The effect of high and low frequency cortical stimulation with a fixed or a poisson distributed interpulse interval on cortical excitability in rats.

Neurostimulation is a promising treatment for refractory epilepsy. We studied the effect of cortical stimulation with different parameters in the rat motor cortex stimulation model. High intensity simulation (threshold for motor response--100 µA), high frequency (130 Hz) stimulation during 1 h decreased cortical excitability, irrespective of the interpulse interval used (fixed or Poisson distributed). Low intensity (10 µA) and/or low frequency (5 Hz) stimulation had no effect. Cortical stimulation appears promising for the treatment of neocortical epilepsy if frequency and intensity are high enough.

Electrical stimulation for the treatment of epilepsy.

Despite the advent of new pharmacological treatments and the high success rate of many surgical treatments for epilepsy, a substantial number of patients either do not become seizure-free or they experience major adverse events (or both). Neurostimulation-based treatments have gained considerable interest in the last decade. Vagus nerve stimulation (VNS) is an alternative treatment for patients with medically refractory epilepsy, who are unsuitable candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. Although responder identification studies are lacking, long-term VNS studies show response rates between 40% and 50% and long-term seizure freedom in 5% to 10% of patients. Surgical complications and perioperative morbidity are low. Research into the mechanism of action of VNS has revealed a crucial role for the thalamus and cortical areas that are important in the epileptogenic process. Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies. There is little evidence-based information on rational targets and stimulation parameters. Amygdalohippocampal DBS has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Data from pilot studies suggest that chronic DBS for epilepsy may be a feasible, effective, and safe procedure. Further trials with larger patient populations and with controlled, randomized, and closed-loop designs should now be initiated. Further progress in understanding the mechanism of action of DBS for epilepsy is a necessary step to making this therapy more efficacious and established.

Vagus nerve stimulation for refractory status epilepticus.

We report on the long-term follow-up of a patient with refractory non-convulsive SE who was successfully treated with VNS. A 7-year old girl with a medical history of thrombosis in the right internal cerebral vein and right thalamic bleeding 8 days after birth, developed epilepsy at the age of 13 months. At the age of 6 she presented with a refractory non-convulsive SE. A vagus nerve stimulator was placed after 11 days of thiopental-induced coma. Three days after VNS implantation, the thiopental-induced coma was successfully withdrawn and electroencephalography showed normalization one week after start of VNS. After a follow-up of 13 months she remains seizure-free and AEDs have been partially tapered. This case illustrates a potential acute abortive effect with sustained long-term seizure reduction of VNS in a 7-year old girl who presented with refractory non-convulsive SE.

Thalamic and limbic involvement in the mechanism of action of vagus nerve stimulation, a SPECT study.

PURPOSE: To unravel the mechanism of action of neurostimulation as a treatment for seizures, functional neuroimaging tools allow minimally invasive research in humans. We performed single-photon emission computed tomography (SPECT) in patients with epilepsy, treated with vagus nerve stimulation (VNS). Changes in regional cerebral blood flow (rCBF) at the time of initial stimulation as well as after chronic treatment were correlated with long-term clinical efficacy. METHODS: In this pilot study, 27 patients (14 female and 13 male) who were treated with VNS at Ghent University Hospital for refractory epilepsy underwent a (99m)Tc-ECD (ethyl cystein dimer) SPECT activation study at the time the first stimulation train was administered. 12 patients underwent an additional (99m)Tc-ECD SPECT activation study 6 months later. Image acquisition was performed on a high-resolution triple-headed gamma camera. Significant rCBF changes were correlated with prospectively assessed clinical efficacy data. RESULTS: Significant rCBF changes were found in the thalamus, the hippocampus and the parahippocampal gyrus. Acute limbic hyper-perfusion and chronic thalamic hypo-perfusion correlate with positive clinical efficacy. CONCLUSIONS: Acute and chronic electrical stimulation of the vagus nerve induces rCBF changes that can be measured by SPECT on a group-basis. The thalamus and the limbic system are thought to play a key role in the mechanism of action of VNS.

Vagus nerve stimulation for refractory epilepsy: a Belgian multicenter study.

INTRODUCTION: Vagus nerve stimulation (VNS) is a symptomatic add-on treatment for patients with medically refractory epilepsy. It consists of continuous electrical stimulation of the left vagus nerve by means of a helical electrode and an implantable, programmable pulse generator. Currently, over 50,000 patients are treated with VNS worldwide. AIM: This uncontrolled, open-label retrospective study evaluates long-term outcome in patients treated with VNS for refractory epilepsy in seven different epilepsy centres in Belgium. METHODS: For the purpose of this study, a minimum of essential inclusion criteria were defined to collect relevant data. This limited the results to basic findings with regards to efficacy on the long term. Inclusion criteria were a follow-up of at least 12 months and a documented seizure diary before implantation and at maximum follow-up. Primary outcome measures were the reduction in mean monthly seizure frequency and the percentage of patients with a seizure reduction of at least 50% (responder rate). RESULTS: About 138 patients (67M/71F) had a mean age of 30 years (range 4-59) at time of implantation and a mean post-implantation follow-up of 44 months (range 12-120). The mean number of AEDs before implantation was 3 (range 1-5). About 117/138 patients had focal epilepsy, 21 patients had symptomatic generalised epilepsy. About 117/138 patients were older than 16 years, 21 patients were 16 or younger. At maximum follow-up, mean stimulation output current was 1.84mA (range 0-3.25). Mean number of AEDs at maximum follow-up remained unchanged. The overall reduction in mean monthly seizure frequency was 51%. Mean seizure frequency before implantation was 41 seizures/month (SD=61; range 1-300), mean seizure frequency after implantation at maximum follow-up was 7 seizures/month (SD=25; range 0-120). Responder rate was 59%. 13% of patients had a seizure frequency decrease between 30% and 50%. About 28% had a seizure frequency decrease of<30%. Seizure freedom was obtained in 12/138 patients (9%). CONCLUSIONS: The long-term experience with VNS in Belgium confirms that VNS is an efficacious adjunctive antiepileptic treatment for patients with refractory epilepsy.

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.

Vagus nerve stimulation and cognition.

Vagus nerve stimulation (VNS) has been developed as an add-on treatment for patients with refractory epilepsy. Based on the clinical observation of improved cognition in many epilepsy patients who received VNS, we reviewed the recent literature for evidence concerning the cognitive effects of this treatment. From most of these studies it seems that, with currently used stimulation parameters, the effects on memory are only of theoretical importance. However, some animal studies suggest positive effects on specific modalities of memory function. In studies in epilepsy patients, there is no evidence of adverse effects on cognition but clear-cut positive effects cannot be expected either. Preliminary results of VNS in the treatment of diseases associated with cognitive decline such as Alzheimer's disease seem promising but need to be further investigated.

Vagus nerve stimulation for refractory epilepsy: a transatlantic experience.

Vagus nerve stimulation (VNS) is an alternative treatment for medically or surgically refractory epilepsy. The long-term efficacy and safety of VNS were evaluated in a large patient series at Ghent University Hospital and Dartmouth-Hitchcock Medical Center. Between March 1995 and February 2003, seizure frequency and type as well as prescribed antiepileptic drugs and side effects were prospectively assessed in 131 patients treated with VNS in either center. Patients with a minimum follow-up duration of 6 months were included in the efficacy and safety analysis. A total of 118 of 131 implanted patients had a minimum postimplantation follow-up period of 6 months (mean, 33 months). The mean age of these patients was 32 years and the mean duration of refractory epilepsy was 22 years. The mean reduction in monthly seizure frequency in all patients was 55% (range, 0-100; SD = 31.6). Seven percent of patients were free of seizures with impaired consciousness, 50% of patients had a seizure frequency reduction of more than 50%, and 21% of patients were nonresponders. Fifteen patients reported stimulation-related side effects such as hoarseness or gagging. In a large patient series from two geographically distinct epilepsy centers located in two different continents, VNS proved to be efficacious and safe during long-term follow-up.

Are psychotic symptoms related to vagus nerve stimulation in epilepsy patients?

Four patients with refractory epilepsy presented with psychotic symptoms following treatment with vagus nerve stimulation (VNS) to control seizures. Besides its anti-epileptic effect VNS has been shown to have an effect on various cognitive and behavioural functions. VNS is known to increase alertness and reduce sedation, which is independent from seizure control. VNS has also been shown to positively affect cognition and to exert strong antidepressant effects. Co-morbidity in epilepsy often comprises psychiatric illnesses. Increased psychiatric symptoms have mainly been described in association with successful outcome following epilepsy surgery as a result of 'forced normalisation'. Different hypotheses on the underlying aetiology of VNS-induced psychotic symptoms other than the previously described 'forced normalisation' are discussed.