[Importance of personality disorders in epilepsy]. / A személyiségzavarok jelentosége epilepsziában.

Epilepsy is one of the most common neurological disorders. Therapeutic success shows high variability between patients, at least 20-30% of the cases are drug-resistant. It can highly affect the social status, interpersonal relationships, mental health and the overall quality of life of those affected.
Although several studies can be found on the psychiatric diseases associated with epilepsy, only a few researches focus on the occurrence of personality disorders accompanying the latter. The aim of this review is to help clinicians to recognize the signs of personality disorders and to investigate their connection and interaction with epilepsy in the light of current experiences.
The researches reviewed in this study confirm that personality disorders and pathological personality traits are common in certain types of epilepsy and they affect many areas of patients’ lives. These studies draw attention to the importance of a multidisciplinary approach to this neurological disorder and to provide suggestions about the available help options. Considering the high frequency of epilepsy-related pathological personality traits that can have a great impact on the therapeutic cooperation and on the patients’ quality of life, it important that the neurologist recognizes early the signs of the patient’s psychological impairment. Thus they can get involved in organizing the support of both the patient and their environment by including psychiatrists, psychologists, social and self-help associations.
As interdisciplinary studies show, epilepsy is a complex disease and besides trying to treat the seizures, it is also important to manage the patient’s psychological and social situation. Cooperation, treatment response and quality of life altogether can be significantly improved if our focus is on guiding the patient through the possibilities of assistance by seeing the complexity and the difficulties of their situation.

New Approach for Untangling the Role of Uncommon Calcium-Binding Proteins in the Central Nervous System.

Although Ca2+ ion plays an essential role in cellular physiology, calcium-binding proteins (CaBPs) were long used for mainly as immunohistochemical markers of specific cell types in different regions of the central nervous system. They are a heterogeneous and wide-ranging group of proteins. Their function was studied intensively in the last two decades and a tremendous amount of information was gathered about them. Girard et al. compiled a comprehensive list of the gene-expression profiles of the entire EF-hand gene superfamily in the murine brain. We selected from this database those CaBPs which are related to information processing and/or neuronal signalling, have a Ca2+-buffer activity, Ca2+-sensor activity, modulator of Ca2+-channel activity, or a yet unknown function. In this way we created a gene function-based selection of the CaBPs. We cross-referenced these findings with publicly available, high-quality RNA-sequencing and in situ hybridization databases (Human Protein Atlas (HPA), Brain RNA-seq database and Allen Brain Atlas integrated into the HPA) and created gene expression heat maps of the regional and cell type-specific expression levels of the selected CaBPs. This represents a useful tool to predict and investigate different expression patterns and functions of the less-known CaBPs of the central nervous system.

Short-Term Amygdala Low-Frequency Stimulation Does not Influence Hippocampal Interneuron Changes Observed in the Pilocarpine Model of Epilepsy.

Temporal lobe epilepsy (TLE) is characterized by changes in interneuron numbers in the hippocampus. Deep brain stimulation (DBS) is an emerging tool to treat TLE seizures, although its mechanisms are not fully deciphered. We aimed to depict the effect of amygdala DBS on the density of the most common interneuron types in the CA1 hippocampal subfield in the lithium-pilocarpine model of epilepsy. Status epilepticus was induced in male Wistar rats. Eight weeks later, a stimulation electrode was implanted to the left basolateral amygdala of both pilocarpine-treated (Pilo, n = 14) and age-matched control rats (n = 12). Ten Pilo and 4 control animals received for 10 days 4 daily packages of 50 s 4 Hz regular stimulation trains. At the end of the stimulation period, interneurons were identified by immunolabeling for parvalbumin (PV), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). Cell density was determined in the CA1 subfield of the hippocampus using confocal microscopy. We found that PV+ cell density was preserved in pilocarpine-treated rats, while the NPY+/nNOS+ cell density decreased significantly. The amygdala DBS did not significantly change the cell density in healthy or in epileptic animals. We conclude that DBS with low frequency applied for 10 days does not influence interneuron cell density changes in the hippocampus of epileptic rats.

Amygdala Low-Frequency Stimulation Reduces Pathological Phase-Amplitude Coupling in the Pilocarpine Model of Epilepsy.

Temporal-lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and warrants the development of new therapies, such as deep-brain stimulation (DBS). DBS was applied to different brain regions for patients with epilepsy; however, the mechanisms of action are not fully understood. Therefore, we tried to characterize the effect of amygdala DBS on hippocampal electrical activity in the lithium-pilocarpine model in male Wistar rats. After status epilepticus (SE) induction, seizure patterns were determined based on continuous video recordings. Recording electrodes were inserted in the left and right hippocampus and a stimulating electrode in the left basolateral amygdala of both Pilo and age-matched control rats 10 weeks after SE. Daily stimulation protocol consisted of 4 × 50 s stimulation trains (4-Hz, regular interpulse interval) for 10 days. The hippocampal electroencephalogram was analyzed offline: interictal epileptiform discharge (IED) frequency, spectral analysis, and phase-amplitude coupling (PAC) between delta band and higher frequencies were measured. We found that the seizure rate and duration decreased (by 23% and 26.5%) and the decrease in seizure rate correlated negatively with the IED frequency. PAC was elevated in epileptic animals and DBS reduced the pathologically increased PAC and increased the average theta power (25.9% ± 1.1 vs. 30.3% ± 1.1; p < 0.01). Increasing theta power and reducing the PAC could be two possible mechanisms by which DBS may exhibit its antiepileptic effect in TLE; moreover, they could be used to monitor effectiveness of stimulation.

Effect of a gymnastics program on sleep characteristics in pregnant women.

OBJECTIVE: The quality and quantity of sleep represent important health issues in pregnant women. Sleep disturbances could be associated, beyond alteration of quality of life, with poor pregnancy outcome. Our aim was to investigate the effect of a regular, specific, medium-term physical training program on sleep characteristics in healthy pregnant women. MATERIALS AND METHODS: A total of 132 healthy pregnant women, with gestational age between 18 weeks and 22 weeks, were enrolled in a prospective study. They were allocated into two groups; the first group involved 79 women (average age, 29.4 years) who performed a specific gymnastics program of 10 weeks, and the second group involved 53 pregnant women (average age, 27.9 years) who did not perform gymnastics. All participants completed a comprehensive questionnaire at baseline and after 10 weeks concerning general data, sleep characteristics, and psycho-emotional status. The changes arising within a diverse set of characteristics were followed and compared for the two groups using parametric and nonparametric statistics. RESULTS: In the control group, we observed significant worsening of 12 out of the 14 studied parameters during the 10-week period. In comparison with the women who did not perform gymnastics, women who performed specific gymnastics showed the following characteristics: (1) significantly less deterioration of psycho-emotional status (stress and anxiety levels); (2) the same general pattern of decrease in sleep quality, which is related to the progression of pregnancy; and (3) a significant attenuation of the worsening of several sleep characteristics, such as restless sleep, snoring, diurnal tiredness, and excessive daytime sleepiness. Nocturnal and diurnal sleep quantity increased significantly in both groups. CONCLUSION: The 10-week training program designed for pregnant women has an overall beneficial effect on sleep characteristics, not by improving them but by attenuating their general deterioration related to the progression of pregnancy. Our data strengthen the general recommendation regarding participation of pregnant women in specific exercise programs, mainly for maintaining their psycho-emotional and general well-being.

Differential effects of sodium channel blockers on in vitro induced epileptiform activities.

Antiepileptic drugs act on voltage gated sodium channels in many different ways: rufinamide is thought to influence the fast inactivation, so its anticonvulsant action could be similar to carbamazepine, whereas lacosamide enhances the slow inactivation; however some antidepressants were also described to act in the same way. Rufinamide, lacosamide, carbamazepine, fluoxetine and imipramine were tested using in vitro models of epileptiform activities. Extracellular local field potentials were recorded using hippocampal slices from immature rats and the pattern of epileptiform activities was analyzed. Seizure-like events (SLE), but not interictal bursts were sensitive to AEDs' action. Rufinamide increased interictal periods by prolonging preictal phase and reducing SLE duration, and was the only tested AED which reduced SLE frequency. Lacosamide's effect resembled that of fluoxetine in the low-Mg2+ model: both drugs reduced markedly the SLE duration, but increased their frequency. Imipramine and fluoxetine irreversibly suppressed SLE in all slices. Some proconvulsive type of action on SLEs such as increasing preictal neuronal activity by rufinamide and increasing SLE frequency by lacosamide, fluoxetine and carbamazepine, were also observed. Newer drugs were more efficient than carbamazepine, and the anticonvulsant action of antidepressants on in vitro epileptiform activities may seem somewhat surprising.

Histopathological changes induced by selective inactivation of menin on the thyroid gland in RET÷PTC3 and E7 transgenic mice. A study of 77 cases.

Multiple Endocrine Neoplasia Type 1 (MEN1) does not involve the thyroid gland, but animal studies have shown that mice with inactivation of menin could develop thyroid pathologies. The objective was to evaluate if the selective inactivation of menin in murine thyroid glands expressing RET÷PTC3 and E7 oncogenes, might induce an increased index of proliferation and a more rapid development of thyroid hyperplasia and÷or tumors. The thyroid glands of 77 mice aged 4-18 months (31 expressing the E7 oncogene and 25 the RET÷PTC3 oncogene) were analyzed for histological changes and Ki67 proliferation index. Fifty-two mice had selective inactivation of menin in the thyroid gland (16 mice with RET÷PTC3 oncogene and 19 mice with E7 oncogene). As compared to wild type, mice with inactivation of menin presented an increased Ki67 proliferation index. Mice presenting the E7 oncogene showed larger thyroid glands with a pattern of diffuse hyperplasia. Mice expressing the RET÷PTC3 oncogene presented larger thyroid glands compared to the wild type mice but smaller compared to E7 mice. The lesions in the RET÷PTC3 group were "proliferative papillary cystic changes" (60%), "cribriform" (16%), "solid" (8%) and a combination of these patterns in the rest of the thyroid glands. The inactivation of menin in the thyroid gland of young mice does not seem to change the histological pattern, but it influences the proliferation of follicular cells. Further molecular studies especially in aged mice are needed to better understand the correlation between certain oncogenes and the inactive status of menin.

The loss of Ivy cells and the hippocampal input modulatory O-LM cells contribute to the emergence of hyperexcitability in the hippocampus.

Epilepsy is a frequent neurological disorder that affects directly 0.5-1.5% of the world's population. Despite advances regarding therapy, about 30% of patients cannot be relieved of seizures, mainly because the pathophysiological mechanisms are still not elucidated completely. Basket, axo-axonic, bistratified, oriens-lacunosum moleculare (O-LM) and Ivy cells exert spatially and temporary different inhibition on principal neurons. Our aim was to evaluate the alterations of these interneuron populations during epileptogenesis. We induced status epilepticus in male Wistar rats using intraperitoneal pilocarpine injection, which was followed, after a latency period, by spontaneous recurrent seizures (SRS). Nissl staining was used for the analysis of gross morphological changes, whereas triple immunofluorescent-labeled sections (parvalbumin, somatostatin, neuropeptide-Y) were used for differentiation of the selected interneuron types. Putative interneurons identified by their neurochemical contents were quantified, and the cell density was calculated. Although animals developing SRS showed similar behavior, the degree of hippocampal sclerosis was different. In animals with hippocampal sclerotic cell death pattern the density of perisomatic inhibitory neurons was higher, but not significantly. The dendritic inhibitory bistratified cells were preserved, whereas the number of O-LM cells showed a significant decrease. A substantial loss was observed in the number and density of Ivy cells. We suggest that the loss of hippocampal input modulatory O-LM cells, and overall excitation controlling Ivy cells, has a role in the emergence of hyperexcitability. In the same time, alterations of output controlling interneurons might contribute to the propagation of the pathological synchronization to the cortex.

Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats.

Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 µg/ml and 3.188 ± 0.71 µg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio.

Untangling the pathomechanisms of temporal lobe epilepsy--the promise of epileptic biomarkers and novel therapeutic approaches.

Epilepsy is one of the most common neurological diseases and it is characterized by the reoccurrence of seizures with variable severity and frequency. The burden of epilepsy, however, is more than having seizures, as the disease is frequently associated with comorbid cognitive and behavioral disorders. Diagnosis as well as treatment suffers both from the inadequate understanding of the underlying epileptogenic molecular, cellular and network mechanisms and the related lack of reliable biomarkers for the development, progression, or even the presence and severity of the epileptic condition. Here we summarize the recent advances in both clinical and experimental approach regarding epilepsy, which may create the premise for identification of clinically useful, reliable biomarkers. Identification of the basic pathomechanisms of epileptogenesis and epilepsy would potentially create new therapeutic approaches that could not only treat but also prevent and cure epilepsy. Current knowledge regarding the electrophysiological alterations as well as the underlying cellular and molecular mechanisms regarding temporal lobe epilepsy is also critically scrutinized.

Liquid chromatography-mass spectrometric determination of rufinamide in low volume plasma samples.

Quantification of rufinamide in plasma was achieved using a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. The chromatographic separation was achieved on a reversed phase column (Zorbax SB-C18 100mm×3mm, 3.5µm) under isocratic conditions. The mobile phase consisted of a mixture of water containing 0.1% formic acid and methanol (50:50, v/v). The mass spectrometric detection of the analyte was in multiple reaction monitoring mode (MRM) using an electrospray positive ionization (ESI positive). The monitored ions were 127m/z derived from 239m/z rufinamide and 108m/z derived from 251m/z the internal standard (lacosamide). Protein precipitation with methanol was applied for sample preparation using only 50µl aliquots. The concentration range was 40-2000ng/ml for rufinamide in plasma. The limit of detection was 1.25ng/ml and the lower limit of quantification was established at 5ng/ml rufinamide concentration. Selectivity and matrix effect was verified using individual human, rat and rabbit plasma samples. Short-term, post-preparative and freeze-thaw stability was also investigated. The proposed method provides accuracy, precision and high-throughput (short runtime 4.5min) for quantitative determination of rufinamide in plasma. This is the first reported liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for analysis of rufinamide from low volume plasma samples. The LC-MS/MS method was validated according to the current official guidelines and can be applied to accurately measure rufinamide level of large number of plasma samples from clinical studies or therapeutic drug monitoring.

Higher cigarette taxes--healthier people, wealthier state: the Hungarian experience.

OBJECTIVE: To prove that higher cigarette taxes eventually decrease smoking and do also increase state incomes from tobacco taxes by using Hungarian figures. METHOD: Collection and analysis of available data on tobacco use, levels of excise and value added taxes on tobacco products and state incomes originating from the tobacco sector. CONCLUSIONS: In Hungary, regular tobacco tax increases resulted in decreased cigarette consumption and its lower prevalence figures in some population groups. State incomes have increased in spite of regular cigarette tax raises. Therefore, there is on conflict of interest between the health and finance portfolios in supporting further tobacco tax increases. Hungary should use regular, above the inflation tobacco tax raises as means for improving population health. Tobacco control advocates should prevent tobacco companies' attempts aimed at deterring decision makers from supporting such tax policies.

Effects of variability in anatomical reconstruction techniques on models of synaptic integration by dendrites: a comparison of three Internet archives.

The first step in building a realistic computational neuron model is to produce a passive electrical skeleton on to which active conductances can be grafted. For this, anatomically accurate morphological reconstructions of the desired cell type are required. In this study compartmental models were used to compare from a functional perspective three on-line archives of rat hippocampal CA1 pyramidal cell morphologies. The topological organization of cells was found to be similar for all archives, but several morphometric differences were observed. The three-dimensional size of the cells, the diameter and tortuosity of dendrites, and the electrotonic length of the main apical dendrite and of the branches in stratum lacunosum moleculare were dissimilar. The experimentally measured kinetics of somatically recorded inhibitory postsynaptic currents evoked in the stratum lacunosum moleculare (data from the literature) could be reproduced only using the archives that contained cells with an electrotonically short main apical dendrite. In the amplitude attenuation of the simulated postsynaptic currents and the voltage escape from the command potential under voltage clamp conditions, a two- to three-fold difference was observed among archives. Upon activation of a single model synapse on distal branches, cells with low dendritic diameter showed a voltage escape larger than 15 mV. The diameter of the dendrites influenced greatly the results, emphasizing the importance of methods that allow an accurate measurement of this parameter. Our results indicate that there are functionally significant differences in the morphometric data available in different archives even if the cell type, brain region and species are the same.