Epilepsy Research

Editorial Board

2010-09-01

Editorial Board

2010-09-01

RCTs with new antiepileptic drugs in children: A systematic review of monotherapy studies and their methodology

Amerins Weijenberg, Martin Offringa, Oebele F. Brouwer, Petra M.C. Callenbach — 2010-09-01

Summary: Few randomised controlled trials (RCTs) have been performed in which a second-generation antiepileptic drug (AED) used as monotherapy was compared with placebo or another AED in children (<18 years of age) with epilepsy. We describe the results of the available studies, assess the validity of these results, and give recommendations for optimal study design for AED monotherapy studies in children with epilepsy.Studies were identified using PubMed (Medline), Embase and the Cochrane Library (January 1990–January 2010). All reports were assessed for methodological quality and results were summarised descriptively.Nine RCTs were included. No difference in efficacy and safety between second-generation AEDs and first-generation AEDs in children was detected. Considerable heterogeneity in study design, inclusion criteria and primary endpoints impaired formal meta-analysis and correct interpretation of results. Follow-up periods were between 2 and 104 weeks; the dosage of the tested AEDs varied between studies, with sometimes use of apparent subtherapeutic dosages; in only two studies the method of randomisation was well described, in only three the power calculations; several studies did not use an intention-to-treat analysis. Although from the available studies first- and second-generation AEDs appear to have similar efficacy and safety in children with epilepsy, these trials are inadequate to provide a sufficient evidence base for decision making. Better trials are needed: AEDs should be studied in optimal paediatric doses, power should be sufficient to detect small but clinically relevant differences, and the follow-up period should be long enough. Most important, primary endpoint to be evaluated should be time to treatment failure or retention rate, since these outcomes combine efficacy and safety.

A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures

Michel Baulac, Teresa Leon, Terence J. O’Brien, Edward Whalen, Jeannette Barrett — 2010-09-01

Summary: Purpose: This study assessed the comparative efficacy of pregabalin for refractory partial seizures.Methods: Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day.Results: During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of −20.0% (p=.001) versus placebo, and −9.7% (p=.080) versus lamotrigine. The responder rate (≥50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine.Discussion: Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

The use of computer-assisted-telephone-interviewing to diagnose seizures, epilepsy and Idiopathic Generalized Epilepsy

2010-09-01

Summary: Background: Computer-assisted-telephone-interviewing (CATI), widely used in market research, could be a useful alternative for conducting diagnostic interviews in epilepsy epidemiology.Methods: We administered a diagnostic seizure questionnaire by CATI, interpreting the responses with standardized classification guidelines, compared against an epilepsy specialist's assessment, for agreement [Kappa statistic (κ)], sensitivity, specificity, positive predictive value, negative predictive value and Youden's Index (YI).Results: 99 outpatients with 382 lifetime events participated: 22 generalized-onset epilepsy [16 Idiopathic Generalized Epilepsy (IGE)], 59 partial-onset epilepsy, 12 non-epileptic and 6 uncertain. We observed almost perfect agreement in diagnosing epilepsy (κ=0.94), seizure-onset types (κ=0.84), simple or complex partial seizures (κ=0.87), any generalized non-convulsive seizure (κ=0.82), and IGE (κ=0.82). Although substantial, agreement was not as close for secondarily generalized seizures (κ=0.74), and generalized tonic-clonic seizures (κ=0.79). This related more to under-recognition of individual generalized non-convulsive seizures rather than misinterpretation of partial seizures.Discussion: Epilepsy diagnostic questionnaires administered by CATI and interpreted with standardized diagnostic guidelines can effectively classify epilepsy, most seizure types and IGE in outpatients with suspected seizures. Applying this diagnostic method in ‘field’ settings will allow firmer conclusions to be drawn on its wider epidemiological utility.

Polymorphisms in CACNA1E and Camk2d are associated with seizure susceptibility of Sprague–Dawley rats

2010-09-01

Summary: Seizures are associated with high intracellular calcium levels. However, conditions characterized by high intracellular calcium levels, such as stroke or traumatic brain injury, do not always evoke epilepsy. We hypothesized that polymorphisms in calcium-related genes CACNA1E and Camk2d contribute to the individual variability in seizure susceptibility.The distribution of one single nucleotide polymorphism (SNP) in the CACNA1E and one in the Camk2d gene was determined in Sprague–Dawley rats that were subjected to amygdala kindling or hyperthermia-induced seizures.The pre-kindling afterdischarge threshold was significantly lower in rats with the CACNA1E GG genotype (45.2±6.7μA) than in the GT genotyped animals (79.3±53.7μA). Among hyperthermia treated rats, the Camk2d G allele was more frequent among rats that did not display behavioral seizures during hyperthermia (67%) than in animals that did show behavioral seizures during hyperthermia (52%, χ2(1)=3.847, p=0.05).SNPs in CACNA1E and Camk2d genes are associated with the individual variability in seizure susceptibility in two experimental seizure models.

Association of serotonin transporter promoter (5-HTTLPR) and intron 2 (VNTR-2) polymorphisms with treatment response in temporal lobe epilepsy

2010-09-01

Summary: Purpose: Temporal lobe epilepsy (TLE) is the most common epilepsy and about 30% of patients have poorly controlled seizures. Neurobiology underlying responsiveness to medical treatment in TLE patients is unclear and there are currently no biological tests to predict course of the disease. Animal and human studies repeatedly suggested serotonergic dysfunction in subjects with TLE. We investigated association of serotonin transporter (5-HTT) gene polymorphisms with medical treatment response in patients with TLE.Methods: We analyzed 5-HTT gene linked polymorphic region (5-HTTLPR) in promoter and variable number of tandem repeats in the second intron of the 5-HTT gene (VNTR-2) in 101 consecutive subjects with TLE.Results: TLE patients with the combination of transcriptionally more efficient genotypes, i.e. 5-HTTLPR L/L and VNTR-2 12/12, had increased seizure refractoriness to antiepileptic medication therapy and shorter periods of seizure freedom, than subjects with other combinations of the 5-HTT genotypes. There were no other clinical or demographic differences among patient groups based on the 5-HTT genotypes.Conclusion: Combination of the 5-HTT genotypes linked with higher 5-HTT gene expression was found to be associated with worse response to optimal drug therapy. Further studies should determine potential role of this 5-HTT genotype polymorphism in epileptogenesis.

Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice

2010-09-01

Summary: Although morphine has anticonvulsant effect in several animal models of seizure, its potential clinical application in epilepsy may be hindered by its adverse effects like the phenomenon of opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizure induced by pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether N-methyl-d-aspartate (NMDA) receptor/nitrergic system blockage was able to prevent the probable tolerance. Our data demonstrated that anticonvulsant effects of a potent dose of morphine (1mg/kg) was abolished in chronic morphine-treated mice (with the same dose of morphine twice daily, 4 days, i.p.). Chronic pretreatment with low and non-effective doses of different NMDA antagonists ifenprodil (0.5mg/kg), MK-801 (0.05mg/kg) and ketamine (0.5mg/kg) as well as the non-selective nitric oxide (NO) synthase inhibitor l-NAME (2mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1mg/kg). Moreover, a single acute injection of the above mentioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1mg/kg). These results demonstrate that anticonvulsant effect of morphine can be subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by NMDA receptor/nitrergic system blockage, suggesting a role for NMDA receptor/NO signaling in the development of tolerance to the anticonvulsant effect of morphine.

Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy

2010-09-01

Summary: Purpose: Status epilepticus (SE) leads to upregulation of pro-inflammatory proteins including cyclooxygenase-2 (cox-2) which could be implicated in the epileptogenic process and epileptic seizures. Recent studies show that cox-2 can regulate expression of P-glycoprotein (P-gp) during epileptogenesis and epilepsy. P-gp could cause pharmacoresistance by reducing brain entry of anti-epileptic drugs such as phenytoin (PHT). Here we have investigated the effects of cox-2 inhibition on epileptogenesis, spontaneous seizures and PHT treatment in a rat model for temporal lobe epilepsy (TLE).Methods: A 3-day treatment with the cox-2 inhibitor SC-58236 (SC) was started 1 day before electrically induced SE. Chronic epileptic rats were treated with SC for 14 days, which was followed by a 7-day period of SC/PHT combination treatment. Seizure activity was monitored continuously using electroencephalography.Results: SC treatment did not affect SE duration, but led to an increased number of rats that died during the first 2 weeks after SE. Cox-2 inhibition during the chronic period led to an increased number of seizures in the 2nd week of treatment in 50% of the rats. SC/PHT treatment reduced seizures significantly for only 2 days.Conclusions: Both SC treatment that started before SE and the 14-day treatment in chronic epileptic rats led to adverse effects in the TLE rat model. Despite a temporal reduction in seizure frequency with SC/PHT treatment, SC does not seem to be a suitable approach for anti-epileptogenic or anti-epileptic therapy.

Targeting the prostaglandin E2 EP1 receptor and cyclooxygenase-2 in the amygdala kindling model in mice

Sarah Verena Fischborn, Jonna Soerensen, Heidrun Potschka — 2010-09-01

Summary: The prostaglandin E2 EP1 receptor as well as the inflammatory enzyme cyclooxygenase-2 have been suggested as targets for disease modulation, improvement of therapeutic response, and restoration of pharmacosensitivity in epilepsies. Translational development of respective add-on approaches requires careful analysis of putative effects on ictogenesis.Therefore we evaluated the impact of the EP1 receptor antagonist SC-51089, the EP1 receptor agonist misoprostol and the COX-2 inhibitors celecoxib and NS-398 in the mouse amygdala kindling model of temporal lobe epilepsy.Neither celecoxib nor NS-398 affected the generation, spread and termination of seizure activity. Whereas SC-51089 did not affect the seizure threshold, the highest dose (30mg/kg) significantly decreased the seizure severity when administered 60min before stimulation. Moreover, SC-51089 significantly prolonged seizure duration at the highest dose. The EP1 receptor agonist misoprostol exerted contrasting effects on seizure duration with a significant decrease in the duration of motor seizure activity.The data suggest that doses of COX-2 inhibitors and EP1 receptor antagonists which exert disease modulating or antiepileptic drug potentiating effects do not negatively affect seizure control in temporal lobe epilepsy. The contrasting impact of the EP1 receptor antagonist and agonist suggests that EP1 receptors can influence endogenous mechanisms involved in termination of seizure activity.

Autonomic and cellular mechanisms mediating detrimental cardiac effects of status epilepticus

2010-09-01

Summary: Prolonged seizure activity (status epilepticus; SE) can result in increased susceptibility to lethal ventricular arrhythmias for an extended period of time following seizure termination. SE is accompanied by acute, intense activation of the sympathetic nervous system (SymNS) and results in myocyte myofilament damage, arrhythmogenic alterations in cardiac electrical activity, and increased susceptibility to ventricular arrhythmias. However, the mechanisms mediating the changes in cardiac function, and the specific arrhythmogenic substrate produced during SE are unknown. To determine if detrimental cardiac effects of SE are mediated by SymNS stimulation of the heart, we examined the effects of B-adrenergic blockade (atenolol) during seizure activity on blood pressure, heart rate, myocyte myofilament injury (cardiac troponin I, cTnI), electrocardiographic activity, and susceptibility to arrhythmias. Furthermore, we determined if SE was associated with altered expression of the Kv4.x potassium channels, which are critical for action potential repolarization and thereby contribute significantly to normal cardiac electrical activity. Lithium-pilocarpine induced SE was associated with acute tachycardia, hypertension, and cardiomyocyte damage. Arrhythmogenic alterations in cardiac electrical activity accompanied by increased susceptibility to experimentally induced arrhythmias were evident during the first 2 weeks following SE. Both were prevented by atenolol treatment during seizures. Furthermore, one and two weeks after SE, myocyte ion channel remodeling, characterized by a decreased expression of cardiac Kv4.2 potassium channels, was evident. These data suggest that the cardiac effects of prolonged and intense SymNS activation during SE induce myofilament damage and downregulation of Kv4.2 channels, which alter cardiac electrical activity and increase susceptibility to lethal arrhythmias.

Brivaracetam does not alter spatial learning and memory in both normal and amygdala-kindled rats

2010-09-01

Summary: Several antiepileptic drugs (AEDs) may induce memory deficits when tested in preclinical models at doses that exert significant protection against seizures. Brivaracetam (BRV) is a novel high-affinity SV2A ligand also displaying inhibitory activity at neuronal voltage-gated sodium channels. In the present study we have investigated the effects of BRV, at doses that exerted marked anticonvulsant effects in kindled rats, upon cognitive functioning and memory in both normal and amygdala-kindled rats using place learning version of Morris water maze. In addition the effect of BRV on long-term potentiation (LTP) in rat hippocampal slices has been investigated.BRV (2.1, 6.8 or 21.0mg/kg i.p.) was injected daily, 60min before each session. Results indicated that in both normal and amygdala-kindled rats BRV did not alter the latency to find the hidden platform or swimming speed during the four consecutive days of learning. Similarly, the time spent in the target quadrant, used as a further independent index of spatial memory, was not modified by BRV treatment. Likewise, BRV did not affect the LTP induction in CA1 hippocampal region when tested at 3–30μM concentration range, which had been demonstrated to significantly reduce epileptiform activity in slice models.Based on the results of the present study it can be expected that BRV will not have detrimental effects on hippocampal-dependent cognitive functions in patients with epilepsy.

Expression patterns of AMOG in developing human cortex and malformations of cortical development

K. Boer, W.G.M. Spliet, P.C. van Rijen, F.E. Jansen, E. Aronica — 2010-09-01

Summary: Adhesion molecule on glia (AMOG) mediates neuronal migration during development and ion homeostasis. Recently, AMOG has been identified as a regulator of the Pi3K–mTOR signaling pathway. In the present study, we investigated the expression pattern of AMOG in human cortex during development and in focal malformations of cortical development.In the developing human cortex, AMOG expression was detected in the cortical plate at 13 gestational weeks and increased in later gestational ages. In adult human control cortex, a diffuse immunoreactivity pattern was observed for AMOG in the grey matter. In the white matter, AMOG was expressed in perivascular astrocytes.In focal cortical dysplasia (n=6) and cortical tubers (n=6), the diffuse AMOG expression pattern was reduced in the grey matter. However, AMOG immunoreactivity was observed in reactive astrocytes and strong perisomatic staining was detected in balloon and giant cells. Double-labeling showed co-localization of AMOG with the precursor cell marker CD34 and phosphorylated S6, used as a marker of mTOR activation.The AMOG expression pattern, with altered cellular distribution, observed in malformations of cortical development suggests that AMOG might contribute to the abnormal cortical development via mTOR activation. Whether dysfunction of AMOG might influence the ionic and osmotic regulation, contributing to neuronal hyperexcitability, deserves further investigation.

Quantitative EEG abnormalities in persons with “pure” epileptic predisposition without epilepsy: A low resolution electromagnetic tomography (LORETA) study

S. Puskás, M. Bessenyei, I. Fekete, K. Hollódy, B. Clemens — 2010-09-01

Summary: Objective: Epileptic predisposition means genetically determined, increased seizure susceptibility. Neurophysiological evaluation of this condition is still lacking. In order to investigate “pure epileptic predisposition” (without epilepsy) in this pilot study the authors prospectively recruited ten persons who displayed generalized tonic–clonic seizures precipitated by 24 or more hours of sleep deprivation but were healthy in any other respects.Methods: 21-channel EEGs were recorded in the morning, in the waking state, after a night of sufficient sleep in the interictal period. For each person, a total of 120s artifact-free EEG was processed to low resolution electromagnetic tomography (LORETA) analysis. LORETA activity (Ampers/meters squared) was computed for 2394 voxels, 19 active electrodes and 1Hz very narrow bands from 1 to 25Hz. The data were compressed into four frequency bands (δ: 0.5–4.0Hz, θ: 4.5–8.0Hz, α: 8.5–12.0Hz, β: 12.5–25.0Hz) and projected onto the MRI figures of a digitized standard brain atlas. The band-related LORETA results were compared to those of ten, age- and sex-matched healthy persons using independent t-tests. p<0.01 differences were accepted as statistically significant.Results: Statistically significant decrease of α activity was found in widespread, medial and lateral parts of the cortex above the level of the basal ganglia. Maximum α decrease and statistically significant β decrease were found in the left precuneus. Statistically not significant differences were δ increase in the medial-basal frontal area and θ increase in the same area and in the basal temporal area.Discussion: The significance of α decrease in the patient group remains enigmatic. β decrease presumably reflects non-specific dysfunction of the cortex. Prefrontal δ and θ increase might have biological meaning despite the lack of statistical significance: these findings are topographically similar to those reported in idiopathic generalized epilepsy in previous investigations.Significance: Quantitative EEG characteristics of the genetically determined epilepsy predisposition were given in terms of frequency bands and anatomical distribution.

Efficacy and tolerability of high oral doses of Levetiracetam in children with epilepsy

Makram Obeid, Amanda W. Pong — 2010-09-01

Summary: Background: Despite the advent of new antiepileptic drugs, many children continue to have refractory seizures. We sought to determine whether oral LEV is helpful in seizure control and tolerable at doses higher than 60mg/kg/day in the pediatric outpatient population.Methods: A retrospective chart review over a 1.5-year period was performed at the Columbia Comprehensive Epilepsy Center to identify children who were treated with levetiracetam doses titrated above the usual 40–60mg/kg/day. Data was collected on seizure semiology, epilepsy type, seizure frequency, concomitant antiepileptic drugs, and adverse effects.Results: Thirty-two children, ranging in age from 1 to 19 years, required high dose levetiracetam. The median dosage of levetiracetam was 146mg/kg/day (range, 70–275mg/kg/day), and the median maximum serum trough level was 43mcg/ml (range, 20–121mcg/ml). All but one patient were taking one or more other antiepileptic drugs. A more than 50% reduction in seizure frequency was observed in 14 children (44%), with 5 achieving seizure freedom (16%). No response to high dose levetiracetam was found in 14 children (44%), and worsening of seizure frequency occurred in 4 (12%). Adverse effects were observed in 4 patients (12%), and were behavioral.Conclusions: Not only do some children tolerate high doses and serum levels of levetiracetam, but they may also benefit from them, suggesting that doses higher than 60mg/kg/day may be considered in children who partially respond to the lower doses.

Triple pathology in epilepsy: Coexistence of cavernous angiomas and cortical dysplasias with other lesions

2010-09-01

Summary: Coexistence of cortical dysplasias (CD) with cavernomas has rarely been reported. We reviewed our surgical specimens from patients who underwent surgery for pharmacoresistant epilepsy between 2003 and 2008, and identified seven cases with cavernoma, of whom two had overlying CD. In addition, each of these patients had a third form of a potentially epileptogenic lesion: hippocampal sclerosis in one, and venous angioma in the other. We conclude that CD is heterogeneous, with milder forms appearing to co-exist with other pathologies, including vascular abnormalities and hippocampal sclerosis.