Current limitations of antiepileptic drug therapy: a conference review

Deckers, C.L.P.; Genton, Pierre; Sills, Graeme J.; Schmidt, Dieter

doi:10.1016/s0920-1211(02)00257-7

Cited by 91 publications

(53 citation statements)

References 38 publications

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“…A small minority of these patients can be rendered seizure free by epilepsy surgery, ketogenic diet, or vagus nerve stimulation. However, modern medicine has no good solution to offer the majority of patients suffering from drugresistant epilepsy, and new treatment modalities are needed to treat this (Brodie and French, 2000;Browne and Holmes, 2001;Deckers et al, 2003;Schmidt and Löscher, 2005;Duncan et al, 2006;French, 2007;Schiller and Najjar, 2008). One of the most promising potential new treatments for drug-resistant epilepsy involves the use of closed-loop neurostimulators.…”

Section: Discussionmentioning

confidence: 99%

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in RatsIn Vivo

Cymerblit‐Sabba¹,

Schiller²

2010

J. Neurosci.

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In epilepsy, the cortical network fluctuates between the asymptomatic interictal state and the symptomatic ictal state of seizures. Despite their importance, the network dynamics responsible for the transition between the interictal and ictal states are largely unknown. Here we used multielectrode single-unit recordings from the hippocampus to investigate the network dynamics during the development of seizures evoked by various chemoconvulsants in vivo. In these experiments, we detected a typical network dynamics signature that preceded seizure initiation. The preictal state preceding pilocarpine-, kainate-, and picrotoxin-induced seizures was characterized by biphasic network dynamics composed of an early desynchronization phase in which the tendency of neurons to fire correlated action potentials decreased, followed by a late resynchronization phase in which the activity and synchronization of the network gradually increased. This biphasic network dynamics preceded the initiation both of the initial seizure and of recurrent spontaneous seizures that followed. During seizures, firing of individual neurons and interneuronal synchronization further increased. These findings advance our understanding of the network dynamics leading to seizure initiation and may in future help in the development of novel seizure prediction algorithms.

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Section: Discussionmentioning

confidence: 99%

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in RatsIn Vivo

Cymerblit‐Sabba¹,

Schiller²

2010

J. Neurosci.

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“…This clinical worsening, after administration of some AEDs influencing the GABA-ergic system, seems to depend on specific interactions of these AEDs with neuronal circuits in the brain. It is possible that AEDs inhibit some neuronal populations, while the others are overstimulated, finally resulting in pro-or anticonvulsant action of these AEDs (Deckers et al, 2003). The experimental data and clinical reports indicate that overstimulation of GABA-ergic neurotransmission potentiates the epileptic attacks (by increasing their frequency) or induces their new forms (especially, the absence attacks) (Murphy and Delanty, 2000).…”

Section: Controlmentioning

confidence: 99%

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

Łuszczki

Świąder

Parada-Turska

et al. 2003

Neuropsychopharmacol

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Polytherapy, based on the rational combining of antiepileptic drugs (AEDs), is required for patients with drug-resistant epilepsy. In such cases, the combinations of AEDs usually offer a significant enhancement of their protective effects against seizures. There has appeared a hypothesis that combining two AEDs, influencing the same neurotransmitter system, results in the potentialization of their anticonvulsant effects. For corroborating this hypothesis, a pharmacological character of interaction between tiagabine (TGB) and gabapentin (GBP)Ftwo novel AEDs affecting the GABA-ergic system, in the maximal electroshock seizure threshold (MEST)-test in mice was evaluated. TGB at the dose of 4 mg/kg and GBP at 75 mg/kg significantly raised the electroconvulsive threshold. Further, using the isobolographic calculations, TGB was coadministered with GBP at three fixed-ratios (1 : 3, 1 : 1, and 3 : 1) of their respective protective drug doses. All examined combinations of TGB with GBP exerted supra-additive (synergistic) interactions against MEST-induced seizures in mice. The interaction index, describing the strength and magnitude of interaction, ranged between 0.25 and 0.50 indicating supraadditivity. Adverse (neurotoxic) effects were evaluated in the chimney (motor performance) and the step-through, light-dark passive avoidance (long-term memory) tests in mice. The examined combinations of TGB with GBP did not affect the motor coordination, except for the fixed-ratio of 1 : 1, at which significant impairment of motor performance was observed. Moreover, all combinations selectively impaired the acquisition of the task in the passive avoidance test, having no impact on consolidation and retrieval in the longterm memory test. The pain threshold test revealed that the observed disturbances in the passive avoidance testing resulted presumably from the antinociceptive activity of these AEDs in combinations. After lengthening the exposing time to the direct current stimulus in the passive avoidance test from 2 to 6 s, the acquisition of the task, in animals receiving the combinations of TGB and GBP was not impaired. Neither the plasma, nor brain concentrations of GBP were affected by TGB application, so pharmacokinetic events that might negatively influence the observed effects are not probable. Results of this study clearly indicate that the activation of the same neurotransmitter system (GABA-ergic) leads to a synergistic interaction. The pain threshold test is a very good paradigm for screening the antinociceptive properties of AEDs, which may disturb the long-term memory testing in animals. Combinations of TGB with GBP (very promising from a preclinical point of view) should be clinically verified for elaborating the most effective treatment regimen in patients with intractable seizures.

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“…For those who continue to have seizures, the physician has two options, an alternative monotherapy (substitution) or a combination therapy (add-on), which generally involves adding a second drug to the current monotherapy. As randomized trials [5,6] did not provide evidence of which strategy should be preferred, clinical practice will presumably present various treatment patterns, as shown by a collaborative survey on prescribing strategies in Mediterranean countries [7] and a survey of expert opinions in the USA [8]. In this complex scenario, with few exceptions [9,10], the utilization of "classical" and "new" antiepileptic drugs is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Alternative monotherapy or add-on therapy in patients with epilepsy whose seizures do not respond to the first monotherapy: An Italian multicenter prospective observational study

Millul

Iudice

Adami

et al. 2013

Epilepsy & Behavior

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. A prospective multicenter observational study was undertaken on children and adults with epilepsy in whom first monotherapy failed, to assess indications and effects of alternative monotherapy vs. polytherapy. Patients were followed until 12-month remission, drug withdrawal, or up to 18 months. Monotherapy and polytherapy were compared for patients' baseline features, indication, retention time, remission, adverse events (AE), quality of life, and direct and indirect costs. Included were 157 men and 174 women, aged 2-86 years. Of the patients, 72.2% were switched to alternative monotherapy. Baseline treatment was changed for lack of efficacy (73.9%) or adverse events (26.1%). Two hundred forty-three completed the study (remission: 175; 72.0%). Retention time, hospital admissions, days off-work and off-school, and quality of life did not differ between the two treatment groups. Patients were followed for 365.3 person-years. Three hundred eighty-three incident AEs were reported by 46.4% of patients in monotherapy and 40.2% in polytherapy (serious AEs: 9.6% vs. 8.7%, mostly nondrug-related).

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Current limitations of antiepileptic drug therapy: a conference review

Cited by 91 publications

References 38 publications

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in RatsIn Vivo

Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in RatsIn Vivo

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

Alternative monotherapy or add-on therapy in patients with epilepsy whose seizures do not respond to the first monotherapy: An Italian multicenter prospective observational study

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