Sexual differentiation of cortical spreading depression propagation after acute and kindled audiogenic seizures in the Wistar audiogenic rat (WAR)

Brain excitability diseases like epilepsy constitute one factor that influences brain electrophysiological features. Cortical spreading depression (CSD) is a phenomenon that can be altered by changes in brain excitability. CSD propagation was presently characterized in adult mate and female rats from a normal Wistar strain and from a genetically audiogenic seizure-prone strain, the Wistar audiogenic rat (WAR), both previously submitted (RAS(+)), or not (RAS(-)), to repetitive acoustic stimulation, to provoke audiogenic kindling in the WAR-strain. A gender-specific change in CSD-propagation was found. Compared to seizure-resistant animals, in the RAS- condition, mate and female WARs, respectively, presented CSD-propagation impairment and facilitation, characterized, respectively, by lower and higher propagation velocities (P<0.05). In contraposition, in the RAS(+) condition, mate and female WARs displayed, respectively, higher and tower CSD-propagation rates, as compared to the corresponding controls. In some Wistar and WAR females, we determined estrous cycle status on the day of the CSD-recording as being either estrous or diestrous; no cycle-phase-related differences in CSD-propagation velocities were detected. In contrast to other epilepsy models, such as Status Epilepticus induced by pilocarpine, despite the CSD-velocity reduction, in no case was CSD propagation blocked in WARs. The results suggest a gender-related, estrous cycle-phase-independent modification in the CSD-susceptibility of WAR rats, both in the RAS(+) and RAS(-) situation. (C) 2008 Elsevier B.V. All rights reserved.

Puzzling challenges in contemporary neuroscience: Insights from complexity and emergence in epileptogenic circuits

The brain is a complex system that, in the normal condition, has emergent properties like those associated with activity-dependent plasticity in learning and memory, and in pathological situations, manifests abnormal long-term phenomena like the epilepsies. Data from our laboratory and from the literature were classified qualitatively as sources of complexity and emergent properties from behavior to electrophysiological, cellular, molecular, and computational levels. We used such models as brainstem-dependent acute audiogenic seizures and forebrain-dependent kindled audiogenic seizures. Additionally we used chemical OF electrical experimental models of temporal lobe epilepsy that induce status epilepticus with behavioral, anatomical, and molecular sequelae such as spontaneous recurrent seizures and long-term plastic changes. Current Computational neuroscience tools will help the interpretation. storage, and sharing of the exponential growth of information derived from those studies. These strategies are considered solutions to deal with the complexity of brain pathologies such as the epilepsies. (C) 2008 Elsevier Inc. All rights reserved.

Chelatable zinc modulates excitability and seizure duration in the amygdala rapid kindling model

Zinc is present in high concentration in many structures of the limbic circuitry, however the role of zinc as a neuromodulator in such synapses is stilt uncertain. In this work, we verified the effects of zinc chelation in an animal model of epileptogenesis induced by amygdala rapid kindling. The basolateral. amygdala was electrically stimulated ten times per day for 2 days. A single stimulus was applied on the third day. Stimulated animals received injections of PBS or the zinc chelator diethildythiocarbamate acid (DEDTC) before each stimulus series. Animals were monitored with video-EEG and were perfused 3 h after the last stimulus for subsequent neo-Timm and Ftuoro-Jade B analysis. Zinc chelation decreased the duration of both behavioral seizures and electrical after-discharges, and also decreased the EEG spikes frequency, without changing the progression of behavioral seizure severity. These results indicate that the zinc ion may have a facilitatory role during kindling progression. (c) 2008 Elsevier B.V. All rights reserved.

Rasmussen encephalitis: long-term outcome after surgery

Rasmussen encephalitis (RE) is characterized by intractable epilepsy, progressive hemiparesis, and unilateral hemispheric atrophy. The progression of the symptoms to significant neurological impairment usually occurs within months to a few years. RE causes are unknown, although evidence of an autoimmune process has been extensively described in the literature. Antiepileptic drugs are usually not effective to control seizures or cerebral atrophy; despite data supporting a beneficial effect of early immunosuppressive and immunomodulatory interventions, for intractable seizures in RE patients with advanced disease, epilepsy surgery in the form of hemispheric disconnection has been considered the treatment of choice. This work describes the clinical and electrographic analyses, as well as the post-operative evolution of patients with RE. This work includes all the patients with RE evaluated from January 1995 to January 2008 by the RibeirA o pound Preto Epilepsy Surgery Program (CIREP), taking variables such as gender; age at epilepsy onset; seizure semiology; seizure frequency; interictal and ictal electroencephalographic (EEG) findings; age at surgery, when done; duration of epilepsy; surgery complications; follow-up duration; anatomo-pathological findings; post-surgery seizure; language and cognitive outcome; and anti-epileptic drug treatment after surgery into account. Twenty-five patients were evaluated; thirteen were female. Mean age of epilepsy onset was 4.4 +/- 2.0 years. There were no differences between patients with slow and fast evolution with respect to age of epilepsy onset (p = 0.79), age at surgery (p = 0.24), duration of epilepsy (0.06), and follow-up (p = 0.40). There were no correlations between the presence of bilateral EEG abnormalities or the absence of spikes and post-operative seizure outcome (p = 0.06). Immunomodulatory therapy was tried in 12 patients (48%). Twenty-three patients underwent surgery. The mean follow-up was 63.3 months. Eleven patients had total seizure control. Twelve individuals persisted with seizures consisting of mild facial jerks (six patients), occasional hemigeneralized tonic-clonic seizures (three patients), and frequent tonic-clonic seizures (three patients). Mental and language impairment was observed in 15 and 12 patients, after surgery, respectively. Eight patients presented post-operative cognitive decline, while only two patients had cognitive improvement. Comparing pre- and post-operative language deficits, 66.7% of the 12 patients with language disturbance did not improve after surgery. This retrospective study reported the clinical and electrographic analysis, as well as the evolution of 23 patients with RE. Patients were divided into two groups: fast evolution and slow evolution to hemiparesis and epilepsia partialis continua. These groups may represent different RE substrates. Fourteen patients achieved satisfactory seizure control, three patients had partial response to surgery, and five patients had maintenance of the pre-operative condition. All patients with left-side involvement presented with some language disturbance, which did not improve after surgery in 66.6% of patients. Cognitive evaluation showed that the majority of the patients did not have any significant improvement, and 38.1% had cognitive deterioration after surgery.

Mild cognitive deficits associated to neocortical microgyria in mice with genetic deletion of cellular prion protein

The cellular prion protein (PrP(c)) has been implicated with the modulation of neuronal apoptosis, adhesion, neurite outgrowth and maintenance which are processes involved in the neocortical development. Malformations of cortical development (MCD) are frequently associated with neurological conditions including mental retardation, autism, and epilepsy. Here we investigated the behavioral performance of female adult PrP(c)-null mice (Prnp(%)) and their wild-type controls (Prnp(+/+)) presenting unilateral polymicrogyria, a MCD experimentally induced by neonatal freeze-lesion in the right hemisphere. injured mice from both genotypes presented similar locomotor activity but Prnp(%) mice showed a tendency to increase anxiety-related responses when compared to Prnp(+/+) animals. Additionally, injured Prnp(%) mice have a poorer performance in the social recognition task than sham-operated and Prnp(%) injured ones. Moreover the step-down inhibitory avoidance task was not affected by the procedure or the genotype of the animals. These data suggest that the genetic deletion of PrP(c) confers increased susceptibility to short-term social memory deficits induced by neonatal freezing model of polymicrogyria in mice. (C) 2008 Published by Elsevier B.V.

Is dystonic posturing during temporal lobe epileptic seizures the expression of an endogenous anticonvulsant system?

In temporal lobe epilepsy (TLE) seizures, tonic or clonic motor behaviors (TCB) are commonly associated with automatisms, versions, and vocalizations, and frequently occur during secondary generalization. Dystonias are a common finding and appear to be associated with automatisms and head deviation, but have never been directly linked to generalized tonic or clonic behaviors. The objective of the present study was to assess whether dystonias and TCB are coupled in the same seizure or are associated in an antagonistic and exclusive pattern. Ninety-one seizures in 55 patients with TLE due to mesial temporal sclerosis were analyzed. Only patients with postsurgical seizure outcome of Engel class I or II were included. Presence or absence of dystonia and secondary generalization was recorded. Occurrence of dystonia and occurrence of bilateral tonic or clonic behaviors were negatively correlated. Dystonia and TCB may be implicated in exclusive, non-coincidental, or even antagonistic effects or phenomena in TLE seizures. A neural network related to the expression of one behavioral response (e.g., basal ganglia activation and dystonia) might theoretically ""displace"" brain activation or disrupt the synchronism of another network implicated in pathological circuit reverberation and seizure expression. The involvement of basal ganglia in the blockade of convulsive seizures has long been observed in animal models. The question is: Do dystonia and underlying basal ganglia activation represent an attempt of the brain to block imminent secondary generalization? (C) 2007 Elsevier Inc. All rights reserved.

Central effects of Tityus serrulatus and Tityus bahiensis scorpion venoms after intraperitoneal injection in rats

A great number of studies on scorpion venoms associate their effects to the autonomic nervous system, and few data are available about their action on the central nervous system (CNS). The aim of this work was to evaluate some central effects after intraperitoneal injection of Tityus serrulatus or T. bahiensis scorpion venoms. The hippocampal concentration of some neurotransmitters and their metabolites were determined. Electroencephalographic and behavioral observations were performed, and all brains were removed for histopathological analysis of hippocampal areas. Both venoms induced electrographic and behavioral alterations despite T bahiensis venom affects less the electrographic activity than T. serrulatus venom. Neurochemical analysis demonstrated no alteration in the extracellular levels of almost all the neurotransmitters evaluated, at least in the hippocampus, and no neuronal loss in this area was observed. Meanwhile, extracellular concentration of HVA increased up to 10 times in approximately 1/3 of the animals of both groups. Scorpion venoms seem to exert a small but important central effect. More studies in this field are necessary because they may be useful in developing new strategies to reduce the damage caused by scorpion stings. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Congenital Bilateral Perisylvian Syndrome: Familial Occurrence, Clinical and Psycholinguistic Aspects Correlated with MRI

Objective: Congenital bilateral perisylvian syndrome (CBPS) is frequently caused by polymicrogyria (PMG). The aim of this study was to correlate the clinical and psycholinguistic aspects with neuroradiological data of patients with CBPS. Methods: Thirty-one patients were studied. We performed a clinical investigation of the patients and their families, including MRI scanning, neuropsychological tests and language evaluation. Results: The statistical analysis showed that: a) prenatal events are associated with the non-familial type of PMG; b) diffuse PMG is associated with pseudobulbar signs, as opposed to BPPP; c) motor deficit is associated with diffuse PMG; d) epilepsy is equally present in patients with both familial or non-familial PMG, but is more frequently seen in patients with diffuse PMG; e) dyslexia and SLI can be a feature of both the diffuse or BPPP, and either familial or sporadic cases of PMG. Conclusions: The severity of clinical manifestations in CBPS is correlated with the extent of cortical involvement. Most patients with CBPS have a history of speech delay or language difficulties and no epilepsy. Dyslexia can be found in patients with PMG.

A new candidate locus for bilateral perisylvian polymicrogyria mapped on chromosome Xq27

Polymicrogyria (PMG) is characterized by an excessive number of small and prominent brain gyri, separated by shallow sulci. Bilateral perisylvian polymicrogyria (BPP) is the most common form of PMG. Clinical signs include pseudobulbar paresis, mental retardation, and epilepsy. Familial forms of BPP have been described and a candidate locus was previously mapped to chromosome Xq28, distal do marker DXS8103. The objective of this study was to perform linkage analysis in one family segregating BPP. A total of 15 individuals, including 8 affected patients with BPP were evaluated. Family members were examined by a neurologist and subjected to magnetic resonance imaging scans. Individuals were genotyped for 18 microsatellite markers, flanking a 42.3 cM interval on ch Xq27-q28. Two-point and multipoint linkage analysis was performed using the LINKAGE package and haplotype reconstruction was performed by GENEHUNTER software. Our results showed a wide spectrum of clinical manifestations in affected individuals with BPP, ranging from normal to mild neurological abnormalities. Two-point linkage analysis yield a Zmax=2.06 at theta=0.00 for markers DXS1205 and DXS1227. Multipoint lod-scores indicate a candidate interval of 13 cM between markers DSXS1205 and DXS8043, on ch Xq27.2-Xq27.3. These results point to a new locus for BPP in a more centromeric location than previously reported. (C) 2008 Wiley-Liss, Inc.

Cloning and function of the rat colonic epithelial K+ channel K(V)LQT1

K(V)LQT1 (K(V)LQ1) is a voltage-gated K+ channel essential for repolarization of the heart action potential that is defective in cardiac arrhythmia. The channel is inhibited by the chromanol 293B, a compound that blocks cAMP-dependent electrolyte secretion in rat and human colon, therefore suggesting expression of a similar type of K+ channel in the colonic epithelium. We now report cloning and expression of K(V)LQT1 from rat colon. Overlapping clones identified by cDNA-library screening were combined to a full length cDNA that shares high sequence homology to K(V)LQT1 cloned from other species. RT-PCR analysis of rat colonic musoca demonstrated expression of K(V)LQT1 in crypt cells and surface epithelium. Expression of rK(V)LQT1 in Xenopus oocytes induced a typical delayed activated K+ current. that was further activated by increase of intracellular cAMP but not Ca2+ and that was blocked by the chromanol 293B. The same compound blocked a basolateral cAMP-activated K+ conductance in the colonic mucosal epithelium and inhibited whole cell K+ currents in patch-clamp experiments on isolated colonic crypts. We conclude that K(V)QT1 is forming an important component of the basolateral cAMP-activated K+ conductance in the colonic epithelium and plays a crucial role in diseases like secretory diarrhea and cystic fibrosis.

Population pharmacokinetics of lamotrigine

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided spare data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (TM) (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.

The calculation of accident risks in fitness for work assessments: diseases that can cause sudden incapacity

Risk equations have been developed to assist in determining fitness for work of people with diseases that may cause rapid loss of control. The four equations calculate the frequency of fatal injury to the person with the disease, the frequency of fatal injury to colleagues in the workplace, and the cost of fatal injury and property damage to the employer, it is suggested that the additional risk of fatal injury to the person with the disease should not exceed the fatal injury rate in high-risk industries such as forestry, fishing and mining. it is also suggested that the additional risk of fatal injury to each colleague should be no more than one-tenth of the fatal injury rate due to motor vehicle accidents in the community. Two hypothetical case examples are given, demonstrating the use of the equations. The equations highlight the need to examine the risks associated with individuals, their specific jobs and their workplaces. They also highlight significant uncertainties in the determination of fitness, which perhaps have been underestimated in the past. Wherever possible, redundant defences should be utilized to prevent accidents in the event of sudden incapacity.

The epileptology of Theodore Herpin (1799-1865)

The Frenchman, Theodore Herpin (1799-1865), in Des Acces Incomplets d'Epilepsie, published posthumously in 1867, provided a very detailed account of a wide range of the possible manifestations of nonconvulsive epileptic seizures. However, he did not note the presence of absence seizures in any of his 300 patients who had experienced, at least in some of their attacks, what he considered were incomplete manifestations of epilepsy, the word epilepsy being taken to refer to full generalized tonic-clonic seizures. In the one patient, Herpin recognized that all epileptic seizures, whether complete or incomplete, began in the same way, and deduced that they must originate in the same place in that patient's brain. He did not develop the latter idea further. His observations, and his interpretation of them, seem to have preceded John Hughlings Jackson's independent development of similar concepts, but Jackson's more extensive intellectual exploration of the implications of his observations made him a more important figure than Herpin in the history of epileptology.

Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary

We have performed immunocytochemistry on rat brains using a highly specific antiserum directed against the originally described form of the glutamate transporter GLT-1 (referred to hereafter as GLT-1alpha), and another against a C-terminal splice variant of this protein, GLT-1B. Both forms of GLT-1 were abundant in rat brain, especially in regions such as the hippocampus and cerebral cortex, and macroscopic examination of sections suggested that both forms were generally regionally coexistent. However, disparities were evident; GLT-1alpha was present in the intermediate lobe of the pituitary gland, whereas GLT-1B was absent. Similar marked disparities were also noted in the external capsule, where GLT1A labeling was abundant but GLT-1B was only occasionally encountered. Conversely, GLT-1B was more extensively distributed, relative to GLT-1alpha, in areas such as the deep cerebellar nuclei. In most regions, such as the olfactory bulbs, both splice variants were present but differences were evident in their distribution. In cerebral cortex, patches were evident where GLT-1B was absent, whereas no such patches were evident for GLT-1alpha. At high resolution, other discrepancies were evident; double-labeling of areas such as hippocampus indicated that the. two splice variants may either be differentially expressed by closely apposed glial elements or that the two splice variants may be differentially targeted to distinct membrane domains of individual glial cells. (C) 2002 Wiley-Liss, Inc.