Tim De Smedt

Deep Brain Stimulation in Patients with Refractory Temporal Lobe Epilepsy

Summary:  Purpose: This pilot study prospectively evaluated the efficacy of long‐term deep brain stimulation (DBS) in medial temporal lobe (MTL) structures in patients with MTL epilepsy.

High Frequency Deep Brain Stimulation in the Hippocampus Modifies Seizure Characteristics in Kindled Rats

Summary:  Purpose: This experimental animal study evaluates the effect of high frequency deep brain stimulation (HFS DBS) on seizures in the Alternate Day Rapid Kindling model for temporal lobe epilepsy (TLE). The target for HFS is the hippocampus, as this structure is often presumed to be the seizure focus in human TLE.

Radiation of the rat brain suppresses seizure-induced Neurogenesis and transiently enhances excitability during kindling acquisition

Summary:  Purpose: Adult hippocampal neurogenesis is enhanced in several models for temporal lobe epilepsy (TLE). In this study, we used low‐dose whole brain radiation to suppress hippocampal neurogenesis and then studied the effect of this treatment on epileptogenesis in a kindling model for TLE.

Rapid kindling in preclinical anti-epileptic drug development: the effect of levetiracetam

PURPOSE This study assesses the use of the serial day Rapid Kindling with Recurrent Hippocampal Seizures (RKRHS) model in drug testing by investigating the anti-epileptic effect of levetiracetam (LEV), a novel anti-epileptic drug (AED) with a unique preclinical profile. METHODS Male Wistar rats (n=16) were implanted with a stimulation/recording electrode unit in the right hippocampus and epidural recording electrodes. One week later, all rats received 12 stimulations each day for several consecutive days according to the serial day RKRHS protocol, until they were fully kindled. Fully kindled rats were then randomly assigned to an active (n=8) and a control (n=6) group and injected once (intraperitoneal, i.p.) with levetiracetam (54 mg/kg) or saline (0.9% NaCl, 2 ml/kg), respectively. One hour later, the rats received additional kindling stimulations, during which the effect of LEV was assessed. RESULTS One hour following injection of LEV, mean seizure stage dropped to 1.67+/-1.03 compared to 5+/-0 in controls (p<0.05). Mean ADD was also significantly shorter in the active group than in controls; 21.16+/-5.03 s versus 57.24+/-8.16s, respectively (p<0.05). A gradual, time-dependent decline was noted in the anti-epileptic effect of LEV but this effect stayed statistically significant at least up to 2.5 h (p<0.05). CONCLUSION LEV was demonstrated to have anti-epileptic properties in RKRHS that compared to those in traditional kindling and contrast with results from classical screening tests. RKRHS may represent a valuable and sensitive screening tool early in the drug screening process.

Serial day rapid kindling is an effective tool in screening the anti-epileptic properties of topiramate

INTRODUCTION In this study, a serial day rapid kindling protocol was used to fully kindle rats in a matter of days. Subsequently, the anticonvulsant profile of a relatively new anti-epileptic drug, topiramate, was evaluated in a cross-over design to further validate this rapid kindling model. METHODS Rats were kindled during three consecutive days, according to the serial day rapid kindling protocol. Topiramate was tested at a dose of 100mg/kg, i.p., over the next 2 days using a cross-over design. The stability of the kindled state was evaluated in all rats during two retest paradigms. During the drug-testing procedure, rats received a single i.p. injection of either topiramate or verhicle. Starting 1 h later the rats received additional kindling stimulations during which their response was measured. RESULTS Serial day rapid kindling induced a long lasting and stable fully kindled state that allowed for the anti-epileptic drug screening procedure. Topiramate reduced both the afterdischarge duration and ameliorated seizure semiology in the kindled rats. DISCUSSION Serial day rapid kindling provided a tool to rapidly kindle rats in 3 days. Using a cross-over design, clear indications on anti-epileptic activity of a given drug can be determined using few laboratory animals.

Towards a cell therapy for temporal lobe epilepsy (TLE)

not submitted Sunday 28 August 2005 12:00 – 13:30 Salle 243 EILAT VIII Session Improving the Effectiveness of New AEDs: Pharmacokinetic Considerations New AEDs in the Elderly: Pharmacokinetic Optimization R.H. Levy 1) University Of Washington, USA. The use of new AEDs in the elderly presents numerous challenges. Pharmacokinetic (PK) optimization pertains to risk of PK and pharmacodynamic drug-drug interactions associated with the presence of co-morbid disorders and age-related altered pharmacokinetic behavior. The Metabolism and Transport Drug Interaction Database (http://dept.washington.edu/didbase) was used to perform a comparative analysis between new and old AEDs in term of risk for drug interactions. Concomitant-therapy considered in this analysis included antidepressants, cardiovascular agents (anticoagulants, antiplatelets), beta-blockers, diuretics, ACE inhibitors, angiotensin receptor antagonists, calcium channel blockers, statins and fibrates. Pronounced differences in drug interaction potential between new and old AEDs pertain to the consequences of enzyme induction by PHT, PB & CBZ on the disposition of SSRIs (paroxetine, sertraline, citalopram and mirtazapine), warfarin, calcium channel blockers, (verapamil, diltiazem, felodipine, nimodipine), some statins (atorvastatin, fluvastatin, lovastatin, simvastatin) and some beta blockers (bisoprodol, carvedilol, metoprolol, timolol). Plasma levels of these drugs would be expected to increase in patients switched from PHT, PB, CBZ to a newer AED. Co-medication with SSRIs, thiazide duretics and CBZ or OXC may be associated with hyponatremia which is of significance in the elderly. Dosage reductions in elderly patients may be required for gababentin, levetiracetam, oxcarbazepine, topiramate and zonisamide because of PK alterations in older patients. Pharmacokinetic Basis of Idiosyncratic Effects M. Bialer 1) Department Of Pharmaceutics, School Of Pharmacy, Faculty Of Medicine, The Hebrew University Of Jerusalem, Jerusalem, Israel. Idiosyncratic effects or idiosyncratic drug reaction (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation. Idiosyncratic effects are unpredictable and can result in significant morbidity and sometimes mortality. These are often discovered after a drug approval during post marketing surveillance of phase IV clinical trials. Although they are dose-dependent in susceptible individuals, they do not occur at clinical doses with most patients. To date no animal or in vitro model exist to predict these adverse drug reactions. Therefore, the understanding of idiosyncratic effects mechanism is rather limited. Antiepileptic drugs (AEDs) have been recognized as being among the most common medications associated with severe cutaneous adverse reactions. Hypersensitivity reactions to the aromatic AEDs: phenytoin (PHT), carbamazepine (CBZ) appear to have immune etiology. One of the mechanisms for drug (AEDs) idiosyncratic hypersensitivity reaction centers around the concept of drug biotransformation to reactive metabolites that irreversibly modify cellular proteins. Thus, it has been proposed that aromatic AEDs may form metabolites that contain a reactive arene oxide moiety in their chemical structure, that could bind to cellular macromolecules and cause cell necrosis or secondary immunological response. Idiosyncratic reaction associated with lamotrigine (LTG) and felbamate (FBM), appears mechanistically distinct from PHT and CBZ hypersensitivity but may involve similar processes: active metabolites that form covalent adduct with vital proteins and macromolecules and subsequently starts a cascade of cell injury that may lead to tissue and organ injury and sometimes even death . One of theories behind FBM idiosyncratic effects is the formation of a reactive electrophilic metabolite atrophaldehyde or ATPAL (that contains a terminal double bond) that is capable of forming covalent protein adduct in vivo. The liver