Treating patients with medically resistant epilepsy

Krauss, Gregory L.; Sperling, Michael R.

doi:10.1212/cpj.0b013e31823d07d1

Cited by 34 publications

(29 citation statements)

References 41 publications

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“…49 It is therefore worth noting that screening and evaluation of ASDs or novel therapies using lamotrigine tolerance as a predictor of drug resistance across the epilepsy population may be useful, but does not fully encapsulate all potential causes of resistance. Further, resistance in patients is not due to treatment with any particular drug or drug class.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

et al. 2019

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Objective The lamotrigine‐resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported. Methods Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (~3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine‐resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score < 3 in the absence of overt compound‐induced side effects. Various ASDs, comprising several mechanistic classes, were administered to fully kindled, lamotrigine‐resistant rats. Where possible, multiple doses of each drug were administered in order to obtain median effective dose (ED 50 ) values. Results Five sodium channel blockers tested (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well‐tolerated in this model. In contrast, compounds targeting either GABA receptors (clobazam, clonazepam, phenobarbital) or GABA‐uptake proteins (tiagabine) produced dose‐dependent efficacy against convulsive seizures. Compounds acting to modulate Ca 2+ channels show differential activity: Ethosuximide was not effective, whereas gabapentin was moderately efficacious. Ezogabine and valproate were also highly effective, whereas topiramate and levetiracetam were not effective at the doses tested. Significance These results strengthen the conclusion that the lamotrigine‐resistant amygdala kindling model demonstrates pharmacoresistance to certain ASDs, including, but not limited to, sodium channel blockers, and supports the utility of the model for helping to identify compounds with potential efficacy against pharmacoresistant seizures.

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Section: Discussionmentioning

confidence: 99%

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

et al. 2019

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“…Approximately 30% of patients with epilepsy fail to respond to current therapies, so there is increasing demand for novel antiepileptic drugs (AEDs) and other therapeutic strategies (16,17). Current AEDs enhance GABAergic function (18), either by modulating the post-synaptic GABAa Rs (barbiturates and benzodiazepines) or by acting on synaptic GABA availability (vigabatrin).…”

Section: Introductionmentioning

confidence: 99%

Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function

et al. 2020

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As a main inhibitory neurotransmitter in the central nervous system, γ-aminobutyric acid (GABA) activates chloride-permeable GABAa receptors (GABAa Rs) and induces chloride ion (Cl −) flow, which relies on the intracellular chloride concentration ([Cl − ] i) of the postsynaptic neuron. The Na-K-2Cl cotransporter isoform 1 (NKCC1) and the K-Cl cotransporter isoform 2 (KCC2) are two main cation-chloride cotransporters (CCCs) that have been implicated in human epilepsy. NKCC1 and KCC2 reset [Cl − ] i by accumulating and extruding Cl − , respectively. Previous studies have shown that the profile of NKCC1 and KCC2 in neonatal neurons may reappear in mature neurons under some pathophysiological conditions, such as epilepsy. Although increasing studies focusing on the expression of NKCC1 and KCC2 have suggested that impaired chloride plasticity may be closely related to epilepsy, additional neuroelectrophysiological research aimed at studying the functions of NKCC1 and KCC2 are needed to understand the exact mechanism by which they induce epileptogenesis. In this review, we aim to briefly summarize the current researches surrounding the expression and function of NKCC1 and KCC2 in epileptogenesis and its implications on the treatment of epilepsy. We will also explore the potential for NKCC1 and KCC2 to be therapeutic targets for the development of novel antiepileptic drugs.

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“…Despite treatment with currently available antiepileptic drugs, 30% of patients with epilepsy still display seizures and are considered drugresistant (1). Despite the development of several new antiepileptic drugs, this proportion of refractory epilepsy patients has not improved over the last decade (2). In addition, current antiepileptic drugs present various and severe side effects due to their action on ubiquitously expressed channels and receptors that are involved in physiological functions (3).…”

Section: Introductionmentioning

confidence: 99%

Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy

et al. 2018

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Epilepsies are characterized by recurrent seizures, which disrupt normal brain function. Alterations in neuronal excitability and excitation-inhibition balance have been shown to promote seizure generation, yet molecular determinants of such alterations remain to be identified. Pannexin channels are nonselective, large-pore channels mediating extracellular exchange of neuroactive molecules. Recent data suggest that these channels are activated under pathological conditions and regulate neuronal excitability. However, whether pannexin channels sustain or counteract chronic epilepsy in human patients remains unknown. We studied the impact of pannexin-1 channel activation in postoperative human tissue samples from patients with epilepsy displaying epileptic activity ex vivo. These samples were obtained from surgical resection of epileptogenic zones in patients suffering from lesional or drug-resistant epilepsy. We found that pannexin-1 channel activation promoted seizure generation and maintenance through adenosine triphosphate signaling via purinergic 2 receptors. Pharmacological inhibition of pannexin-1 channels with probenecid or mefloquine-two medications currently used for treating gout and malaria, respectively-blocked ictal discharges in human cortical brain tissue slices. Genetic deletion of pannexin-1 channels in mice had anticonvulsant effects when the mice were exposed to kainic acid, a model of temporal lobe epilepsy. Our data suggest a proepileptic role of pannexin-1 channels in chronic epilepsy in human patients and that pannexin-1 channel inhibition might represent an alternative therapeutic strategy for treating lesional and drug-resistant epilepsies.

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Treating patients with medically resistant epilepsy

Cited by 34 publications

References 41 publications

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

Role of NKCC1 and KCC2 in Epilepsy: From Expression to Function

Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy

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