The role of cortisol in trust behavior: Results from an experimental study on healthy controls and patients with juvenile myoclonic epilepsy.

Trust is one of the foundations of human society and pervades all aspects of human live. Research on humans focused primarily on identifying the biological basis of trust behavior in healthy subjects, and this evidence hints to certain brain areas, hormones, and genetic factors to be fundamentally involved. The contribution of cortisol in trust has not yet elicited much attention in research, especially when specifically examined at basal cortisol levels. Trust has been previously studied in some neurological diseases but not in patients with epilepsy, and the influence of hormones on trust in these diseases remains yet unknown. Against this background, we designed an experimental study with a group of patients with juvenile myoclonic epilepsy and a group of healthy controls to compare trust behavior and plasma cortisol levels between the two groups. This economic game is frequently used in research to operationalize trust behavior. All participants further underwent neuropsychological assessment. Our results showed that there was no significant difference in trust behavior during the trust game, but a trend toward lower trust in patients. Furthermore, there was a significant difference in cortisol levels between groups with lower levels in patients. Interestingly, cortisol levels correlated with trust only in the patient group, but not in the control group. Future studies should specifically differentiate the effect of induced cortisol increases (e.g., acute stress) versus the effect of basal cortisol levels reflecting homeostasis or chronic stress on trust behavior and leverage the potential of comparison between patients and healthy controls.

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.

Expression analysis of beta-secretase 1 (BACE1) and its naturally occurring antisense (BACE1-AS) in blood of epileptic patients.

Beta-secretase 1 (BACE1) gene encodes a transmembrane protease from the peptidase A1 family of aspartic proteases whose role in the pathogenesis of Alzheimer's disease has been assessed. The enzymatic activity of BACE1 on several proteins implicated in epileptogenesis implies its role in the pathogenesis of epilepsy. In the present study, we assessed expression of BACE1 and its naturally occurring antisense (BACE1-AS) in peripheral blood of 40 epileptic patients and 40 age- and sex-matched healthy subjects. We did not detect either any difference in the expression of these genes between cases and controls or significant correlation between their expressions and participants' age. However, we demonstrated a significant correlation between expression levels of BACE1 and BACE1-AS which supports the previously suggested feed-forward mechanism of regulation between these two transcripts. Future studies in larger sample sizes are needed to elaborate the function of BACE1 in epilepsy.

Valproic acid malabsorption in 30 year-old female patient - Case study.

AIM: Valproic acid (VPA) is used in epilepsy treatment and as a stabilizer in bipolar affective disorder for over 40 years. Although, the pharmacokinetic properties of valproic acid are well known, it is often forgotten that the formulation of the drug significantly influences its gastrointestinal absorption. CASE: We are describing the case of 30 year-old female patient, diagnosed at the age of 13 with juvenile myoclonic epilepsy. Complete ineffectiveness of the treatment was caused by malabsorption of sodium valproate and valproic acid in the patient. The change of the drug formulation resulted in a several times higher bioavailability of the drug and a partial improvement of the patient's clinical condition. COMMENTARY: Low concentration of valproic acid after administration the slow-released tablets are usually observed. However, a low bioavailability beside the bad compliance should be considered when the minimal level is extremely low during therapy. It is known that form of the drug, beside presence of food and its components, as well as gastrointestinal tract condition or interactions with other drugs can influence the drug level. Modification of the formulation of the drug may lead to improvement of absorption and increase its effectiveness.

Lack of association between the prothrombin rs1799963 polymorphism and juvenile myoclonic epilepsy.

UNLABELLED: Juvenile myoclonic epilepsy (JME) accounts for 26% of generalized idiopathic epileptic syndromes. The highest levels of thrombin activity are closely involved in the development of neurological diseases, including epilepsy. The prothrombin c.20210G>A (rs1799963) variation, which alters prothrombin mRNA stability, is associated with high plasma prothrombin levels. OBJECTIVE: The present study was designed to investigate whether the SNP rs1799963 is a risk factor for JME in the northeastern Brazilian population. RESULTS: The polymorphism was genotyped in 207 controls and 123 patients using polymerase chain reaction-restriction fragment length polymorphism method. No significant differences were observed in the genotype and allele frequencies of this polymorphism between cases and controls. CONCLUSION: These results present no evidence for an association of rs1799963 with JME. Further studies including other types of epilepsy are required to investigate the involvement of prothrombin gene in the genetic susceptibility to chronic seizure.

Lack of association between the prothrombin rs1799963 polymorphism and juvenile myoclonic epilepsy / Ausência de associação entre o polimorfismo G20210A (rs1799963) da protrombina e epilepsia mioclônica juvenil

Juvenile myoclonic epilepsy (JME) accounts for 26% of generalized idiopathic epileptic syndromes. The highest levels of thrombin activity are closely involved in the development of neurological diseases, including epilepsy. The prothrombin c.20210G>A (rs1799963) variation, which alters prothrombin mRNA stability, is associated with high plasma prothrombin levels. Objective : The present study was designed to investigate whether the SNP rs1799963 is a risk factor for JME in the northeastern Brazilian population. Results : The polymorphism was genotyped in 207 controls and 123 patients using polymerase chain reaction-restriction fragment length polymorphism method. No significant differences were observed in the genotype and allele frequencies of this polymorphism between cases and controls. Conclusion : These results present no evidence for an association of rs1799963 with JME. Further studies including other types of epilepsy are required to investigate the involvement of prothrombin gene in the genetic susceptibility to chronic seizure. .

Epilepsia mioclônica juvenil (EMJ) representa 26% das síndromes epilépticas idiopáticas generalizadas. Níveis elevados de atividade da trombina estão intimamente envolvidos no desenvolvimento de distúrbios neurológicos, incluindo epilepsia. A variante c.20210G>A (rs1799963) do gene de protrombina, que altera a estabilidade do RNAm, está associada com altos níveis de protrombina no plasma. Objetivo: Investigar se o SNP rs1799963 é um fator de risco para EMJ em uma amostra da população do nordeste brasileiro. Resultados : O polimorfismo foi genotipado em 123 pacientes e 207 controles usando a reação de polimerase em cadeia com restrição de polimorfismo. Não observamos diferença significativa nas frequências alélicas e genotípicas deste polimorfismo, entre as populações de pacientes e controle. Conclusão : Estes resultados não demonstram evidências para uma associação do polimorfismo rs1799963 com EMJ. Estudos posteriores, incluindo outros tipos de epilepsia, são necessários para investigar o envolvimento do gene protrombina na susceptibilidade genética a crises crônicas. .

Low-dose sodium valproate in the treatment of idiopathic generalized epilepsies.

OBJECTIVE: Most patients with idiopathic generalized epilepsies (IGEs) have good seizure control when on antiepileptic drugs. To analyze prospectively the response to low-dose sodium valproate (VPA) treatment (<1000 mg/day) together with plasma VPA levels in a cohort of patients with IGE. METHODS: Patients with IGE were selected and followed for almost 2 years. In patients on VPA with no seizures in the last year, VPA dose was lowered to <1000 mg/day. Newly diagnosed patients with IGE started treatment on VPA directly on this low dose. RESULTS: Fifty-four patients were included, with juvenile myoclonic epilepsy (JME) in 23 (42.6%), juvenile absence epilepsy (JAE) in 17 (31.5%), and generalized tonic-clonic seizures only (GTCS only) in 14 (25.9%). VPA at low dose was administered to 38 (70%) patients. Mean plasma VPA level was 44.21 mg/l (18-78; SD 15.18). Seizure relapse during the 2-year follow-up was observed in 8 (21%). A reduction in adverse events was observed (P < 0.048). The only factor related to efficacy of VPA at low dose was syndromic diagnosis. Low-dose VPA controlled 92.9% (13) of patients with GTCS only, 78.3% (18) of those with JME, and 29.5% (5) of those with JAE. CONCLUSIONS: Low-dose VPA was a highly effective treatment for the majority of those with JME and GTCS only. The seizures in JAE tended to be more resistant to treatment, usually requiring higher doses of VPA or polytherapy.

Antiepileptic drugs: a case report in a pregnancy with a neural tube defect.

While receiving lamotrigine, a patient pregnant with triplets suffered a double fetal neural tube defect. Plasma homocysteine, folate, vitamins B12 and B6 (pyridoxal phosphate), and red cell folate levels were measured in samples while she was receiving folic acid therapy for 1 month during the second trimester of pregnancy. Some mutations were sought, involved in homocysteine metabolism and linked with the folate metabolism. Her results were compared with those of a pregnant woman with normal triplets and with those of 58 pregnant women, with a normal pregnancy. Results indicated a decrease in vitamin B12 and B6 values in plasma in the patient, and a genotype AG (polymorphism A66G) was observed, but was not found in the pregnant woman with normal triplets. Even if lamotrigine therapy is not known to be associated with significant changes in red cells or in serum folate, periconceptional folic acid supplementation is counseled for women, along with periconceptional B12 and B6 vitamin supplementation when their plasma values are decreased.

Uptake of GABA and activity of GABA-transaminase in platelets from epileptic patients.

The aim of the present study was to assess the activity of GABA-transaminase (GABA-T) and the kinetic parameters of GABA uptake in platelets from patients with distinct epileptic syndromes. We studied 14 patients with juvenile myoclonic epilepsy (JME), 19 patients with refractory localization-related epilepsy (RLE) and 20 healthy volunteers who were matched for age and sex. Acute effects of valproate (VPA) and lamotrigine (LTG) on the uptake of GABA and the activity of GABA-T in platelets in vitro were also analyzed. The mean activity of GABA-T in JME patients was significantly higher than in control subjects, whereas RLE patients did not significantly differ from controls. The capacity of GABA uptake was least in JME patients, intermediate in RLE patients and highest in controls. In vitro VPA (concentrations 150-1200 microM) or LTG (concentrations 1-100 microM) had no significant effects on GABA uptake. Our results indicate marked differences in the platelet uptake of GABA and the activity of catabolic enzyme GABA-T between patients with generalized and localization-related epileptic syndromes. The observed peripheral alterations may indicate an impairment in the function of brain GABAergic systems.