indicated that interictal concentrations of serum IL-6, IFNγ, IL-17a, IFNλ3, and CSF IL-6, IL-17a, IFNλ3 were significant biomarkers for patients with severe epilepsy. mRNA levels of IL-6, IFNγ, IL-17a, and IFNλ3 were elevated in different types of epilepsy. Activation of all STATs was elevated in epilepsy, and STAT3 was activated 9-fold in average, which was the highest among all STATs.ConclusionsInterictal serum IL-6, IFNγ, IL-17a, IFNλ3, and CSF IL-6, IL-17a, IFNλ3 could be used as potential biomarkers for severe epilepsy. Activation of STATs, especially STAT3, was important in epilepsy. Our findings pointed out crucial roles of cytokine levels in epilepsy.

The analysis of sleep structure and its influence factors in epilepsy

Objective To investigate sleep structure characteristics in different types of epilepsy, and to analyze the factors affecting sleep quality in epilepsy. Methods Forty six epilepsies and 13 controls were assessed with polysomnography. Results N2[(71.33±11.91)% vs (55.54±6.94)%, P<0.05]in generalized epilepsy was significantly higher than controls. N3[(9.75±10.70)% vs (18.31±4.64)%, P<0.05]and rapid eye movement stage(REM)[(8.58±6.32)% vs (17.77±4.66)%, P<0.05]in generalized epilepsy were significantly lower than controls. The sleep latency of REM in unclassification of attack was significantly lower than other groups(P<0.05). Age older than 35 years old in epilepsy was easy to have decreased sleep efficiency(P=0.014), and the onset age after 35 years old in epilepsy regularly had difficulty in falling asleep (P=0.038). Conclusions Generalized epilepsy has obviously sleep structural abnormalities; Age older than 35 years old in epilepsy is easy to have decreased sleep efficiency, and the onset age after 35 years old in epilepsy regularly has difficulty in falling asleep. Key words: Epilepsy/PP; Sleep; Polysomnography

High-Frequency Oscillations in Pediatric Epilepsy: Methodology and Clinical Application

Increasing evidence indicates that the brain generates signals in a wide-frequency range, including high-frequency brain signals. High-frequency brain signals are also called high-frequency oscillations (HFOs), ripples, or fast ripples. There are no established terms for describing HFOs in a variety of frequency ranges. HFOs are clinically important because early detection of epileptic (or pathologic) high-frequency brain signals may significantly change the clinical management of epilepsy, including pediatric epilepsy. In this article, we review the cerebral mechanisms of HFOs and the maturational changes of HFOs in the developing brain. Newly developed methods for the detection and localization of HFOs are discussed. We describe many recent findings in the literature from invasive electrocorticography recordings, scalp electroencephalography, and magnetoencephalography. We also discuss the clinical importance of HFOs as markers of epileptogenicity and their application in different types of epilepsies. As successful surgical treatment in medically refractory epilepsies largely depends on the identification of epileptogenic zones, the use of HFOs may significantly improve surgical outcomes. Indeed, the removal of brain tissue generating pathological high-frequency signals has been related to better postsurgical outcomes than removal of the seizure onset zones. This indicates that HFOs may mark cortex that needs to be removed to achieve seizure control. The link between the epileptogenic zone and HFOs suggests that their study can elucidate the pathophysiology of epileptogenesis and ictogenesis. In addition, HFOs may reflect the predisposition of the tissue to generate seizures. Finally, we discuss how HFOs can be used to study childhood absence epilepsy, which can only be studied noninvasively.

Commentary: Revised recommendation from CMDh on use of valproate in women is ethically incomplete and neglects the interests of women.

Commentary: Revised recommendation from CMDh on use of valproate in women is ethically incomplete and neglects the interests of women.

Neurometabolic Disorders-Related Early Childhood Epilepsy: A Single-Center Experience in Saudi Arabia

Data on the pattern of epilepsy caused by metabolic disorders in the first 2 years of life are limited in developing countries. We aimed to identify the metabolic causes of epilepsy presented in the first 2 years of life and to describe their clinical, radiological, molecular, and electroencephalographic characteristics. This retrospective study was conducted between January 2010 and December 2011 at Saad Specialist Hospital (Al Khobar, Saudi Arabia). All patients younger than 2 years at the onset of epilepsy caused by metabolic disorders were reviewed. The International League Against Epilepsy definition was used, and febrile convulsion was excluded. Of 221 children diagnosed with epilepsy in the first 2 years of life at our hospital, 24 had metabolic diseases. The characteristics of these 24 children included the following: consanguinity in 18 patients (75%), developmental delay in 13 (54%), generalized tonic-clonic seizures in 10 (42%), infantile spasms in four (17%), myoclonic in seven (29%), and focal seizures in three. The diagnosis was confirmed by DNA studies in 17 patients (71%) and enzyme assay in seven (29%). The main diagnoses were peroxisomal disorders (n=3), nonketotic hyperglycinemia (n=3), Menkes disease (n=2), neuronal ceroid lipofuscinosis (n=2), biotinidase deficiency (n=2), and mitochondrial disorder (n=2). The remaining patients had lysosomal storage disease, aminoacidopathy, fatty acid oxidation defects, and organic aciduria. Seizure freedom was achieved in one third of patients in this cohort. Different metabolic disorders were identified in this cohort, which caused different types of epilepsy, especially myoclonic seizures and infantile spasms.

Prevalencia de obesidad y síndrome metabólico en pacientes pediátricos con epilepsia tratados en monoterapia con ácido valproico

Valproic acid (VPA) is a useful antiepileptic drug for controlling different types of epilepsy. It has several side effects and is associated to increased body weight, as well as metabolic and endocrine disorders, including metabolic syndrome. To determine the prevalence of obesity and metabolic syndrome among paediatric patients with epilepsy treated in monotherapy with VPA. The study was cross-sectional, observational and analytical. A sample of patients treated with VPA between 2010-2014 were studied and the body mass index (BMI), abdominal perimeter, arterial blood pressure, glucose, triglycerides and high density lipoproteins (HDL) were studied in search of obesity and metabolic syndrome. Obesity was defined as a BMI above the 95th percentile, and metabolic syndrome was considered if at least three of the following criteria were fulfilled: abdominal perimeter above the 90th percentile, systolic arterial pressure above the 90th percentile, triglycerides above 110 mg/dL and HDL below 40 mg/dL. A total of 47 patients with a mean age of 10.1 ± 4 years were studied; 51.06% were males. Eight (17%) of them developed obesity and, of those, two (25%) had metabolic syndrome. Three patients went on to become overweight (6%). Statistically significant differences were observed in the mean age in comparison to the BMI groups, where the obese patients were adolescents (ANOVA, p = 0.0001) and those who took more VPA per day were the obese (ANOVA, p = 0.024). Patients treated with VPA who become obese may go on to develop metabolic syndrome. They require careful monitoring and, if they are seen to put on weight, withdrawal of the drug should be considered.

The stigma of epilepsy and its effects on marital status.

BackgroundNo previous studies have examined marital status of patients with epilepsy and epilepsy-related factors on perceived and enacted stigmas in Iran. In the present study, marital status of patients with epilepsy (PWE’s) in Birjand city in the east of Iran was investigated.MethodsA multicenter cross-sectional study was conducted to identify factors contributing to the marital status of PWE’s in a cross-sectional study with 471 participants. Diagnosis of epilepsy in participants (374 cases) was confirmed by at least two neurologists.ResultsMarriage rate of PWE’s was 27.3% (n = 102 patients) and divorce rate was 54.8% (n = 205 patients). Divorce rate in women was significantly higher than in men (62.6% vs. 46.4%; P < 0.05), and there were no significant differences between the different types of epilepsy (P > 0.05).ConclusionsThe stigma of epilepsy has impacts on marital status of PWE’s. The PWE’s suffering from the enacted stigma of epilepsy are significantly more likely to get divorced in comparison with other patients.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-762) contains supplementary material, which is available to authorized users.

Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's

Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's

A physiologically based pharmacokinetic model for Valproic acid in adults and children

Valproic acid is an anti-convulscant drug that is widely used in the treatment of different types of epilepsy and since its introduction the clinical use has increased rapidly both as a sole agent and in combination therapies. The mechanism of action has been linked to blockade of voltage-dependent sodium channels and potentiation of GABAergic transmission. The most widely used route of administration of Valproic acid is oral, although it can also be given intravenously and rectally and its pharmacokinetics has been studied extensively. The aim of this work was to develop a physiologically based pharmacokinetic model for plasma and tissue/organ prediction in children and adults following intravenous and oral dosing of Valproic acid. The plasma/tissue concentration profile will be used for clinical trial simulation in Dravet syndrome, a rare form of epilepsy in children where the combination of Valproic acid, stiripentol and clobazam has shown remarkable results. A physiologically based pharmacokinetic model was developed with compartments for gut lumen, enterocyte, gut tissue, systemic blood, kidney, liver, brain, spleen, muscle and rest of body. System and drug specific parameters for the model were obtained from the literature from in vitro and in vivo experiments. The model was initially developed for adults and scaled to children using age-dependent changes in anatomical and physiological parameters and ontogeny functions for enzyme maturation assuming the same elimination pathways in adults and children. The results from the model validation showed satisfactory prediction of plasma concentration both in terms of mean prediction and variability in children and adults following intravenous and oral dosing especially after single doses. The model also adequately predicts clearance in children. Due to limited distribution of Valproic acid into tissues, the concentration in plasma is about 8–9 times higher than tissues/organs. The model could help to improve clinical outcome in the treatment of Dravet syndrome through dose optimisation.

The Peptide Network between Tetanus Toxin and Human Proteins Associated with Epilepsy.

Sequence matching analyses show that Clostridium tetani neurotoxin shares numerous pentapeptides (68, including multiple occurrences) with 42 human proteins that, when altered, have been associated with epilepsy. Such a peptide sharing is higher than expected, nonstochastic, and involves tetanus toxin-derived epitopes that have been validated as immunopositive in the human host. Of note, an unexpected high level of peptide matching is found in mitogen-activated protein kinase 10 (MK10), a protein selectively expressed in hippocampal areas. On the whole, the data indicate a potential for cross-reactivity between the neurotoxin and specific epilepsy-associated proteins and may help evaluate the potential risk for epilepsy following immune responses induced by tetanus infection. Moreover, this study may contribute to clarifying the etiopathogenesis of the different types of epilepsy.

Surgical management and long-term outcome of pediatric patients with different subtypes of epilepsy associated with cerebral cavernous malformations

Sufficient data on surgical treatment and seizure outcome of pediatric patients with different types of epilepsy, especially drug-resistant epilepsy and associated cerebral cavernous malformations, are scarce. The aim of this study was to carefully evaluate seizure outcome using the International League Against Epilepsy (ILAE) classification with regard to the presurgical symptom duration. Fifty-one pediatric patients younger than 19 years with cerebral cavernous malformations of all CNS localizations have been surgically treated at the authors' institution. Twenty-two patients with seizures or epilepsy who harbored cortically located supratentorial cerebral cavernous malformations underwent surgical treatment and were retrospectively analyzed. More extensive resections were used in 82% of all patients with epilepsy symptoms for longer than 2 years. Eighty-two percent of patients with symptom duration shorter than 2 years underwent circumscribed lesionectomy including the surrounding hemosiderotic rim. The overall rate of mild permanent, unanticipated postoperative deficits was 4.5%; the rate of anticipated neurological deficits was 9%. The mean follow-up was longer than 117 months in all groups. Seizure outcome was excellent in the group with symptom duration shorter than 2 years (100% ILAE Class 1). Seizure outcome was significantly worse in the group with longer symptom duration (p = 0.02). Seven patients were seizure free after surgery. Seizure outcome was stable over the years. Since seizure outcome is worse with longer seizure duration, early surgery and, if needed, interdisciplinary intervention, is recommended. Even in cases of multiple cerebral cavernous malformations and epilepsy, surgery should be considered.

WITHDRAWN: Traditional Chinese medicine for epilepsy.

Seizures are poorly controlled in many people with epilepsy, despite current antiepileptic treatments. Some turn to alternative or complementary therapy to treat their condition and the use of traditional Chinese medicinal herbs (TCMH) is increasingly popular. However, it remains unclear whether the existing evidence is rigorous enough to support its use.To determine the effectiveness and safety of traditional Chinese medicine in people with epilepsy.Our search included the Cochrane Epilepsy Group's Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 1), MEDLINE (1950 to 2007) and EMBASE (1974 to 2007).Randomised controlled trials evaluating traditional Chinese medicine in people of any age with any type of epilepsy, and comparing one formula of TCM with no intervention, placebo or single Western medicine (monotherapy).Two review authors independently extracted trial data and assessed quality. We assessed the following outcomes: (a) seizure freedom for at least one year; (b) 50% or greater reduction in seizure frequency; (c) percentage reduction in seizure frequency and duration; and (d) adverse events.Five short-term studies involving 1125 participants met the inclusion criteria. All the studies were of poor methodological quality and had a high probability of selection, detection and performance bias.Two studies assessed seizure freedom for one year. One found no difference between Xiaxingci granule and phenytoin for primary generalized tonic-clonic seizures (RR 1.00; 95% CI 0.07 to 14.90).The other study found no difference between Dianxianning pill and valproate (RR 13.00; 95% CI 0.74 to 227.72) for different types of epilepsy.Three studies assessed a 50% or greater reduction in seizure frequency. One found an advantage for Tianmadingxian capsule when compared to phenytoin (RR 1.37; 95% CI 1.23 to 1.53) in different types of epilepsy, the second an advantage for Zhixian I pill when compared to phenytoin (RR 1.31; 95% CI 1.16 to 1.48) in primary generalized tonic-clonic seizure, and the third an advantage for an 'Antiepilepsy capsule' when compared to phenobarbital (RR 1.21; 95% CI 1.02 to 1.43) for primary and secondary generalized tonic-clonic seizure. One study reported the incidence of adverse effects and the Peto odds ratio was 0.04 (99% CI 0.01 to 0.12, P < 0.00001) favouring TCMH compared to phenobarbital.The current evidence is insufficient to support the use of traditional Chinese medicine as a treatment for epilepsy. Much larger, high quality randomised clinical trials are needed to evaluate the effectiveness and safety of traditional Chinese medicinal herbs for treating epilepsy.

The Antiepileptic Potential of Nucleosides

Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

Hvordan virker antiepileptika?

There are currently around 25 antiepileptic drugs in use in Norway, of which 15 have entered the market in the last 20 years. All have somewhat different effect- and adverse effect profiles and mechanisms of action. Here we present a brief overview of current knowledge regarding the basic mechanisms of action of these drugs. The review is based on a discretionary selection of relevant articles found through a literature search in PubMed and our own clinical and research experience. There are, roughly speaking, four main mechanisms; 1) modulation of ion channels (sodium and calcium channel blockers, potassium channel openers), 2) potentiation of GABAergic inhibition, 3) reduction of glutamatergic excitation and 4) modulation of presynaptic neurotransmitter release. Some of the drugs have several mechanisms of action, and for some of them it is unclear which mechanism is clinically most important. To some extent, the drugs' mechanisms of action predict their effect against different types of epilepsy and seizures. For instance, sodium channel blockers work best against focal seizures, while calcium channel blockers work best against absences, a type of generalised seizure. Optimal treatment of patients with epilepsy requires not only thorough knowledge of seizure- and epilepsy classification, but also insight into the mechanisms of action of antiepileptic drugs.

Development of an Integrated Population Pharmacokinetic Model for Oral Levetiracetam in Populations of Various Ages and Ethnicities

Levetiracetam [E Keppra(®)] is a second generation antiepileptic drug for different types of epilepsy in adults and children ≥1 month. The objective is to develop a population pharmacokinetic model to describe the pharmacokinetics of levetiracetam in Japanese children and adults as well as North American children, the purpose being to explore potential dosing recommendations in Japanese children. Levetiracetam plasma concentration-time data were obtained from Japanese adult and pediatric clinical studies. The data were analyzed through non-linear mixed effects modelling. The model was used to perform simulations and compare the exposure in Japanese children and adults. It was subsequently extended to North American children through an external validation. A one-compartment model with first-order absorption and first-order elimination adequately described the data. The exposure parameters determined based on the simulations in children were well within the adult range. The external validation against historical data from North American children was successful. The integrated population pharmacokinetic model provided a good description of the data, confirming the similarity of levetiracetam pharmacokinetics in these various populations. In Japanese children, a target dose of 10 to 30 mg/kg twice daily ensures the same exposure as the recommended dose in Japanese adults of 500 to 1,500 mg twice daily.