Pharmacoresistant Partial Epilepsy Research Articles

Frameless robot-assisted stereoelectroencephalography in children: technical aspects and comparison with Talairach frame technique.

OBJECTIVE Robot-assisted stereoelectroencephalography (SEEG) is gaining popularity as a technique for localization of the epileptogenic zone (EZ) in children with pharmacoresistant epilepsy. Here, the authors describe their frameless robot-assisted SEEG technique and report preliminary outcomes and relative complications in children as compared to results with the Talairach frame-based SEEG technique. METHODS The authors retrospectively analyzed the results of 19 robot-assisted SEEG electrode implantations in 17 consecutive children (age < 17 years) with pharmacoresistant epilepsy, and compared these results to 19 preceding SEEG electrode implantations in 18 children who underwent the traditional Talairach frame-based SEEG electrode implantation. The primary end points were seizure-freedom rates, operating time, and complication rates. RESULTS Seventeen children (age < 17 years) underwent a total of 19 robot-assisted SEEG electrode implantations. In total, 265 electrodes were implanted. Twelve children went on to have EZ resection: 4 demonstrated Engel class I outcomes, whereas 2 had Engel class II outcomes, and 6 had Engel class III-IV outcomes. Of the 5 patients who did not have resection, 2 underwent thermocoagulation. One child reported transient paresthesia associated with 2 small subdural hematomas, and 3 other children had minor asymptomatic intracranial hemorrhages. There were no differences in complication rates, rates of resective epilepsy surgery, or seizure freedom rates between this cohort and the preceding 18 children who underwent Talairach frame-based SEEG. The frameless robot-assisted technique was associated with shorter operating time (p < 0.05). CONCLUSIONS Frameless robot-assisted SEEG is a safe and effective means of identifying the EZ in children with pharmacoresistant partial epilepsy. Robot-assisted SEEG is faster than the Talairach frame-based method, and has equivalent safety and efficacy. The former, furthermore, facilitates more electrode trajectory possibilities, which may improve the localization of epileptic networks.

Hippocampus and epilepsy: Findings from human tissues

Surgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often enhanced and GABAergic inhibition is preserved. Typically epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in the neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated, not in the hippocampus but in the subiculum, an output region, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity.

WHICH GENETIC PATHWAYS UNDERLIE PHARMACORESISTANT EPILEPSY?

Purpose A third of people with epilepsy are pharmacoresistant. As pharmacoresistance is a complex trait, a genome-wide pathway-level approach is likely to prove especially fruitful in its study. Methods We performed a genome-wide association study (GWAS) of pharmacoresistant partial epilepsy, with discovery and replication cohorts including, in total, 421 cases and 2624 normal population controls, and 5,519,310 genotyped and imputed SNPs. Results At the single variant level, there was no overlap in the top results of the two cohorts. However, at the gene-set and pathway level, there was clear replication of results between the two cohorts. For the combined ‘mega-analysis’, there were 71 distinct enriched pathways. We showed using network analysis that these enriched pathways form a highly interconnected network in which each pathway is directly connected, on average, to 8.4 other pathways. The enriched pathways, therefore, form a coherent whole, and changes in one pathway in this network will have a cascading effect on the rest of the network. Finally, we identified, using betweenness centrality network analysis, the most important central pathway in this network: signalling by NGF. Conclusion We have performed the first ever GWAS of pharmacoresistant partial epilepsy and identified the most central pathway underlying this phenotype.

Epileptic seizure predictors based on computational intelligence techniques: A comparative study with 278 patients

The ability of computational intelligence methods to predict epileptic seizures is evaluated in long-term EEG recordings of 278 patients suffering from pharmaco-resistant partial epilepsy, also known as refractory epilepsy. This extensive study in seizure prediction considers the 278 patients from the European Epilepsy Database, collected in three epilepsy centres: Hôpital Pitié-là-Salpêtrière, Paris, France; Universitätsklinikum Freiburg, Germany; Centro Hospitalar e Universitário de Coimbra, Portugal.For a considerable number of patients it was possible to find a patient specific predictor with an acceptable performance, as for example predictors that anticipate at least half of the seizures with a rate of false alarms of no more than 1 in 6h (0.15h−1). We observed that the epileptic focus localization, data sampling frequency, testing duration, number of seizures in testing, type of machine learning, and preictal time influence significantly the prediction performance.The results allow to face optimistically the feasibility of a patient specific prospective alarming system, based on machine learning techniques by considering the combination of several univariate (single-channel) electroencephalogram features. We envisage that this work will serve as benchmark data that will be of valuable importance for future studies based on the European Epilepsy Database.

Everolimus for the Treatment of Subependymal Giant Cell Astrocytoma Probably Causing Seizure Aggravation in a Child with Tuberous Sclerosis Complex: A Case Report

We are reporting on a 13.5-year-old girl with tuberous sclerosis complex (TSC) who was treated with everolimus because of giant cell astrocytoma and bilateral angiomyolipoma. She suffered from pharmacoresistant partial epilepsy with clusters of tonic and tonic-clonic seizures. Treatment with carbamazepine and sulthiame had led to a stable situation for more than 2.5 years. The dosage of everolimus had to be increased and refractory status epilepticus followed after 12 days. In the absence of any other possible cause, we believe that the status epilepticus was provoked by everolimus. So far, only a few cases of possible seizure aggravation by everolimus have been reported. The clinical relevance of possible negative effects in epileptic patients remains unclear. Similar observations should be documented and reported.

Chirurgie de l’épilepsie : quand y penser ? Quels sont les bons candidats ?

Epilepsy surgery concerns any patient with pharmacoresistant partial epilepsy, responsible for disability. Children and adult patients can be candidates for epilepsy surgery. A presurgical evaluation, adapted to each patient, must identify the most precisely the cortical area, where the seizures originate, using converging data: the clinical and electroencephalographic semiology of the seizures, the structural and sometimes functional brain imagings, and evaluate if the removal of the epileptogenic focus may induce a neurological or cognitive deficit, using neuropsychological tests and sometimes functional brain imagings. Such therapeutical strategy should be evoked as soon as possible in patients for whom the epilepsy becomes pharmacoresistant, and these patients should be oriented in specialized centres. The results of epilepsy surgery vary according to the lobar origin of the epileptogenic focus and to the existence of a visible lesion on brain MRI. A multidisciplinary evaluation of the benefits and risks should be presented to the patient. Results of the surgery are usually excellent when a focus is clearly identified and the neuropsychological tests did not predict a deficit.

Identification of reproducible ictal patterns based on quantified frequency analysis of intracranial EEG signals

The identification of the epileptogenic zone (EZ) is crucial for planning epilepsy surgery in patients with drug-resistant partial epilepsy. This task may require intracerebral encephalography (EEG) monitoring, the results of which are usually interpreted by visual presurgical inspection. A computer-assisted method for rapidly identifying reproducible ictal patterns based on the analysis of time, frequency, and spatial domains of stereo-EEG (SEEG) signals is described here. A new method for EZ detection was tested on SEEG recordings performed by intracerebral electrodes in eight patients with pharmacoresistant partial epilepsy. SEEG data were exported to a program developed in LabView. Prevalent frequencies during seizure events were evaluated by Fourier transform and further integral algorithms. Different frequencies and the relative powers were simultaneously evaluated in all recording leads. Patterns characterized by specific and prevalent frequencies were identified in a subset of recording sites during both seizure onset and seizure development. Three-dimensional (3D) maps of the measurements obtained from each recording channel were reconstructed on magnetic resonance coordinates to visualize the spatial distribution of the EZ. With this method, the reproducibility of ictal patterns in the same patient was characterized. The boundaries of the EZ identified with this algorithm correlated well with the EZ recognized with the traditional approach (n = 8). The spatial distribution of specific SEEG signals associated with different types of seizures was also analyzed in two patients. We describe a computer-assisted method to acquire information on EZ boundaries and to verify reproducibility of seizure patterns from intracerebral recordings performed in patients with pharmacoresistant partial epilepsies.

Partial Seizures

Event Abstract Back to Event Partial Seizures Jorge J. Asconapé1* 1 Loyola University Health System, Department of Neurology, United States Learning objectives: Describe the most frequent clinical manifestations of partial seizures related to the anatomic region of origin Understand the modern drug selection process for the medical treatment of partial seizures Identify the syndrome of Mesial Temporal Lobe Epilepsy secondary to hippocampal sclerosis, and the role of temporal lobectomy. Identify the role of surgery and neuromodulation in the management of patients with pharmaco-resistant partial epilepsy. The temporal lobes are the most frequent source of partial seizures in clinical practice. Approximately 70% of complex partial seizures originate in the temporal lobes. Temporal lobe epilepsy is divided in two types: mesial temporal lobe epilepsy (MTLE) and lateral or neocortical temporal lobe epilepsy (LTLE). Distinguishing these two types is difficult clinically, since the seizure semiology is very similar, but becomes an important issue when surgery is considered. The frontal lobes are the second most common location of seizure foci; they are also the second most common location where resective surgery is performed. From an anatomo-clinical perspective, seven distinct areas have been delineated in the frontal lobes epilepsies. Occipital lobe seizures are more rare, accounting for < 10% of all the epilepsies. The first line of therapy of partial seizure is almost always medical. Practically every antiepileptic drug currently available can be effective in controlling partial seizures, making the process of drug selection relatively easy. The choice of a drug is mostly based on its tolerability profile and its drug interaction potential. If seizures remain poorly controlled after adequate trials of 2 to 4 antiepileptic drugs, as monotherapy or in different combinations, patients should be evaluated for possible epilepsy surgery. Anterior temporal lobectomy or selective amygdalo-hippocampectomy is the therapy of choice as soon as refractoriness to medical therapy has been established. Neuromodulation has been utilized in the treatment of epilepsy for several decades, but has become more widely used in recent years. Vagus nerve stimulation remains an effective and safe palliative therapy for partial seizures. Deep brain stimulation of the anterior nucleus of the thalamus has recently been proven effective in a well-controlled study, and is currently being reviewed by the FDA. Responsive neurostimulation is another promising technique currently under clinical investigation. Conference: Paroxysmal Neurology Symposium, Chicago, United States, 7 Apr - 7 Apr, 2010. Presentation Type: Oral Presentation Topic: Abstracts Citation: Asconapé JJ (2010). Partial Seizures. Front. Neurol. Conference Abstract: Paroxysmal Neurology Symposium. doi: 10.3389/conf.fneur.2010.07.00007 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Apr 2010; Published Online: 07 Apr 2010. * Correspondence: Jorge J Asconapé, Loyola University Health System, Department of Neurology, Maywood, IL, United States, jasconape@lumc.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jorge J Asconapé Google Jorge J Asconapé Google Scholar Jorge J Asconapé PubMed Jorge J Asconapé Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Verbal cognition and attention deficits do not explain the verbal memory decline associated with pharmacoresistant partial epilepsy

The aim of this study was to explore whether change in verbal memory with time in patients with epilepsy is influenced by performance on tasks assessing verbal cognition or attention/processing speed. Thirty-six patients and twenty-five healthy controls were tested twice with median retest intervals of 4.8 and 3.1 years, respectively. Aspects of verbal memory, verbal cognition, and attention/processing speed were assessed. Decline in one verbal memory variable (Cronholm–Molander Memory Test Paired Associates—Delayed Recall) was the strongest correlate of epilepsy. The second strongest correlate was a decrease in one attention/processing speed variable (Digit Symbol). The relationship between decline in verbal memory and epilepsy was not influenced by the decline in attention/processing speed, and the results did not support the notion that limited mental reserves as reflected in impaired verbal cognition or attention/processing speed can explain the relationship between verbal memory and epilepsy.

Stiripentol

Stiripentol (STP) is a new antiepileptic compound made by Biocodex. It recently proved to increase the GABAergic transmission in vitro in an experimental model of immature rat. Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2, and CYP2C19 in vivo in epileptic patients. Whereas the studies in adult patients were disappointing, the trials conducted in pediatric populations demonstrated a specific efficacy of STP in severe myoclonic epilepsy in infancy, Dravet syndrome, when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in pediatric patients with pharmacoresistant partial epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account, with doses of the combined antiepileptic drugs adjusted to improve the tolerability of the therapeutic association.

Ictal Brain Hyperperfusion Contralateral to Seizure Onset: The SPECT Mirror Image

Ictal single-photon emission computed tomography (SPECT) may help localize the seizure-onset zone (SOZ) by detecting changes in regional cerebral blood flow induced by epileptic discharges. This imaging method also reveals hyperperfusions in areas of seizure propagation, including the hemisphere contralateral to the SOZ. We have studied the occurrence, the topography, and the clinical value of such contralateral ictal hyperperfusion areas (HPAs). We examined data from presurgical evaluations of 36 consecutive patients with pharmacoresistant partial epilepsy of various localizations. Ictal and interictal SPECT examinations were made with 99mTc-ECD, and the scans were processed for coregistration, normalization, subtraction, and merging with MRI images. Contralateral HPAs were observed in 72% of the patients: 50% of mesiotemporal epilepsy cases with hippocampal sclerosis, 85.7% of the other mesiotemporal epilepsies, 85.7% of neocortical lateral temporal epilepsies, and 87.5% of extratemporal epilepsies. Contralateral HPAs were usually symmetrical to the SOZ, forming a mirror image, observed in 57.1% of the patients. They could be slightly asymmetrical in mesiotemporal epilepsies, perhaps because of the particular anatomic pathways linking temporal lobes. In neocortical epilepsies, they were located in the cortex homotopic to the SOZ. We show that the symmetrical nature of the mirror image usually does not disturb SPECT interpretation. It can confirm the location of the SOZ (11 patients) and even occasionally improve the precision of its definition (nine patients) by restraining several potential SOZ-related HPAs to a single one or by permitting a restricted localization of the SOZ in a large HPA.

Stiripentol

Stiripentol (STP) is a new antiepileptic compound produced by Biocodex. It is not structurally related to any of the other currently marketed antiepileptic products as it belongs to the group of aromatic allylic alcohols. It has recently been proved to increase GABAergic transmission in experimental models. It has been studied and used in France and Canada for > 10 years, but its clinical development was delayed due to the inhibitory effect of STP on hepatic cytochrome P450 (CYP). Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2 and CYP2C19 in vivo in epileptic patients. Although the studies in adult patients were disappointing, the trials conducted in paediatric populations demonstrated a specific efficacy of STP in a severe form of early childhood epilepsy, Dravet syndrome (severe myoclonic epilepsy in infancy), when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in paediatric patients with pharmacoresistant partial epilepsy. Nevertheless, two controlled adjunctive-therapy trials were recently completed in paediatric populations with epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account by adjusting the doses of the combined antiepileptic drugs in order to improve the tolerability of the therapeutic association.

Non-parametric Evaluation of Memory Changes at Group and Individual Level Following Temporal Lobe Resection for Pharmaco-resistant Partial Epilepsy

ABSTRACT Group versus individual verbal and visuospatial memory outcome following epilepsy surgery was evaluated by a non-parametric method in 25 left and 29 right temporal lobectomy patients. Twenty-five controls were assessed twice. Analyses of change at an individual level evaluated by this statistical approach based on paired-ranks were compared to results with a method based on distances (Reliable Change). The left temporal lobectomy group deteriorated in the two verbal memory variables (p < 0.01 and 0.05). High levels of individual changes unexplained by group patterns were disclosed in the three memory variables analyzed in the patients. Significant individual change, although less pronounced, also occurred in the controls. Group versus individual outcome was adequately distinguished by the non-parametric method. To properly analyze memory change after epilepsy surgery, evaluation at group and individual level ought to combined.

Verbal memory decline and adverse effects on cognition in adult patients with pharmacoresistant partial epilepsy: a longitudinal controlled study of 36 patients

The aim of this study was to delineate possible longitudinal cognitive changes in adult patients with a long history of pharmacoresistant partial epilepsy. Thirty-six patients and thirty healthy controls were investigated at baseline. A reassessment was conducted, with median test intervals of 4.8 years for the patients and 3.1 years for controls. A standardized battery was used for assessment of general cognitive level and memory. At baseline, patients performed at a significantly lower level on general cognition, immediate recall of pairs of associated words, and retention of learned words and visuospatial stimuli, compared with controls. Analyses of change over time in the patients disclosed significant verbal memory decline in retention of pairs of associated words. Group comparisons of change over time revealed adverse effects in the performance aspect of general cognition on the patients. Also, group comparisons indicated impaired performance across time for the patients in retention of pairs of associated words and retention of visuospatial stimuli. The adverse effect on memory and general cognition in this patient group over the period was clear-cut when compared with the longitudinal changes in an adequate control group.

Adding topiramate to valproate therapy may cause reversible hepatic failure

The authors report a 51‐year‐old women with pharmacoresistant partial epilepsy who tolerated well valproate monotherapy and in combination with several other antiepileptic drugs, but developed symptoms and signs of reversible hepatic failure under a combination of valproate and topiramate. Symptoms resolved after discontinuation of VPA. This case provides further anecdotal evidence that topiramate may increase the risk of liver failure when given in combination with other potentially hepatotoxic antiepileptic drugs.

Expression of the multidrug transporter P-glycoprotein in brain capillary endothelial cells and brain parenchyma of amygdala-kindled rats.

Based on data from brain biopsy samples of patients with pharmacoresistant partial epilepsy, overexpression of the multidrug transporter P-glycoprotein (PGP) in brain capillary endothelium has recently been proposed as a potential mechanism of resistance to antiepileptic drugs (AEDs). We examined whether PGP is overexpressed in brain regions of amygdala-kindled rats, a widely used model of temporal lobe epilepsy (TLE), which is often resistant to AEDs. Rats were kindled by stimulation of the basolateral amygdala (BLA); electrode-implanted but nonkindled rats and naive (not implanted) rats served as controls. PGP was determined by immunohistochemistry either 1 or 2 weeks after the last kindled seizure, by using a monoclonal anti-PGP antibody. Six brain regions were examined ipsi- and contralateral to the BLA electrode: the BLA, the hippocampal formation, the piriform cortex, the substantia nigra, the frontal and parietal cortex, and the cerebellum. In both kindled rats and controls, PGP staining was observed mainly in microvessel endothelial cells and, to a much lesser extent, in parenchymal cells. The distribution of PGP expression across brain regions was not homogeneous, but significant differences were found in both the endothelial and parenchymal expression of this protein. In kindled rats, ipsilateral PGP expression tended to be higher than contralateral expression in several brain regions, which was statistically significant in the piriform cortex and parietal cortex. However, compared with controls, no significant overexpression of PGP in capillary endothelial cells or brain parenchyma of kindled rats was seen in any ipsilateral brain region, including the BLA. For comparison with kindled rats, kainate-treated rats were used as positive controls. As reported previously, kainate-induced seizures significantly increased PGP expression in the hippocampus and other limbic brain regions. Amygdala-kindling does not induce any lasting overexpression of PGP in several brain regions previously involved in the kindling process. In view of the many pathophysiologic and pharmacologic similarities between the kindling model and TLE, these data may indicate that PGP overexpression in pharmacoresistant patients with TLE is a result of uncontrolled seizures but not of the processes underlying epilepsy. It remains to be determined whether transient PGP overexpression is present in kindled rats shortly after a seizure, and whether pharmacoresistant subgroups of kindled rats exhibit an increased expression of PGP. Furthermore, other multidrug transporters, such as multidrug resistance-associated protein, might be involved in the resistance of kindled rats to AEDs.

Influence on ictal seizure semiology of rapid withdrawal of carbamazepine and valproate in monotherapy.

To quantify changes in ictal seizure semiology during rapid withdrawal of carbamazepine (CBZ) and valproate (VPA) from a monoregimen in presurgical evaluation. Therapeutic intensive seizure analysis (TISA) with video-EEG monitoring was used in 33 patients with pharmacoresistant partial epilepsy undergoing complete withdrawal of CBZ (20 patients) or VPA (13 patients) from a monoregimen. Monitoring phases included a 3-day baseline phase, a 3-day rapid antiepileptic drug (AED) withdrawal phase, and another 3-day AED-free phase with AEDs in subtherapeutic levels. Seizure variables as complete processes and their various elements (ictal signs) were analyzed, including duration (seconds), intensity (on a scale of 0 to 3), frequency (number per 3 days), and total duration of seizures and ictal signs in 3 days (seconds). The localization of seizure patterns on ictal EEG recording (EEG seizure onset) and the first appearing clinical ictal phenomena (initial ictal signs) were recorded. A total of 188 seizures in the CBZ group and 57 seizures in the VPA group were investigated. Compared with the baseline phase, the CBZ group showed increases in duration, frequency of seizures, various ictal signs, and secondarily generalized tonic and clonic signs during the following two phases. Significantly increased values of the VPA group were observed in seizure duration and frequency of hypermotoric phenomena during the AED-free phase. More patients in the CBZ group had secondarily generalized clonic signs during the AED-free phase. EEG seizure onset and initial ictal signs showed no obvious changes between study phases. Withdrawal of CBZ is followed more quickly by an increase of seizure frequency and severity than is the case for VPA withdrawal. Both CBZ and VPA withdrawal influences seizure propagation rather than the seizure-onset characteristics, which speaks in favor of its use in presurgical evaluation.

In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats.

The multidrug transporter P-glycoprotein (P-gp) is expressed at high levels in a variety of tissues such as the endothelial cells of the blood-brain barrier (BBB) capillaries, where it is thought to be involved in the exclusion of various drugs from the capillary endothelial cells, blocking their entry into brain. It was previously shown that pharmacoresistant partial epilepsy is associated with an increased expression of P-gp in brain capillary endothelium and astrocytes, leading to the hypothesis that increased P-gp expression may be involved in medically intractable epilepsy. However, it is not known whether the distribution of antiepileptic drugs (AEDs) into the brain is limited by P-gp. We used in vivo microdialysis in freely moving rats to study whether the concentration of the major AED phenytoin (PHT) in the extra-cellular fluid (ECF) of the cerebral cortex can be enhanced by inhibition of P-gp. Three different P-gp inhibitors, sodium cyanide, verapamil, and PSC 833, were used. These drugs were given via the microdialysis probe in the right frontal cortex, while a probe in the left cortex served as vehicle control side. Perfusion with the inhibitor started 15-60 min before systemic (i.p.) administration of PHT, 50 mg/kg. PHT rapidly entered the brain ECF compartment, but ECF plasma ratios at time of maximal ECF levels were only approximately 0.04. All P-gp inhibitors significantly increased the ECF concentrations of PHT after local administration, indicating that P-gp in the BBB normally limits the distribution of PHT into the brain parenchyma. Cremorphor EL, the vehicle used to administer PSC, also was able to increase ECF PHT, which is explained by the previously reported inhibitory effect of cremophor on P-gp. Provided that multidrug transporters such as P-gp also are involved in the BBB outward transport of other AEDs, increased expression of multidrug transporters, leading to inadequate accumulation of AEDs in the brain, would be a likely explanation for pharmacoresistant epilepsy.

Excitotoxicity. Experimental correlates to human epilepsy.

Neurochemical observations on cortical biopsies form 48 patients under surgical treatment for pharmacoresistant partial epilepsy showed a 70-80% increase in glutamate concentration when expressed in relation to neuron specific enolase. Intraperitoneal administration of one of its receptor agonists, kainic acid (KA), to the rat led to increased epileptogenic activity of the limbic type in a dose-dependent fashion. The KA injection also led to a neuronal cell death and a gliosis, closely correlated to the extent of seizure activity. In biopsies from human epileptogenic cortex, the concentration of neuron specific enolase correlated inversely to that of glial fibrillary acidic protein, a marker for astrocytic glial cells. Stimulation of the KA receptor decreased the extent of phosphorylation of the largest subunit of neurofilaments (NF-H) that have consequences for structural stability and axonal transport. Phosphorylated NF-H decreased also in human epileptic cortex, indicating either an overactivity of excitatory neurotransmitters or a loss of axonal compartments.