Treatment Of Absence Epilepsy Research Articles

Ethosuximide is an allosteric blocker of girk channels with Gβγ and is subunit dependent.

Ethosuximide (ETX) is a common drug in the treatment of absence epilepsy. ETX is known to act via inhibition of T-type voltage gated Ca2+ channels. Later, it was shown that ETX blocks GIRK channels as well. Recently, ETX was shown to reduce absence-like epileptiform activity in mice carrying disease-causing mutations in GNB1 gene, which encodes for Gβ1 subunit. Gβγ subunits are the main gating factor of GIRK channels. Here, we study the mechanism by which ETX blocks GIRK channels. We confirmed that CaV3.2, as well as CaV1.2 channels are weakly blocked by ETX at therapeutic doses (0.25-0.75 mM), as was shown previously. Homotetrameric GIRK2 channels co-expressed with Gβγ subunits were almost completely inhibited at therapeutic doses of ETX, while heterotetrameric GIRK1/2 channels were mildly inhibited, and GIRK1/3 were non-sensitive. We found that the open channel mutant GIRK2N94H or ivermectin activated GIRK2WT channel were not sensitive to ETX, suggesting that it is not an open channel blocker. The affinity of ETX to GIRK2 homotetramers was increased with increasing doses of Gβγ, suggesting an allosteric inhibition. Exchange of the GIRK2 transmembrane domain (TM) with GIRK3's (GIRK2G3TM) turned the channel non-sensitive to ETX block, the opposite exchange made GIRK3G2TM more sensitive to ETX block. This data suggests that ETX blocks GIRK channels in subunit-dependent manner, it is an allosteric- rather than open channel blocker, and its binding site may be located within the TM or extracellular domain of the channel.

Symposium Title: Multiscale Modeling of Brain Dynamics and Cognitive Processes

Absence epilepsy, characterized by transient loss of awareness and bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) on electroencephalography (EEG) during absence seizures, is generally believed to arise from abnormal interactions between the cerebral cortex (Ctx) and thalamus. Recent animal electrophysiological studies suggested that changing the neural activation level of the external globus pallidus (GPe) neurons can remarkably modify firing rates of the thalamic reticular nucleus (TRN) neurons through the GABAergic GPe–TRN pathway. However, the existing experimental evidence does not provide a clear answer as to whether the GPe–TRN pathway contributes to regulating absence seizures. Here, using a biophysically based mean-field model of the GPe-corticothalamic (GCT) network, we found that both directly decreasing the strength of the GPe–TRN pathway and inactivating GPe neurons can effectively suppress absence seizures. Also, the pallido-cortical pathway and the recurrent connection of GPe neurons facilitate the regulation of absence seizures through the GPe–TRN pathway. Specifically, in the controllable situation, enhancing the coupling strength of either of the two pathways can successfully terminate absence seizures. Moreover, the competition between the GPe–TRN and pallido-cortical pathways may lead to the GPe bidirectionally controlling absence seizures, and this bidirectional control manner can be significantly modulated by the Ctx–TRN pathway. Importantly, when the strength of the Ctx–TRN pathway is relatively strong, the bidirectional control of absence seizures by changing GPe neural activities can be observed at both weak and strong strengths of the pallido-cortical pathway.These findings suggest that the GPe–TRN pathway may have crucial functional roles in regulating absence seizures, which may provide a testable hypothesis for further experimental studies and new perspectives on the treatment of absence epilepsy.

Insights on the role of external globus pallidus in controlling absence seizures

Absence epilepsy, characterized by transient loss of awareness and bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) on electroencephalography (EEG) during absence seizures, is generally believed to arise from abnormal interactions between the cerebral cortex (Ctx) and thalamus. Recent animal electrophysiological studies suggested that changing the neural activation level of the external globus pallidus (GPe) neurons can remarkably modify firing rates of the thalamic reticular nucleus (TRN) neurons through the GABAergic GPe–TRN pathway. However, the existing experimental evidence does not provide a clear answer as to whether the GPe–TRN pathway contributes to regulating absence seizures. Here, using a biophysically based mean-field model of the GPe-corticothalamic (GCT) network, we found that both directly decreasing the strength of the GPe–TRN pathway and inactivating GPe neurons can effectively suppress absence seizures. Also, the pallido-cortical pathway and the recurrent connection of GPe neurons facilitate the regulation of absence seizures through the GPe–TRN pathway. Specifically, in the controllable situation, enhancing the coupling strength of either of the two pathways can successfully terminate absence seizures. Moreover, the competition between the GPe–TRN and pallido-cortical pathways may lead to the GPe bidirectionally controlling absence seizures, and this bidirectional control manner can be significantly modulated by the Ctx–TRN pathway. Importantly, when the strength of the Ctx–TRN pathway is relatively strong, the bidirectional control of absence seizures by changing GPe neural activities can be observed at both weak and strong strengths of the pallido-cortical pathway.These findings suggest that the GPe–TRN pathway may have crucial functional roles in regulating absence seizures, which may provide a testable hypothesis for further experimental studies and new perspectives on the treatment of absence epilepsy.

Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

ABSTRACTIntroduction: Several drugs targeting the GABAergic system are used in the treatment of epilepsy, but only one drug targeting glutamate receptors is on the market. This is surprising because an imbalance between excitatory and inhibitory neurotransmission lies at the core of the pathophysiology of epilepsy. One possible explanation is that drug development has been directed towards the synthesis of molecules that inhibit the activity of ionotropic glutamate receptors. These receptors mediate fast excitatory synaptic transmission in the central nervous system (CNS) and their blockade may cause severe adverse effects such as sedation, cognitive impairment, and psychotomimetic effects. Metabotropic glutamate (mGlu) receptors are more promising drug targets because these receptors modulate synaptic transmission rather than mediate it.Areas covered: We review the current evidence that links mGlu receptor subtypes to the pathophysiology and experimental treatment of convulsive and absence seizures.Expert opinion: While mGlu5 receptor negative allosteric modulators have the potential to be protective against convulsive seizures and hyperactivity-induced neurodegeneration, drugs that enhance mGlu5 and mGlu7 receptor function may have beneficial effects in the treatment of absence epilepsy. Evidence related to the other mGlu receptor subtypes is more fragmentary; further investigations are required for an improved understanding of their role in the generation and propagation of seizures.

Effect of anticonvulsant therapy for absence epilepsy on heart function.

Monitoring of the heart status during increasing stress-induced load allowed us to evaluate heart function after treatment of absence epilepsy with anticonvulsants of various types of action. Functional load against the background of treatment with lamotrigine or convulex had different effects on the dynamics of heart rate variability, hemodynamic parameters of the heart, and risk of life-threatening arrhythmias. The decrease in hemodynamic parameters and ischemic changes in the myocardium after convulex therapy occurred at a lower functional load associated with more pronounced reduction in parasympathetic tone and heart rate variability than after lamotrigine therapy. This suggests that the heart of animals treated with convulex has lower functional capacities and, therefore, stress-induced decompensation and prenosological status developed earlier.

Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice.

Epilepsies are debilitating neurological disorders characterized by repeated episodes of pathological seizure activity. Absence epilepsy (AE) is a poorly understood type of seizure with an estimated 30% of affected patients failing to respond to antiepileptic drugs. Thus, novel therapies are needed for the treatment of AE. A promising cell-based therapeutic strategy is centered on transplantation of embryonic neural stem cells from the medial ganglionic eminence (MGE), which give rise to gamma-aminobutyric acidergic (GABAergic) interneurons during embyronic development. Here, we used the Stargazer (Stg) mouse model of AE to map affected loci using c-Fos immunohistochemistry, which revealed intense seizure-induce activity in visual and somatosensory cortices. We report that transplantation of MGE cells into the primary visual cortex (V1) of Stg mice significantly reduces AE episodes and lowers mortality. Electrophysiological analysis in acute cortical slices of visual cortex demonstrated that Stg V1 neurons exhibit more pronounced increases in activity in response to a potassium-mediated excitability challenge than wildtypes (WT). The defective network activity in V1 was significantly altered following WT MGE transplantation, associating it with behavioral rescue of seizures in Stgs. Taken together, these findings present MGE grafting in the V1 as a possible clinical approach in the treatment of AE.

Absence Epilepsy: Older vs Newer AEDs

Over the last one to two decades, several new antiepileptic drugs (AEDs) have become available. These medications have different mechanisms of action, metabolism, efficacy, and side effect profiles. Hence, it has become possible to customize medications for a particular patient. It has also become possible to use various combinations of treatments for refractory epilepsies. As medication options have increased, our goal has shifted to not only to maximize seizure control but also to minimize side effects. However, the older AEDs are still widely used. So the question arises-are newer medications better than older AEDs for the treatment of absence epilepsy? Based on a large multicenter class I study, older AEDs-ethosuximide and valproic acid-are more efficacious than newer AEDs. Due to reduced side effects, ethosuximide remains the first line treatment for childhood absence epilepsy.

A multicenter, randomized, placebo‐controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy

To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy. Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14. The double-blind phase was followed by an open-label follow-up. Nine of 38 patients (23.7%) were responders in the levetiracetam group, compared with one of 21 (4.8%) in the placebo group (p = 0.08). Seven of 38 patients (18.4%) were free from clinical and EEG seizures during the last 4 days of the trial (including 24-h EEG monitoring on day 14) compared with none of the patients treated with placebo (p = 0.04). Seventeen patients remained seizure-free on levetiracetam after 1 year follow-up. Of the 41 patients who discontinued levetiracetam due to lack of efficacy (n = 39) or adverse events (n = 2), 34 became seizure-free on other treatments. Although superiority to placebo just failed to reach statistical significance for the primary end point, the overall findings are consistent with levetiracetam having modest efficacy against absence seizures. Further controlled trials exploring larger doses and an active comparator are required to determine the role of levetiracetam in the treatment of absence epilepsy.

Use of a new antiepileptic drug or an old one as first drug for treatment of absence epilepsy

Treatment of absence epilepsy requires understanding the efficacy and side effects of several drugs, one of which first became available more than 50 years ago. Methods for drug development and procedures for evaluating their safety and efficacy over that time have changed dramatically. Observational studies of the efficacy of ethosuximide, a drug developed in the 1950s, reported complete seizure control in 40-60% of patients. Valproic acid, a drug with a broad spectrum of effect, showed robust efficacy as well for control of absence seizures. Because side effects limit use in some patients, newer drugs were evaluated in patients with absence seizures. Of drugs becoming available in the last 15 years, lamotrigine has some effect in absence seizures. Although older and newer drugs presently are used without the rigorous underpinnings of the highest quality of evidence, our analysis found that ethosuximide, valproate, and lamotrigine are effective in the treatment of absence seizures, with ethosuximide quite possibly being the first drug of choice.

Enhancement of anti-absence effects of ethosuximide by low doses of a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist in a genetic animal model of absence epilepsy

N-Acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THIQ-10c) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist that has been demonstrated to antagonize generalized tonic–clonic seizures in different animal models of epilepsy. In the study described here, we tested the potential effect of such a compound alone or co-administered with ethosuximide in a genetic animal model of absence epilepsy, the WAG/Rij rat. The intraperitoneal or intracerebroventricular microinjection of THIQ-10c alone was unable to significantly modify the number and duration of spike-and-wave discharges (SWDs). In contrast, intracerebroventricular administration of AMPA induced a dose-dependent increase in the number of SWDs. THIQ-10c dose-dependently antagonized this effect. Furthermore, co-administration of THIQ-1c with ethosuximide (50 mg/kg, intraperitoneally) was able to significantly increase the efficacy of the anti-absence drug. In conclusion, although noncompetitive AMPA receptor antagonists alone might not be useful in the treatment of absence epilepsy because of their low therapeutic index, combining them with ethosuximide might be helpful in controlling absence seizures in patients not tolerating this drug or in refractory patients.

Antiepileptic Drug Monotherapy Versus Poly therapy: A Historical Perspective

SummaryMonotherapy (administration of a single drug) for the treatment of epilepsy has been the gold standard for almost two decades, although exceptions to this rule are still accepted in selected forms of epilepsy. Before this contemporary approach, other attitudes prevailed. The first effective antiepileptic drugs (AEDs), e.g., bromides and, much later, phcnobarbital (PB), were administered in association with central nervous system stimulants to counterbalance sedative effects. Phenytoin was the first effective nonsedative AED and was often administered together with phenobarbitai at moderate dosages to avoid the toxicity associated with a higher dosage of a single AED. PB was also co‐administered with ethosuximide in the treatment of absence epilepsy, to prevent the occurrence of both absence seizures and generalized tonic‐clonic seizures. Although the practice of monotherapy has become increasingly prevalent, the recent availability of new AEDs has created new problems. In fact, because of the introduction of these AEDs as effective add‐on therapy, the use of “rational polypharmacy” was reinvented. From a historical perspective, however, the trend toward simple, cost‐effective management of seizures with a single AED is still a goal.

Effects of loreclezole on epileptic activity and on EEG and behaviour in rats with absence seizures

The antiepileptic profile of loreclezole, a new putative antiepileptic compound, has been determined in rats of the WAG/Rij strain, a genetic model of generalized absence epilepsy. In addition, the effects of 0, 5, 10 and 20 mg/kg loreclezole on the spectral content of the background EEG and on spontaneous behaviour of rats were investigated. Both the number of spike-wave discharges and their total duration dose-dependently decreased following administration of loreclezole. Furthermore, the behaviour of the animals was not markedly influenced and significant changes in the background EEG were not noticed after administration. These data suggest that the broad-spectrum antiepileptic loreclezole can be a valuable new drug in the treatment of absence epilepsy.

Computer model of ethosuximide's effect on a thalamic neuron.

Ethosuximide appears to have a specific effect on the low-threshold calcium current in thalamic cells. This may be related to its efficacy in the treatment of absence epilepsy. We used a computer model of an individual thalamocortical neuron to better understand the alteration in the low-threshold calcium current under voltage clamp and to predict response to current injection in the presence of ethosuximide. The full model included nine voltage-sensitive ionic channels and a realistic dendritic morphology. The model reproduced the two major responses seen in tissue slices: repetitive spiking with depolarization and the low-threshold calcium spike elicited on release from hyperpolarization. The alteration in low-threshold calcium current with ethosuximide can be explained by a 10-mV depolarizing shift in the steady-state activation curve for this channel with a 10% reduction in maximum channel permeability. Simulations of current injection showed that ethosuximide diminished the low-threshold calcium spike while leaving the tonic firing pattern unaffected. Our results support the hypothesis that ethosuximide's effects on low-threshold calcium current might selectively alter the dynamics of slow bursting in thalamic cells.

Once-daily ethosuximide in the treatment of absence epilepsy

Once-daily ethosuximide was used to treat 10 consecutive children with typical absence seizures. Three patients had gastrointestinal side effects which resolved when the same total daily dose was divided into 2 doses. Two other patients continued to have seizures on ethosuximide, whether given once or twice daily. Five patients had complete seizure control without adverse effects on once-daily ethosuximide.

Valproate in the treatment of absence epilepsy in children: a study of dose-response relationships.

Seven children with absence epilepsy were treated with valproate (VPA). All but one child became free of absence seizures during VPA monotherapy. EEG was recorded for 24 h before start of VPA treatment and repeatedly during treatment. Correlation between plasma VPA concentration and reduction of the number of epileptic discharges was significant. Plasma concentration of 440-660 microM VPA was needed to achieve at least 50% reduction of seizure activity.