Pieter Claeys

Long-term deep brain stimulation for refractory temporal lobe epilepsy

dial temporal lobe onset. One patient had a bilateral regional temporal lobe onset with predominant involvement of the left side. One patient had a left-sided regional medial temporal lobe onset. Six out of the seven patients had a > 50% reduction of interictal spikes during the initial AHDBS trial period. In one patient who showed very infrequent spiking, seizure frequency that had significantly decreased was used as a criterion for implantation. All patients were implanted with an internal generator. The mean follow up in these patients was 14 months (range: 5.5‐21 months). One patient has been free of complex partial seizures (CPS) for 1.5 years and has been tapered off two antiepileptic drugs (AEDs). Three of the seven patients have a ≥50% reduction in seizure frequency: one of the three patients is seizure free during the day, and two of the three patients have been tapered off one AED. Two of the seven patients have a reduction of 25% of seizure frequency but have still been tapered off two AEDs; one of these patients had bilateral seizure onset and is currently being revised for bilateral AHDBS. In one patien,t no change in seizure frequency occurred. None of the patients report side effects. DISCUSSION

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.

Seizures in the intrahippocampal kainic acid epilepsy model: characterization using long-term video-EEG monitoring in the rat.

Objective –  Intrahippocampal injection of kainic acid (KA) in rats evokes a status epilepticus (SE) and leads to spontaneous seizures. However to date, precise electroencephalographic (EEG) and clinical characterization of spontaneous seizures in this epilepsy model using long‐term video‐EEG monitoring has not been performed.

Analysis of initial slow waves (ISWs) at the seizure onset in patients with drug resistant temporal lobe epilepsy

Summary:  Rationale: The goal of this study is to analyze initial slow waves (ISWs) at seizure onset in patients with refractory temporal lobe epilepsy. ISWs are a specific type of ictal EEG pattern characterized by a slow wave at the seizure onset followed by low voltage fast activity.

Acute vagus nerve stimulation does not suppress spike and wave discharges in genetic absence epilepsy rats from Strasbourg.

We evaluated the efficacy of vagus nerve stimulation (VNS) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a validated model for absence epilepsy. In the first experiment, we investigated whether VNS applied at seizure onset can interrupt spike and wave discharges (SWD). In the second experiment, we investigated whether SWD are suppressed or shortened in duration when VNS is applied several hours per day. Both control and VNS groups underwent EEG and VNS electrode implantation. For the first experiment, a randomized crossover design was used. Stimuli (amplitude: 3 V; frequency: 30 Hz; pulse duration: 500 micros) were given when an SWD occurred on the EEG. The experiment was repeated the next day. In the second experiment, treated animals were stimulated (amplitude: 1.5 mA; frequency: 30 Hz; pulse duration: 500 micros; on/off time cycle: 30 s / 5 min) for 3h per day, during five consecutive days. In the first experiment, the duration of the SWD was increased on day 1, (P < 0.05). There was no difference in SWD duration on Day 2. In the second experiment, no significant differences could be found in number, duration and EEG frequency of SWD. VNS applied at the onset of an SWD can prolong the duration of SWD in GAERS. As a 5-day stimulation protocol had no effect, long-term VNS might be necessary to affect SWD.

Generator replacement in epilepsy patients treated with vagus nerve stimulation

PURPOSE In epilepsy patients treated with vagus nerve stimulation (VNS), the occurrence of end of battery life (EOBL), when the generator will no longer deliver any stimulation, was investigated with regard to seizure control. EOBL is preceeded by end of effective stimulation (EOES) when irregular stimulation may occur. METHODS In 14/78 patients, treated with VNS at Ghent University Hospital, generators were replaced at different times following EOES or EOBL. We retrospectively analysed the time of occurrence of EOES and EOBL and seizure control before and after generator replacement. RESULTS EOES or EOBL was indicated by loss of seizure control, decreased perception of stimulation and recurrence of depression in 3, 3 and 1/14 patient(s), respectively. In 2 and 1/14 patient(s), EOBL and premature generator failure, respectively, were detected during routine check-up at the epilepsy clinic. In 4/14 patients, generator replacement was performed before estimated EOES. Pre-replacement seizure control could not be regained in 2/14 patients in whom replacement had been postponed for several months. Estimation of EOES and EOBL occurrence proved difficult in individual patients. CONCLUSION EOES or EOBL may be indicated by loss of seizure control, decreased or irregular perception of stimulation by the patient and loss of other VNS-induced effects. Postponing generator replacement may result into permanent loss of seizure control. In responders we suggest generator replacement before EOBL. Our results call for performance of prospective studies in larger patient groups that may eventually lead to general guidelines on the indication and timing of generator replacement.

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.

Enterocolitis: an adverse event in refractory epilepsy patients treated with levetiracetam?

INTRODUCTION Levetiracetam (LEV) is a recently marketed novel anti-epileptic drug with a promising efficacy and safety profile. In this report we describe two patients who presented with enterocolitis and discuss the possible relationship with concurrent LEV intake. PATIENTS In two patients. LEV was initiated to control refractory complex partial seizures (CPS). The first patient was treated with 1500 mg/day and complained of abdominal pain and weight loss 6 months later. Internal examination and colonoscopy revealed a punctate colitis. The second patient presented with bloody stool 1 month after LEV initiation. Colonoscopy showed punctate colitis. In both patients gastrointestinal symptoms disappeared following tapering of LEV. DISCUSSION There are no reports in the literature describing colitis related to LEV intake. Three possible mechanisms of action are discussed. Colitis may be part of a hypersensitivity syndrome caused by LEV. Pharmacodynamic interactions with other anti-epileptic drugs, for example, carbamazepine may play a role. A haematological adverse event is another possibility since piracetam, a related molecule, has a known impact on erythrocytes and platelets. CONCLUSION The close temporal relationship between initiation of LEV intake, symptomatic colitis and clinical improvement following LEV tapering, suggests that colitis may be a possible and previously undescribed adverse effect of LEV.

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