Veerle De Herdt

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.

Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model

J. Neurochem. (2011) 117, 461–469.

Electrical stimulation for the treatment of epilepsy.

SummaryDespite 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 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.

A decade of experience with deep brain stimulation for patients with refractory medial temporal lobe epilepsy

In this study, we present long-term results from patients with medial temporal lobe (MTL) epilepsy treated with deep brain stimulation (DBS). Since 2001, 11 patients (8M) with refractory MTL epilepsy underwent MTL DBS. When unilateral DBS failed to decrease seizures by > 90%, a switch to bilateral MTL DBS was proposed. After a mean follow-up of 8.5 years (range: 67-120 months), 6/11 patients had a ≥ 90% seizure frequency reduction with 3/6 seizure-free for > 3 years; three patients had a 40%-70% reduction and two had a < 30% reduction. In 3/5 patients switching to bilateral DBS further improved outcome. Uni- or bilateral MTL DBS did not affect neuropsychological functioning. This open study with an extended long-term follow-up demonstrates maintained efficacy of DBS for MTL epilepsy. In more than half of the patients, a seizure frequency reduction of at least 90% was reached. Bilateral MTL DBS may herald superior efficacy in unilateral MTL epilepsy.

Effects of vagus nerve stimulation on pro- and anti-inflammatory cytokine induction in patients with refractory epilepsy

The role of the vagus nerve in controlling and modulating inflammatory responses under physiological conditions has been investigated. The purpose of this study is to assess changes in the immunological state evoked by vagus nerve stimulation in humans, by measuring cytokines produced by peripheral blood mononuclear cells (PBMC). We compared induction of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha by lipopolysaccharide (LPS)-stimulated PBMC which were isolated from patients treated with vagus nerve stimulation for refractory epilepsy. We observed a significant decrease in IL-8 induction by LPS-stimulated PBMC after 6 months of vagus nerve stimulation in comparison to the pre-stimulation state. No significant changes were seen in the induction of IL-1beta, TNF-alpha, IL-6 or IL-10. The present study shows that cytokine induction by PBMC isolated from patients with refractory epilepsy is altered by long-term vagus nerve stimulation.

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 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.

Efficacy of vagus nerve stimulation for refractory epilepsy among patient subgroups: A re-analysis using the Engel classification

Optimal candidates for VNS as a treatment for refractory epilepsy have not been identified. In this retrospective two-center study, we used the Engel classification for evaluating seizure outcome, and tried to identify predictive factors for outcome by means of subgroup analysis. The medical records of patients who have been treated with VNS for at least one year at Dartmouth-Hitchcock Medical Center and Ghent University Hospital were evaluated. Seizure frequency outcome was assessed using the Engel classification for the study population as a whole, and for patient subgroups with regard to mental functioning, seizure type, predisposing factors for developing epilepsy, age at time of VNS implantation and epilepsy duration. 189 patients (102M/87F) were included in the study (mean FU: 41 months). 6% had a class I outcome (seizure-free), 13% a class II outcome (almost seizure-free), 49% a class III outcome (worthwhile improvement) and 32% had a class IV outcome (no improvement). When patients were divided into specific subgroups, a statistically significant better outcome was found patients with normal mental functioning (p=0.029). In our series, results for VNS are clearly inferior to resective surgery, but comparable to other treatment modalities for refractory epilepsy. With combined class I and II outcomes around 20%, and another 50% of patients having worthwhile improvement, VNS is a viable alternative when resective surgery is not feasible.

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 Alzheimers disease seem promising but need to be further investigated.