Biomedical subjects

Tim De Smedt

Publications and source records attributed to Tim De Smedt.

4 recordsLinked to original sources

PubMed2006

Neuromodulation with levetiracetam and vagus nerve stimulation in experimental animal models of epilepsy.

Epilepsy is a neurological disorder consisting of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Epilepsy treatment is successful in the majority of the cases; however; still one third of the epilepsy patients are refractory to treatment. Besides the ongoing research on the efficacy of antiepileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic, neuromodulatory changes in the epileptic network. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. LEV acts rapidly on seizures in both animal models and humans. In addition, preclinical studies suggest that LEV may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in epilepsy models and patients with, in addition, a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two rodent models mimicking epilepsy in humans. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that treatment with LEV and VNS can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals.

Animals↗

PubMed2005

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.

Animals↗

PubMed2005

Chronic levetiracetam treatment early in life decreases epileptiform events in young GAERS, but does not prevent the expression of spike and wave discharges during adulthood.

PURPOSE: In Genetic Absence Epilepsy Rats from Strasbourg (GAERS), age-related absence seizures start to appear from postnatal day (PN) 30 concomitant with 'spike and wave discharges' (SWDs) appearing on cortical EEG recordings. The aim of this study was to investigate the effect of early chronic levetiracetam (LEV) treatment on the development of SWDs in young and adult GAERS. METHODS: From PN 23 until PN 60, LEV (54 mg/kg, i.p.) was administered once daily to GAERS (n=8), while control GAERS (n=7) received saline (0.9% NaCl, i.p.). All animals were implanted with four epidural EEG electrodes at PN 51. EEG was recorded for 3h daily, during the last 4 days of the treatment (PN 57-PN 60) and during 4 additional days after treatment had been terminated (PN 61-PN 64). The animals were monitored again at the age of 4 months (PN 120-PN 124), about 2 months after the last administration of LEV. RESULTS: During treatment, epileptiform events in the LEV group were significantly reduced (62%, P<0.05) in comparison with the control group. During the following 4 days, epileptiform events were reduced in the LEV group, with an average difference of 53% (P=0.064). Once the animals had reached adult age, there was no difference in epileptiform events between the LEV group and controls. CONCLUSION: In this study, chronic LEV administration induced a reduction in epileptiform events in young GAERS. This effect persisted to some extent after treatment cessation (PN 61-PN 64), which might indicate a slowing down of epileptogenic processes. However, at the age of 4 months all animals revealed a similar expression of epileptiform discharges.

Aging↗

PubMed2003

Neurostimulation for refractory epilepsy.

Neurostimulation is an emerging treatment for refractory epilepsy. To date the precise mechanism of action remains to be elucidated. Better insight in the mechanism of action may identify seizure types or syndromes that respond to such a treatment and may guide the search for optimal stimulation parameters and finally improve clinical efficacy. In the past ten years some progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in patients and animals undergoing vagus nerve stimulation (VNS). Interesting results have been found in VNS-treated patients that underwent evoked potential measurements, cerebrospinal fluid investigation, neuropsychological testing and PET, SPECT and fMRI testing. Desynchronisation of abnormal synchronous epileptic activity is one of the hypotheses on the mode of action that might primarily be responsible for an anti-seizure effect. There is however increasing evidence from research and clinical observation that VNS might establish a true and long-term anti-epileptic effect. It has been shown that VNS influences neurotransmission in the brain and provokes long-term changes in cerebral blood flow in areas crucial for epileptogenesis such as the thalamus and medial temporal lobe structures. Deep brain stimulation (DBS) for epilepsy has regained interest. Central nervous system structures known to play a key role in the epileptogenic network such as the thalamus and subthalamic nucleus have been targeted. Another approach is to target the ictal onset zone such as the medial temporal lobe. At Ghent University Hospital 10 patients have been treated with long-term amygdalohippocampal DBS. Several hypotheses have been raised for the mechanism of action of DBS for refractory seizures. Seizure reduction may be due to a microlesion caused by electrode insertion or by provoking a reversible functional lesion due to the effect of electrical current on hyperexcitable tissue. Neurophysiological techniques such as evoked potentials monitoring and intraoperative single unit potential recordings may guide correct electrode placement, individual DBS titration and elucidation of the mechanims of action of DBS for epilepsy.

Animals↗