levetiracetam and Epilepsy--Temporal-Lobe

Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is a syndrome that is often refractory to drug treatment. The effects on specific syndromes are not currently available from the pre-marketing clinical development of new AEDs; this does not allow the prediction of whether new drugs will be more effective in the treatment of some patients.. We have reviewed all the existing literature relevant to the understanding of a potential effectiveness in MTLE-HS patients for the latest AEDs, namely brivaracetam, eslicarbazepine, lacosamide, perampanel and retigabine also including the most relevant clinical data and a brief description of their pharmacological profile. Records were identified using predefined search criteria using electronic databases (e.g., PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published up to the 15 June 2015 were included.. All the drugs considered have the potential to be effective in the treatment of MTLE-HS; in fact, they possess proven efficacy in animal models; currently considered valuable tools for predicting drug efficacy in TLE. Furthermore, for some of these (e.g., lacosamide and eslicarbazepine) data are already available from post-marketing studies while brivaracetam acting on SV2A like levetiracetam might have the same potential effectiveness with the possibility to be more efficacious considering its ability to inhibit voltage gated sodium channels; finally, perampanel and retigabine are very effective drugs in animal models of TLE.

Topics: Acetamides; Anticonvulsants; Carbamates; Clinical Trials as Topic; Dibenzazepines; Epilepsy, Temporal Lobe; Hippocampus; Humans; Lacosamide; Levetiracetam; Nitriles; Phenylenediamines; Piracetam; Pyridones; Sclerosis; Syndrome

We evaluated a 39-year-old pregnant woman with right temporal lobe epilepsy. During the second trimester, seizure deterioration was responsive to an increased daily dose of levetiracetam (LEV). However, immediately after delivery, new non-habitual seizures emerged along with a sharply increased LEV concentration. The frequency of habitual seizures also slightly increased. The non-habitual seizures completely disappeared, and the frequency of the habitual seizures improved to the baseline level after the LEV dosage was reduced. Thus, a paradoxical effect of an increased LEV blood concentration was assumed to be a potential cause of these events. Peripartum pharmacokinetic fluctuations in LEV levels should be monitored carefully.

Topics: Adult; Anticonvulsants; Epilepsy, Temporal Lobe; Female; Humans; Levetiracetam; Piracetam; Postpartum Period; Pregnancy; Seizures; Treatment Outcome

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies. Pharmacological treatment with anti-seizure drugs (ASDs) remains the mainstay in epilepsy management. Levetiracetam (LEV) is a second-generation ASD with a novel SV2A protein target and is indicated for treating focal epilepsies. While there is considerable literature in acute models, its effect in chronic epilepsy is less clear. Particularly, its effects on neuronal excitability, synaptic plasticity, adult hippocampal neurogenesis, and histological changes in chronic epilepsy have not been evaluated thus far, which formed the basis of the present study. Six weeks post-lithium-pilocarpine-induced status epilepticus (SE), epileptic rats were injected with levetiracetam (54 mg/kg b.w. i.p.) once daily for two weeks. Following LEV treatment, Schaffer collateral - CA1 (CA3-CA1) synaptic plasticity and structural changes in hippocampal subregions CA3 and CA1 were evaluated. The number of doublecortin (DCX

Topics: Animals; Dentate Gyrus; Epilepsy; Epilepsy, Temporal Lobe; Hippocampus; Levetiracetam; Mossy Fibers, Hippocampal; Neuronal Plasticity; Rats

To determine the effects of Levetiracetam (LEV) therapy using EEG microstates analysis in a population of newly diagnosed Temporal Lobe Epilepsy (TLE) patients. We hypothesized that the impact of LEV therapy on the electrical activity of the brain can be globally explored using EEG microstates. Twenty-seven patients with TLE were examined. We performed resting-state microstate EEG analysis and compared microstate metrics between the EEG performed at baseline (EEG

Topics: Brain; Brain Mapping; Electroencephalography; Epilepsy, Temporal Lobe; Humans; Levetiracetam

To determine the predictive power for seizure-freedom of 19-channels EEG, measured both before and after three months the initiation of the use of Levetiracetam (LEV), in a cohort of people after a new diagnosis of temporal-lobe epilepsy (TLE) using a machine-learning approach.. Twenty-three individuals with TLE were examined. We dichotomized clinical outcome into seizure-free (SF) and non-seizure-free (NSF) after two years of LEV. EEG effective power in different frequency bands was compared using baseline EEG (T0) and the EEG after three months of LEV therapy (T1) between SF and NSF patients. Partial Least Square (PLS) analysis was used to test and validate the prediction of the model for clinical outcome.. A total of 152 features were extracted from the EEG recordings. When considering only the features calculated at T1, a predictive power for seizure-freedom (AUC = 0.750) was obtained. When employing both T0 and T1 features, an AUC = 0.800 was obtained.. This study provides a proof-of-concept pipeline for predicting the clinical response to anti-seizure medications in people with epilepsy.. Future studies may benefit from the pipeline proposed in this study in order to develop a model that can match each patient to the most effective anti-seizure medication.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Electroencephalography; Epilepsy, Temporal Lobe; Female; Humans; Levetiracetam; Machine Learning; Male; Middle Aged; Prognosis; Retrospective Studies; Treatment Outcome; Young Adult

To determine the quantitative EEG responses in a population of drug-naïve patients with Temporal Lobe Epilepsy (TLE) after Levetiracetam (LEV) initiation as first antiepileptic drug (AED). We hypothesized that the outcome of AED treatment can be predicted from EEG data in patients with TLE.. Twenty-three patients with TLE and twenty-five healthy controls were examined. Clinical outcome was dichotomized into seizure-free (SF) and non-seizure-free (NSF) after two years of LEV. EEG parameters were compared between healthy controls and patients with TLE at baseline (EEG. AED therapy induces an increase in EEG power for Alpha (p = 0.06) and a decrease in Theta (p < 0.05). Connectivity values were lower in SF compared to NSF patients (p < 0.001). Quantitative EEG predicted outcome after LEV treatment with an estimated accuracy varying from 65.2% to 91.3% (area under the curve [AUC] = 0.56-0.93) for EEG. AED therapy induces EEG modifications in TLE patients, and such modifications are predictive of clinical outcome.. Quantitative EEG may help understanding the effect of AEDs in the central nervous system and offer new prognostic biomarkers for patients with epilepsy.

Topics: Adult; Aged; Alpha Rhythm; Analysis of Variance; Anticonvulsants; Area Under Curve; Beta Rhythm; Brain; Case-Control Studies; Connectome; Delta Rhythm; Electroencephalography; Electroencephalography Phase Synchronization; Epilepsy, Temporal Lobe; Female; Gamma Rhythm; Humans; Levetiracetam; Male; Middle Aged; Prognosis; Reproducibility of Results; Retrospective Studies; ROC Curve; Theta Rhythm; Young Adult

Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.

Topics: Animals; Anticonvulsants; Brain; Drug Therapy, Combination; Epilepsy, Temporal Lobe; Levetiracetam; Male; Mice; Proof of Concept Study; Protein Interaction Mapping; Topiramate; Transcriptome

Levetiracetam (LEV) is an antiepileptic drug with a novel pharmacological mechanism. Advances in functional magnetic resonance imaging (fMRI) enable researchers to explore the cognitive effects of antiepileptic drugs on the living brain. This study aimed to explore how the functional connectivity patterns of the cognitive networks changed in association with LEV treatment.. Patients with temporal lobe epilepsy (TLE), including both users and nonusers of LEV, were included in this study along with healthy controls. Core cognitive networks were extracted using an independent component analysis approach. Functional connectivity patterns within and between networks were investigated. The relationships between functional connectivity patterns and clinical characteristics were also examined.. The patterns of intranetwork connectivity in the default mode network (DMN), left executive control network (lECN), and dorsal attention network (DAN) differed among the three groups. The internetwork interactions did not show intergroup differences once corrected for multiple comparisons. No correlation between functional connectivity and clinical characteristics was found in patients with TLE.. Changes in intranetwork connectivity are a key effect of LEV administration.. Alterations in intranetwork connectivity patterns may underlie the cognitive effects of LEV administration; this finding improves our understanding of the neural mechanisms of LEV therapy.

Topics: Brain; Brain Mapping; Epilepsy, Temporal Lobe; Humans; Levetiracetam; Magnetic Resonance Imaging; Nerve Net

The intracellular pH (pHi) of mammalian central neurons is tightly regulated and small pHi-fluctuations can fine-tune inter-/intracellular signaling, excitability, and synaptic plasticity. The research-gap about the pHi-regulation of human brain neurons is addressed here by testing possible influences of the anticonvulsant levetiracetam (LEV). BCECF-AM-loaded neocortical pyramidal cells were fluorometrically investigated in slice-preparations of tissue resected from the middle temporal gyrus of five adults with intractable temporal-lobe epilepsy. Recovery-slope from intracellular acidification following an ammonium prepulse (APP) was used to measure the pHi-regulation. Among twenty pyramidal cells exposed to 50 μM LEV, the resting pHi (7.09 ± 0.14) was lowered in eight (40%) neurons, on average by 0.02 ± 0.011 pH-units. In three (15%) and nine (45%) neurons, a minimal alkaline shift (0.017 ± 0.004 pH-units) and no pHi-shift occurred, respectively. The LEV-induced pHi-shifts were positively correlated with the resting pHi (r = 0.6, p = 0.006, n = 20). In five neurons, which all had responded on LEV with an acidification before, the recovery from APP-acidification was significantly delayed during LEV (p < 0.001). This inhibitory LEV-effect on pHi-regulation i) was similar to that of 200 μM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (n = 2) and ii) did not occur under nominal bicarbonate-free conditions (n = 2). Thus, LEV lowered the pHi of human neocortical pyramidal cells most likely by a weakening of the transmembrane HCO3(-)-mediated acid-extrusion. This might contribute to LEV's anticonvulsive potency. Neurons with more acidic resting pHi-values showed a minimal alkalization upon LEV providing a mechanism for paradoxical proconvulsive LEV-effects rarely observed in epilepsy patients. The significance of these subtle pHi-shifts for cortical excitability and plasticity is discussed.

Topics: Adult; Anticonvulsants; Bicarbonates; Epilepsy, Temporal Lobe; Female; Humans; Hydrogen-Ion Concentration; Levetiracetam; Male; Pyramidal Cells; Temporal Lobe; Young Adult

Temporal lobe epilepsy (TLE), the common form of epilepsy in adults, often displays complex partial seizures and cognitive deficits. The underlying mechanisms of such deficits are not yet well understood. Many contributing factors, such as initial epileptogenic lesion, seizure type, age of onset, and treatment side effects have been proposed. Levetiracetam (LEV) is a novel anti-epileptic drug (AED) used to treat partial seizures and idiopathic generalized epilepsy. It has been suggested that LEV exerts antiepileptic properties by modulation of synaptic release of neurotransmitters. However, its neuroprotective effects on learning and memory are not yet well demonstrated. Here we showed the impairment of spatial memory in the pilocarpine-induced experimental TLE rats, which can be improved by LEV. Furthermore, we found chronic LEV treatment partially reversed the SE-induced synaptic dysfunction in hippocampal LTP induction in vivo. In addition, LEV treatment can alleviate the SE-induced abnormal GluR1 phosphorylation at Ser(831) site, which may contribute to the rescue of synaptic transmission. These results indicate the neuroprotective role for LEV while it exhibits an antiseizure effect on experimental epileptic models.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Levetiracetam; Long-Term Potentiation; Male; Maze Learning; Muscarinic Agonists; Neuroprotective Agents; Pilocarpine; Piracetam; Rats; Rats, Sprague-Dawley; Spatial Memory

Temporal lobe epilepsy is considered to be the most frequent of all epileptic syndromes. Recently, several retrospective studies suggest that limbic encephalitis (LE) may be a cause for adult onset unexplained seizure disorders in patients. This report describes two cases of adult onset epilepsy with voltage-gated potassium channel antibodies (VGKC-abs)-associated LE that responded well to levetiracetam (LEV). As demonstrated by these two cases and reviewing previous reports, we propose that the therapeutic regimen for VGKC-abs associated seizures still needs to be determined and LEV may be effective in treating this kind of disorders.

Topics: Antibodies; Anticonvulsants; Brain; Epilepsy, Temporal Lobe; Female; Humans; Levetiracetam; Middle Aged; Piracetam; Positron-Emission Tomography; Potassium Channels, Voltage-Gated; Tomography, X-Ray Computed

Despite more than 20 clinically approved antiepileptic drugs (AEDs), there remains a substantial unmet clinical need for patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we previously evaluated whether epileptic rats respond differently to AEDs and discovered AED responsive and resistant animals in the same models. In the present study, we used the same approach for the widely used intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. In a first step, we examined anti-seizure effects of 6 AEDs on spontaneous recurrent focal electrographic seizures and secondarily generalized convulsive seizures in epileptic mice, showing that the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs seemed to suppress generalized convulsive seizures. Next we investigated the inter-individual variation in the anti-seizure effects of these AEDs and, in case of focal seizures, found responders and nonresponders to all AEDs except carbamazepine. Most nonresponders were resistant to more than one AED. Our data further validate the intrahippocampal kainate mouse model as a model of difficult-to-treat focal seizures that can be used to investigate the determinants of AED efficacy.

Topics: Animals; Anticonvulsants; Carbamazepine; Diazepam; Disease Models, Animal; Drug Resistance; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Female; Hippocampus; Kainic Acid; Levetiracetam; Mice; Phenobarbital; Phenytoin; Piracetam; Seizures; Valproic Acid

Mesial temporal lobe epilepsy (MTLE) is the most prevalent type of partial epileptic disorders. In this study, we have analyzed the impact of levetiracetam (LEV) in the pilocarpine model of MTLE.. Sprague-Dawley rats (n=19) were injected with pilocarpine (380 mg/kg, i.p.) to induce a status epilepticus. Twelve animals were used as controls and seven were treated with LEV. They were implanted with bipolar electrodes in the CA3 subfield of the hippocampus, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored continuously from day 4 to day 14 after SE.. Only 29% of LEV-treated animals had seizures compared to all controls following a latent period that was similar in duration. Seizure rates were lower in LEV-treated animals. In LEV-treated animals without seizures, lower interictal spike rates were found in all regions compared to controls. Analysis of interictal high-frequency oscillations (HFO s) revealed that LEV-treated animals without seizures had lower rates of interictal spikes with ripples (80-200 Hz) in CA3, EC and subiculum (p<0.01), whereas rates of interictal spikes with fast ripples (250-500 Hz) were significantly lower in CA3 and subiculum, compared to controls.. Our findings indicate that the anti-ictogenic properties of LEV are mirrored by decreases of interictal spike rate in temporal lobe regions, and are accompanied by subregion-specific decreases of HFO occurrence in CA3 and subiculum. Overall, this evidence suggest that LEV may inhibit neural network activity in regions that are known to play important roles in MTLE.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Hippocampus; Levetiracetam; Male; Periodicity; Pilocarpine; Piracetam; Rats, Sprague-Dawley; Seizures; Treatment Outcome; Video Recording

Suicide is a major cause of premature mortality in patients with epilepsy. We aimed to identify the clinical correlates of suicide in these patients.. We conducted a matched, case-control study based on a clinical case registry of epilepsy patients (n = 35,638) treated between January 1994 and December 2011 at an academic tertiary medical center in Seoul, Korea. Each epilepsy patient in the suicide group (n = 74) was matched with three epilepsy patients in the nonsuicide group (n = 222) by age, gender, and approximate time at first treatment. The clinical characteristics of the patients in both groups were then compared.. In a univariate analysis, seizure frequency during the year before suicide, use of antiepileptic drug polytherapy, lack of aura before seizure, diagnosis of temporal lobe epilepsy, use of levetiracetam, psychiatric comorbidity, and use of antidepressants were all significantly higher in the suicide group than in the nonsuicide group. Multivariate analysis revealed that a high seizure frequency (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.04-10.2), a lack of aura before seizure (OR 4.0, 95% CI 1.7-9.3), temporal lobe epilepsy (OR 3.7, 95% CI 1.6-8.6), and use of levetiracetam (OR 7.6, 95% CI 1.1-53.7) and antidepressants (OR 7.2, 95% CI 1.5-34.1) were all associated with a higher probability of suicide.. Patients with temporal lobe epilepsy who experience seizures weekly or more frequently, experience a lack of aura, use levetiracetam, or take antidepressants are all at a higher risk of suicide and should be monitored closely.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Antidepressive Agents; Case-Control Studies; Epilepsy; Epilepsy, Temporal Lobe; Female; Humans; Levetiracetam; Male; Middle Aged; Piracetam; Republic of Korea; Risk Factors; Suicide; Young Adult

We used functional MRI (fMRI) and a left-lateralizing verbal and a right-lateralizing visual-spatial working memory (WM) paradigm to investigate the effects of levetiracetam (LEV) on cognitive network activations in patients with drug-resistant temporal lobe epilepsy (TLE).. In a retrospective study, we compared task-related fMRI activations and deactivations in 53 patients with left and 54 patients with right TLE treated with (59) or without (48) LEV. In patients on LEV, activation patterns were correlated with the daily LEV dose.. We isolated task- and syndrome-specific effects. Patients on LEV showed normalization of functional network deactivations in the right temporal lobe in right TLE during the right-lateralizing visual-spatial task and in the left temporal lobe in left TLE during the verbal task. In a post hoc analysis, a significant dose-dependent effect was demonstrated in right TLE during the visual-spatial WM task: the lower the LEV dose, the greater the abnormal right hippocampal activation. At a less stringent threshold (p < 0.05, uncorrected for multiple comparisons), a similar dose effect was observed in left TLE during the verbal task: both hippocampi were more abnormally activated in patients with lower doses, but more prominently on the left.. Our findings suggest that LEV is associated with restoration of normal activation patterns. Longitudinal studies are necessary to establish whether the neural patterns translate to drug response.. This study provides Class III evidence that in patients with drug-resistant TLE, levetiracetam has a dose-dependent facilitation of deactivation of mesial temporal structures.

Topics: Adult; Anticonvulsants; Brain; Chi-Square Distribution; Epilepsy, Temporal Lobe; Female; Humans; Image Processing, Computer-Assisted; Levetiracetam; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Oxygen; Piracetam; Young Adult

Topics: Anticonvulsants; Brain; Epilepsy, Temporal Lobe; Female; Humans; Levetiracetam; Male; Piracetam

Ictal asystole (IA) is uncommonly diagnosed and has been implicated as a potential cause of sudden unexpected death in epilepsy. Sudden unexpected death in epilepsy is an increasingly recognizable condition and is more likely to occur in patients with medically intractable epilepsy and those suffering from convulsive epilepsy. We report 2 cases of recent onset of prolonged syncope and unrevealing cardiac work up. The inpatient video-EEG monitoring recorded left temporal ictal discharges followed by IA. Although the role of cardiac pacing is controversial in these patients, both patients had favorable outcome following cardiac pacemaker insertion. This report demonstrates the variability in IA pathophysiology and clinical manifestations. It also advocates that cardiac pacing might have a role in the management of IA.

Topics: Aged; Anticonvulsants; Bradycardia; Electroencephalography; Epilepsy, Temporal Lobe; Female; Heart Arrest; Humans; Inpatients; Levetiracetam; Middle Aged; Monitoring, Physiologic; Pacemaker, Artificial; Phenytoin; Piracetam; Syncope; Video Recording

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site.

Topics: Absorbable Implants; Animals; Anticonvulsants; Disease Models, Animal; Drug Delivery Systems; Electroencephalography; Epilepsy, Temporal Lobe; Lactic Acid; Levetiracetam; Male; Neurotoxins; Piracetam; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Tetanus Toxin; Time Factors

Topics: Adult; Anticonvulsants; Deja Vu; Epilepsy, Temporal Lobe; Epilepsy, Tonic-Clonic; Female; Humans; Levetiracetam; Piracetam; Seizures, Febrile; Treatment Outcome

Tolerance to drug treatment is a serious problem in the treatment of epilepsy. We previously showed that tolerance to levetiracetam (LEV) developed within 4 days after the start of the treatment in a rat model for spontaneous seizures after electrically induced status epilepticus. In the current study we tested whether the development of tolerance to LEV could be prevented by alternating between LEV and valproate (VPA) treatment.. Before starting the alternating therapy with LEV and VPA (3 day LEV-3 day VPA, two cycles), we assessed the efficacy of VPA monotherapy by administering VPA to chronic epileptic rats via osmotic minipumps during 7 days. The anticonvulsive effects were determined by continuous video-EEG (electroencephalography) monitoring, and the concentration of VPA and LEV was measured in plasma using gas chromatography.. VPA significantly suppressed spontaneous seizures in chronic epileptic rats for 5 days. Hereafter, seizure frequency increased to pretreatment values despite adequate VPA blood levels. Seizure duration was reduced for 6 days during treatment. Seizure severity was reduced throughout the 7-day treatment period. Alternating treatment of LEV and VPA did not prevent development of tolerance; however, seizures were suppressed significantly longer compared to VPA and LEV monotherapy.. Because alternating treatment with LEV and VPA led to a prolonged effective seizure control in the animal model, it would be worthwhile to explore the possibilities of using an alternating treatment protocol in pharmacoresistant patients in whom an effective treatment is hampered by tolerance to antiepileptic drugs.

Topics: Animals; Anticonvulsants; Dentate Gyrus; Disease Models, Animal; Drug Administration Schedule; Drug Resistance; Drug Tolerance; Electric Stimulation; Electroencephalography; Epilepsy; Epilepsy, Temporal Lobe; Humans; Levetiracetam; Male; Piracetam; Rats; Rats, Sprague-Dawley; Status Epilepticus; Treatment Outcome; Valproic Acid

The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined.. Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-alpha, RGS2, Egr2/krox-20 and beta-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration.. The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Epilepsy, Temporal Lobe; Gene Expression; Genes, Immediate-Early; Hippocampus; Levetiracetam; Male; Neuronal Plasticity; Piracetam; Rats; Rats, Wistar; RNA, Messenger; Seizures; Synapses; Synaptic Transmission; Time Factors

Topics: Adult; Anticonvulsants; Catatonia; Epilepsy, Temporal Lobe; Humans; Levetiracetam; Lorazepam; Male; Neurosurgical Procedures; Piracetam; Temporal Lobe; Treatment Outcome

We previously showed that gene expression of synaptic vesicle protein 2A (SV2A), the binding site for the antiepileptic drug levetiracetam, is reduced during epileptogenesis in the rat. Since absence of SV2A has been associated with increased epileptogenicity, changes in expression of SV2A could have consequences for the progression of epilepsy. Therefore we investigated hippocampal SV2A protein expression of temporal lobe epilepsy (TLE) patients and in rats during epileptogenesis and in the chronic epileptic phase.. SV2A immunocytochemistry and Western blot analysis were performed on the hippocampus of autopsy controls, patients that died from status epilepticus (SE), and pharmacoresistant TLE patients. In addition, in epileptic rats, SV2A expression was determined after SE during the acute, latent, and chronic epileptic phase.. In control tissue, presynaptic SV2A was expressed in all hippocampal subfields, with strongest expression in mossy fiber terminals. SV2A positive puncta were distributed in a patchy pattern over the somata and dendrites of neurons. SV2A decreased throughout the hippocampus of TLE patients with hippocampal sclerosis (HS), compared to autopsy control, SE, and non-HS tissue. In most rats, SV2A was already decreased in the latent period especially in the inner molecular layer and stratum lucidum. Similarly as in humans, SV2A was also decreased throughout the hippocampus of chronic epileptic rats, specifically in rats with a progressive form of epilepsy.. These data support previous findings that reduced expression of SV2A could contribute to the increased epileptogenicity. Whether this affects the effectiveness of levetiracetam needs to be further investigated.

Topics: Adolescent; Adult; Animals; Anticonvulsants; Blotting, Western; Child; Disease Models, Animal; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Infant; Levetiracetam; Male; Membrane Glycoproteins; Microscopy, Confocal; Middle Aged; Nerve Tissue Proteins; Piracetam; Rats; Sclerosis; Status Epilepticus; Young Adult

Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition.

Topics: Adult; Anticonvulsants; Cohort Studies; Epilepsy; Epilepsy, Temporal Lobe; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Hippocampus; Humans; Ireland; Levetiracetam; Male; Membrane Glycoproteins; Nerve Tissue Proteins; Piracetam; Polymorphism, Genetic; Synaptic Vesicles; United Kingdom

Pharmacoresistance is a major problem in the treatment of epilepsy. We showed previously that pharmacoresistance, at least partially, is due to an up-regulation of the multidrug transporter (MDT) P-glycoprotein (P-gp): inhibition of P-gp improves seizure control in phenytoin-treated epileptic rats (poststatus epilepticus rat model for temporal lobe epilepsy). Since it has been suggested that levetiracetam (LEV) is no substrate for MDTs, we hypothesized that LEV would more adequately control seizures in this rat model.. Chronic epileptic rats were treated repeatedly with LEV (2-week interval; different dosages) via continuous infusion using osmotic minipumps, 5-6 months after electrically induced status epilepticus. The anticonvulsive effects were determined by video-EEG monitoring and the concentration of LEV was measured in plasma and brain homogenates using gas chromatography.. LEV adequately entered the epileptic brain and dose-dependently suppressed spontaneous seizures in chronic epileptic rats for 3-4 days. Hereafter, seizure frequency increased, while LEV plasma levels did not change. Seizure behavior was less severe throughout the whole treatment. LEV did not affect seizure duration. After a withdrawal period of 2 weeks all rats initially responded again to LEV.. The initial seizure control by LEV supports the observation that LEV is not impeded by MDTs. However, the failure to control seizures for a longer period of time indicates the development of tolerance to this drug. This poses another problem in the treatment of this kind of epilepsy. Whether tolerance may be prevented by intermittent administration of LEV should be further investigated.

Topics: Animals; Anticonvulsants; Chromatography, Gas; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Infusion Pumps; Levetiracetam; Male; Phenytoin; Piracetam; Rats; Rats, Sprague-Dawley; Temporal Lobe; Videotape Recording

GABAA receptors from the brain of patients afflicted with mesial temporal lobe epilepsy (MTLE) become less efficient (run-down) when repetitively activated by GABA. Experiments were designed to investigate whether the antiepileptic drug, levetiracetam (LEV), which is used as an adjunctive treatment for medically intractable MTLE, counteracts the GABAA receptor run-down.. GABAA receptors were microtransplanted from the brains of patients afflicted with MTLE into Xenopus oocytes. The GABA-current run-down, caused by repetitive applications of GABA, was investigated using the standard two-microelectrode voltage-clamp technique. Additionally, the GABA-current run-down was investigated directly on pyramidal neurons in human MTLE cortical slices.. It was found that, in oocytes injected with membranes isolated from the MTLE neocortex, the GABA-current run-down was inhibited by a 3-h pretreatment with 0.5-100 microM LEV. Moreover, the GABAA receptors of pyramidal neurons in human neocortical slices exhibited a current run-down that was significantly reduced by 1 microM LEV. Interestingly, the run-down in oocytes injected with membranes isolated from the MTLE hippocampal subiculum was not affected by LEV.. We report that the antiepileptic LEV strengthens GABA inhibition of neuronal circuits by blocking the receptor run-down in the cortex whilst leaving the run-down of GABAA receptors in the hippocampal subiculum unaltered. These findings point to the GABAA receptor run-down as an important event in epileptogenesis and as a possible target for testing and screening antiepileptic drugs.

Topics: Adult; Aged; Animals; Anticonvulsants; Brain Tissue Transplantation; Cell Membrane; Child; Epilepsy, Temporal Lobe; Female; gamma-Aminobutyric Acid; Hippocampus; Humans; Levetiracetam; Male; Microelectrodes; Neocortex; Neural Inhibition; Patch-Clamp Techniques; Piracetam; Pyramidal Cells; Receptors, GABA-A; Synaptic Transmission; Xenopus

Hippocampal sclerosis (HS) has been described as a relevant factor for the development of topiramate-related depression and cognitive deficits. The aim of our study was to clarify whether patients with temporal lobe epilepsy (TLE) and HS were also at risk during therapy with levetiracetam (LEV).. Data of 156 patients was analysed: 78 with TLE and HS and 78 with TLE and normal MRI matched for age, starting dose and titration schedule of LEV. Patients were selected from a population of consecutive patients started on LEV between 2000 and 2002.. No differences were observed in prevalence of cognitive adverse events and depression between the two groups.. LEV treatment is not associated with cognitive adverse events and depression in patients with hippocampal sclerosis.

Topics: Adult; Anticonvulsants; Cognition Disorders; Depression; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Levetiracetam; Male; Piracetam; Sclerosis

The effect of testosterone on brain excitability is unclear. The excitatory aspect of testosterone's action in the brain may be due to its conversion to estrogen via aromatase. We report herein a 61-year-old man with temporal lobe epilepsy and sexual dysfunction due to low testosterone levels. Use of an aromatase inhibitor, letrozole, normalized his testosterone level and improved his sexual functioning. Letrozole, in addition to standard antiseizure medication, was also associated with improved seizure control. This was sustained and, further, was associated with seizure exacerbation after withdrawing letrozole, and subsequent seizure improvement after restarting it. During the course of treatment, his serum testosterone level increased, sex hormone-binding globulin decreased (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels increased, while serum estradiol levels remained undetectable. Letrozole may, therefore, have produced a central alteration in the testosterone/estrogen ratio, thereby impairing estrogen-mediated feedback control of the pituitary, resulting in the observed increase in circulating LH and FSH levels. This experience suggests that aromatase inhibitors should be further investigated as a beneficial treatment modality for male patients with epilepsy.

Topics: Anticonvulsants; Aromatase Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electroencephalography; Epilepsy, Temporal Lobe; Erectile Dysfunction; Estradiol; Follicle Stimulating Hormone; Humans; Letrozole; Levetiracetam; Libido; Luteinizing Hormone; Male; Middle Aged; Nitriles; Piracetam; Quality of Life; Sex Hormone-Binding Globulin; Testosterone; Triazoles

A 26 year old female with right mesial temporal sclerosis presented with events characterized by repetitive piloerection (goose bumps). These events were monitored using prolonged video-EEG. The events occurred at a rate of one per every 15 min, and were demonstrated to be simple partial seizures of right mesial temporal origin. The manifestations included piloerection, cold shivers and ictal tachycardia. These were effectively treated with lorazepam. Acute repetitive pilomotor seizures are rare. This is the first reported case with right mesial temporal sclerosis.

Topics: Acute Disease; Adult; Electroencephalography; Epilepsy, Temporal Lobe; Female; Humans; Levetiracetam; Piloerection; Piracetam

This study compared levetiracetam (Keppra) with reference antiepileptic drugs (AEDs) in the rat pilocarpine model of temporal lobe epilepsy. Electroencephalogram (EEG) recordings showed that i.p. administration of valproate (300 mg/kg), phenobarbital (5 mg/kg) and clonazepam (0.5 mg/kg) all significantly delayed the appearance of the first epileptic spike discharge in hippocampus as well as synchronous epileptiform activity in hippocampus and cortex. In contrast, i.p. administration of levetiracetam (17 mg/kg) only significantly delayed the appearance of the latter. This was corroborated by findings showing that i.p. administration of levetiracetam (17 mg/kg) significantly opposed pilocarpine-induced increases in the amplitude of the orthodromic population spike in the hippocampal CA3 area of urethane-anaesthetised rats, while valproate (200 mg/kg), phenobarbital (10 mg/kg) and clonazepam (1 mg/kg) had no effect. Pre-treatment i.p. with phenobarbital (10 mg/kg) and clonazepam (0.5 mg/kg) significantly reversed seizure-induced changes in aspartate and GABA concentrations while valproate (300 mg/kg) significantly reduced aspartate concentrations further. In contrast, levetiracetam (34 mg/kg) significantly counteracted all seizure-induced alterations in amino acid concentrations. Midazolam induced significant seizure protection after microinjection into substantia nigra pars reticulata (SNR, 50 nmol), nucleus accumbens (NA, 25 nmol) and caudate putamen (CP, 25 nmol), whereas phenytoin (50 nmol) only showed significant seizure protection after injection into the latter area. Levetiracetam differed by significant seizure protection after injection into SNR (1,000 nmol) and NA (3,000 nmol). These results suggest that levetiracetam is distinct from other AEDs by its ability to selectively suppress synchronisation of neuronal spike and burst firing in hippocampus.

Topics: Animals; Anticonvulsants; Aspartic Acid; Clonazepam; Electroencephalography; Epilepsy, Temporal Lobe; gamma-Aminobutyric Acid; Hippocampus; Injections, Intraperitoneal; Levetiracetam; Male; Microinjections; Phenobarbital; Pilocarpine; Piracetam; Rats; Rats, Sprague-Dawley; Valproic Acid

Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures.. Wistar rats were subjected to pilocarpine-induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2-week period with implantation of LEV-filled minipumps (drug period), after which pumps were replaced by drug-free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring.. Average seizure frequency during the pre- and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats.. The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time-consuming, such trials should be added to the preclinical characterization of novel AEDs.

Topics: Animals; Anticonvulsants; Epilepsy, Temporal Lobe; Female; Infusion Pumps; Levetiracetam; Muscarinic Agonists; Pilocarpine; Piracetam; Rats; Rats, Wistar; Time Factors

Levetiracetam (LEV) is an interesting novel antiepileptic drug with proven efficacy in both animal models and patients with partial epilepsy. To study whether the efficacy of the drug changes during chronic treatment, we evaluated the anticonvulsant activity of LEV during prolonged daily administration in amygdala-kindled rats.. On the basis of the anticonvulsant potency and duration of action after acute doses, LEV was administered in fully kindled rats three times daily at 108 mg/kg i.p. for 3 weeks. For the study of anticonvulsant efficacy, the afterdischarge threshold was determined before, during, and after the drug treatment period. To determine whether the pharmacokinetics of the drug change during prolonged treatment, LEV levels were repeatedly determined in plasma during the treatment period.. LEV markedly increased the afterdischarge threshold and decreased the seizure severity and duration after initial dosing, but a marked loss of anticonvulsant efficacy developed during chronic treatment. This loss of efficacy was not due to alterations in drug elimination, indicating the development of functional tolerance to LEV during repeated administration. After the termination of treatment, no withdrawal signs (e.g., changes in behavior, body temperature, body weight, or seizure threshold) were observed.. The data demonstrate that chronic administration of LEV leads to a significant reduction in anticonvulsant efficacy in the kindling model of temporal lobe epilepsy. Whether this experimental observation has clinical relevance must await monotherapy trials with long-term follow-up of patients who initially responded to LEV.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Epilepsy, Temporal Lobe; Female; Kindling, Neurologic; Levetiracetam; Piracetam; Rats; Rats, Wistar; Substance Withdrawal Syndrome