			Home About us Contact

Pharmacoresistant Epilepsy (pharmacoresistant + epilepsy)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Therapy Discovery for Pharmacoresistant Epilepsy and for Disease-modifying Therapeutics: Summary of the NIH/NINDS/AES Models II Workshop

EPILEPSIA, Issue 12 2003
James P. Stables
First page of article [source]

Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

EPILEPSIA, Issue 7 2003
Nicolette Gouder
Summary: Purpose: Because of the high incidence of pharmacoresistance in the treatment of epilepsy (20,30%), alternative treatment strategies are needed. Recently a proof-of-principle for a new therapeutic approach was established by the intraventricular delivery of adenosine released from implants of engineered cells. Adenosine-releasing implants were found to be effective in seizure suppression in a rat model of temporal lobe epilepsy. In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy. Methods: A mouse model for drug-resistant mesial temporal lobe epilepsy was used, in which recurrent spontaneous seizure activity was induced by a single intrahippocampal injection of kainic acid (KA; 200 ng in 50 nl). Results: After injection of the selective adenosine A1 -receptor agonist, 2-chloro- N6 -cyclopentyladenosine (CCPA; either 1.5 or 3 mg/kg, i.p.), epileptic discharges determined in EEG recordings were completely suppressed for a period of ,3.5 h after the injections. Seizure suppression was maintained when 8-sulfophenyltheophylline (8-SPT), a non,brain-permeable adenosine-receptor antagonist, was coinjected systemically with CCPA. In contrast, systemic injection of carbamazepine or vehicle alone did not alter the seizure pattern. Conclusions: This study demonstrates that activation of central adenosine A1 receptors leads to the suppression of seizure activity in a mouse model of drug-resistant epilepsy. We conclude that the local delivery of adenosine into the brain is likely to be effective in the control of intractable seizures. [source]

Unilateral Intracarotid Amobarbital Procedure for Language Lateralization

EPILEPSIA, Issue 11 2005
Jörg Wellmer
Summary:,Purpose: The determination of language dominance as part of the presurgical workup of patients with pharmacoresistant epilepsies has experienced fundamental changes. With the introduction of noninvasive functional magnetic resonance imaging (fMRI), the number of patients receiving intracarotid amobarbital procedures (IAPs) for assessment of language dominance has decreased considerably. However, recent studies show that because of methodologic limitations of fMRI, IAP remains an important tool for language lateralization. The current study examines whether unilateral instead of bilateral IAP is an adequate way to apply IAP with reduced invasiveness. Methods: We retrospectively examine the predictive value of unilateral IAP for the results of bilateral IAP based on a sample of 75 patients with various types of language dominance. Target parameters are the prediction of the language-dominant hemisphere and the identification of patients with atypical language dominance. For language assessment based on unilateral IAP, we introduce the measure hemispheric language capacity (HLC). Results: Unilateral IAP performed on the side of intended surgery quantifies language capacity contralateral to the intended surgery. It detects atypical (bilateral or right) language dominance in the majority of patients. Experience with a separate series of 107 patients requiring presurgical language lateralization shows that in >80%, bilateral IAPs are redundant. Conclusions: Unilateral IAP is principally sufficient for language lateralization in the presurgical evaluation of patients with pharmacoresistant epilepsies. Necessity of bilateral IAP is restricted to few indications (e.g., callosotomy). In times of noninvasive language lateralization, we propose unilateral IAP as the method of choice for the verification of doubtful (bilateral) fMRI activation patterns. [source]

High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy

EPILEPSIA, Issue 1 2010
Wolfgang Löscher
Summary Purpose:, Progress in the management of patients with medically intractable epilepsy is impeded because we do not fully understand why pharmacoresistance happens and how it can be predicted. The presence of multiple seizures prior to medical treatment has been suggested as a potential predictor of poor outcome. In the present study, we used an animal model of temporal lobe epilepsy to investigate whether pharmacoresistant rats differ in seizure frequency from pharmacoresponsive animals. Methods:, Epilepsy with spontaneous recurrent seizures (SRS) was induced by status epilepticus. Frequency of SRS was determined by video/EEG (electroencephalography) monitoring in a total of 33 epileptic rats before onset of treatment with phenobarbital (PB). Results:, Thirteen (39%) rats did not respond to treatment with PB. Before treatment with PB, average seizure frequency in PB nonresponders was significantly higher than seizure frequency in responders, which, however, was due to six nonresponders that exhibited > 3 seizures per day. Such high seizure frequency was not observed in responders, demonstrating that high seizure frequency predicts pharmacoresistance in this model, but does not occur in all nonresponders. Discussion:, The data from this study are in line with clinical experience that the frequency of seizures in the early phase of epilepsy is a dominant risk factor that predicts refractoriness. However, resistance to treatment also occurred in rats that did not differ in seizure frequency from responders, indicating that disease severity alone is not sufficient to explain antiepileptic drug (AED) resistance. These data provide further evidence that epilepsy models are useful in the search for predictors and mechanisms of pharmacoresistance. [source]

Predictors of pharmacoresistant epilepsy: Pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy

EPILEPSIA, Issue 10 2008
Alexandra M. Gastens
Summary Purpose:, Patients with intractable temporal lobe epilepsy (TLE) exhibit an increased risk of psychiatric comorbidity, including depression, anxiety, psychosis, and learning disorders. Furthermore, a history of psychiatric comorbidity has been suggested as a predictor of lack of response to therapy with antiepileptic drugs (AEDs) in patients with epilepsy. However, clinical studies on predictors of pharmacoresistant epilepsy are affected by several confounding variables, which may complicate conclusions. In the present study, we evaluated whether behavioral alterations in epileptic rats are different in AED nonresponders versus responders. Methods:, For this purpose, we used an animal model of TLE in which AED responders and nonresponders can be selected by prolonged treatment of epileptic rats with phenobarbital (PB). Behavioral and cognitive abnormalities were compared between responders and nonresponders as well as between epileptic rats and nonepileptic controls in a battery of tests. Results:, Fifteen epileptic rats with spontaneous recurrent seizures (SRS) either responding (11 rats) or not responding (4 rats) to PB were used for this study. The nonresponders differed markedly in behavioral and cognitive abnormalities from responders and nonepileptic controls in tests of anxiety (open field, elevated-plus maze test), behavioral hyperexcitability (approach-response, touch-response, pick-up tests), and learning and memory (Morris water maze). Discussion:, Our hypothesis that AED-resistant rats will show more severe behavioral and cognitive changes than AED-responsive rats was confirmed by the present experiments. The data substantiate that rodent models of TLE are useful to delineate predictors of pharmacoresistant epilepsy. [source]

The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of Epilepsy

EPILEPSIA, Issue 7 2007
Wolfgang Löscher
Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source]

Seizures Lead to Elevation of Intracranial Pressure in Children Undergoing Invasive EEG Monitoring

EPILEPSIA, Issue 6 2007
Aash K Shah
Summary:,Purpose: To study the effects of intracranial subdural grid electrode placement and seizures on intracranial pressure (ICP) in children undergoing invasive EEG monitoring. Methods: Sixteen children with pharmacoresistant epilepsy who underwent two-stage epilepsy surgery with subdural grid placement were included in the study. The ICP was recorded at baseline and with each seizure prospectively. A variety of seizure parameters including type of seizure, length of seizure, extent of seizure spread, and number of subdural grid electrodes inserted were analyzed retrospectively and correlated with the change in ICP. Results: A total of 48 seizures in 16 children were studied. The mean baseline ICP correlated positively with age of the child. Generalized tonic,clonic seizures were associated with the highest rise in ICP. Similarly, ICP rise was associated with seizures involving more electrodes indicating a larger area of brain participating in the seizure. Conclusion: Seizures in general and generalized tonic,clonic seizures, in particular, increase ICP temporarily in patients who are undergoing invasive EEG monitoring with subdural grids. [source]

Vagus Nerve Stimulation Therapy Induces Changes in Heart Rate of Children during Sleep

EPILEPSIA, Issue 5 2007
Boubker Zaaimi
Summary:,Purpose: This study analyzed changes in the heart rates of children receiving vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy. Methods: Changes in the heart rates of ten children receiving VNS therapy for pharmacoresistant epilepsy were evaluated with polysomnographic recordings, including electrocardiogram (ECG), EEG, thoraco-abdominal distension, nasal airflow, and VNS artifacts. Measurements during stimulation were compared with those at baseline for each patient. Result: While the VNS therapy pulse generator was delivering stimulation, the heart rates of four children increased significantly (p < 0.01), decreased for one child, and increased at the end of the stimulation for one child. The heart rates of four children did not change. Changes in heart rate varied during VNS, within stimulation cycles for individual children and from one child to another. Changes in heart rate differed between rapid eye movement (REM) and non-REM (NREM) sleep states. Respiratory changes (increases in frequency and decreases in amplitude) were concomitant with the changes in heart rate. Conclusion: In this case series of children with pharmacoresistant epilepsy, cardiorespiratory variations occurred while the VNS therapy pulse generator was delivering stimulation. Understanding these variations may allow further optimization of VNS parameters. [source]

Heat Shock Protein-27 Is Upregulated in the Temporal Cortex of Patients with Epilepsy

EPILEPSIA, Issue 12 2004
Hans-J Bidmon
Summary:,Purpose: Heat shock protein-27 (HSP-27) belongs to the group of small heat shock proteins that become induced in response to various pathologic conditions. HSP-27 has been shown to protect cells and subcellular structures, particularly mitochondria, and serves as a carrier for estradiol. It is a reliable marker for tissues affected by oxidative stress. Oxidative stress and related cellular defence mechanisms are currently thought to play a major role during experimentally induced epileptic neuropathology. We addressed the question whether HSP-27 becomes induced in the neocortex resected from patients with pharmacoresistant epilepsy. Methods: Human epileptic temporal neocortex was obtained during neurosurgery, and control tissue was obtained at autopsy from subjects without known neurologic diseases. The tissues were either frozen for Western blot analysis or fixed in Zamboni's fixative for the topographic detection of HSP-27 at the cellular level by means of immunohistochemistry. Results: HSP-27 was highly expressed in all epilepsy specimens and in the cortex of a patient who died in the final stage of multiple sclerosis (positive control), whereas only low amounts of HSP-27 were detectable in control brains. In epilepsy patients, HSP-27 was present in astrocytes and in the walls of blood vessels. The intracortical distribution patterns varied strongly among the epilepsy specimens. Conclusions: These results demonstrate that HSP-27 becomes induced in response to epileptic pathology. Although the functional aspects of HSP-27 induction during human epilepsy have yet to be elucidated, it can be concluded that HSP-27 is a marker for cortical regions in which a stress response has been caused by seizures. [source]

Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

Effectiveness of the ketogenic diet in a broad range of seizure types and EEG features for severe childhood epilepsies

ACTA NEUROLOGICA SCANDINAVICA, Issue 1 2010
S. Beniczky
Background,,, Ketogenic diet (KD) is an effective treatment for pharmacoresistant epilepsy: more than half of the patients show a greater than 50% reduction in seizures. Objective,,, To identify clinical or electroencephalogram (EEG) variables predicting the response to KD. Methods,,, Clinical and EEG data were retrospectively analysed from 50 consecutive patients treated by KD for severe, pharmacoresistant epilepsy. Most of the patients (70%) had retarded mental and motor development. Results,,, Three months after the start of the KD two-thirds (33) of the patients were responders (had a more than 50% reduction in seizure frequency). The presence of epileptiform EEG discharges in the temporal region correlated with an unfavourable response (P = 0.03). The presence of bilateral synchronous epileptiform discharges, and the presence of complex partial seizures approached significance but all other variables did not. Conclusions,,, Our results further support that KD is efficient in a wide variety of epileptic patients with a broad range of EEG features. However, patients with epileptiform discharges in the temporal region are less likely to achieve therapeutic response. [source]

Don't be afraid to treat depression in patients with epilepsy!

ACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009
D. Kondziella
Major depression and related depressive disorders are highly prevalent in the general population and even more so in patients with epilepsy. Yet depression in these patients remains underdiagnosed and undertreated. This is particularly worrisome as depression has greater negative impact on quality of life than seizure frequency. Additionally, depression is associated with poorer seizure control, and the risk of suicide in patients with epilepsy is greatly increased. Reluctance to treat depression results from the traditional belief that antidepressants should be restricted in epilepsy because of a supposed decrease in seizure threshold. However, there is growing evidence that many antidepressants rather have anticonvulsant effects. Experimental studies show that in critical brain regions such as the frontal lobes and the limbic system enforced serotonergic circuits increase seizure threshold. Clinical data suggest that modern antidepressants may reduce seizure frequency in patients with pharmacoresistant epilepsy. Here we review the concept that selective reuptake inhibitors of serotonin (SSRIs) have a positive effect on the mood disorder as well as on epilepsy. When adhering to the usual precautions, treatment with SSRIs in patients with epilepsy and depression is safe and should not be withheld. [source]

Parenchymal lesions in pharmacoresistant temporal lobe epilepsy: dual and multiple pathology

ACTA NEUROLOGICA SCANDINAVICA, Issue 3 2005
S. H. Eriksson
Objectives,,, Dual pathology is reported in 5,30% of temporal lobe resections performed in pharmacoresistant epilepsy. Dual pathology may be of importance for surgical planning and also for the understanding of the pathogenesis of epilepsy. We describe the frequency of dual or multiple pathology, i.e. more than one histopathological diagnosis, in adults with temporal lobe resections. Material and Methods,,, Surgical specimens from 33 consecutive patients with resections including mesial as well as neocortical temporal structures were reviewed. All histopathological findings were recorded. Post-mortem specimens from 11 control subjects were also reviewed. Results,,, Dual or multiple pathology was found in almost half of the epilepsy patients (48%). Hippocampal sclerosis was found in 25 patients (76%), malformations of cortical development in 15 (46%), of which 12 (36%) were microdysgenesis, and low-grade tumours in seven (21%). Apart from mild gliosis, there were no histopathological changes in the control specimens. Conclusion,,, Dual or multiple pathology was a common finding in this group of adults with temporal lobe resections. In order to increase our understanding of how aetiological factors may combine in the development of seizures, we consider it relevant and important to report all histopathological findings in epilepsy surgery series. [source]