Robrecht Raedt

Endothelial Outgrowth Cells Are Not Derived From CD133 + Cells or CD45 + Hematopoietic Precursors

Objective—Two types of endothelial progenitor cells (EPCs), early EPCs and late EPCs (also called endothelial outgrowth cells [EOCs]), were described in vitro previously. In this report, we dissect the phenotype of the precursor(s) that generate these cell types with focus on the markers CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR2) that have been used to identify putative circulating endothelial precursors. We also included CD45 in the analysis to assess the relation between CD34+ hematopoietic progenitors (HPC), CD34+ endothelial precursors, and both in vitro generated EPC types. Addressing this issue might lead to a better understanding of the lineage and phenotype of the precursor(s) that give rise to both cell types in vitro and may contribute to a consensus on their flowcytometric enumeration. Methods and Results—Using cell sorting of human cord blood (UCB) and bone marrow (BM) cells, we demonstrate that EOC generating precursors are confined to a small CD34+CD45− cell fraction, but not to the CD34+CD45+ HPC fraction, nor any other CD45+ subpopulation. CD34+CD45+ HPC generated monocytic cells that displayed characteristics typical for early EPCs. Phenotypic analysis showed that EOC generating CD34+CD45− cells express VEGFR2 but not CD133, whereas CD34+CD45+ HPC express CD133 as expected, but not VEGFR2. Conclusion—EOCs are not derived from CD133+ cells or CD45+ hematopoietic precursors.

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…25 years later! What do we know about the effects on cognition?

VNS therapy was delivered to patients for the first time in 1988. After 25 years, insight in the antiepileptic and antidepressant mechanism of action of VNS has grown steadily. The effects on cognition and especially memory remain controversial. This review provides an elaborate overview of studies addressing cognition and describes potential underlying mechanisms for the reported effects. Short-term VNS has an effect on verbal memory recognition when administered at the correct timing and dosage. Chronic VNS resulted into a positive effect on the cognitive status in an Alzheimer population. Positive effect of chronic VNS in epilepsy or depression patients on global cognitive functioning are less convincing. Neither do the results reveal a negative effect which has major implications for chronic treatment of neurology patients. A cascade of neurochemical processes put in motion by changes in NE concentrations in reaction to stimulation of the vagal nerve may underlie the VNS-induced effects on cognition and memory. In Alzheimer pathology, NE may act as an anti-inflammatory agent on brainstem nuclei.

Ictal-onset localization through connectivity analysis of intracranial EEG signals in patients with refractory epilepsy.

Fifteen percent to 25% of patients with refractory epilepsy require invasive video–electroencephalography (EEG) monitoring (IVEM) to precisely delineate the ictal‐onset zone. This delineation based on the recorded intracranial EEG (iEEG) signals occurs visually by the epileptologist and is therefore prone to human mistakes. The purpose of this study is to investigate whether effective connectivity analysis of intracranially recorded EEG during seizures provides an objective method to localize the ictal‐onset zone.

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.

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.

Comparison of hippocampal Deep Brain Stimulation with high (130 Hz) and low frequency (5 Hz) on afterdischarges in kindled rats

Hippocampal Deep Brain Stimulation (DBS) is proposed as an experimental treatment for refractory epilepsy, but the optimal stimulation parameters are undetermined. High frequency hippocampal DBS at 130Hz is effective in both animals and patients with epilepsy. Low frequency stimulation (approximately 5Hz) is assumed to have anti-epileptic properties but the efficacy is highly debated. This animal study compares the effects of both stimulation modalities in kindled rats. Sprague Dawley rats (n=20) were fully kindled according to the Alternate Day Rapid Kindling-protocol. After a baseline kindling period, rats were divided into a high frequency group (HFS, 130Hz, n=11) and a low frequency group (LFS, 5Hz, n=9), both receiving 10 days of continuous DBS. During and after DBS, the seizure susceptibility of all rats was tested and the characteristics of the afterdischarges (ADs) were compared between both treatments. During HFS, AD threshold was higher (p<0.05) and at the stimulated site, AD latency was longer (p<0.01) than during baseline period. During LFS, a similar but smaller change was observed, but did not reach significance. The duration of the AD was not affected by either HFS or LFS. After termination of HFS, the effects on AD latency and AD threshold recovered to baseline. In conclusion, high frequency stimulation at 130Hz is more effective than LFS (5Hz) in affecting excitability in epileptic rats. This is reflected in a higher AD threshold and longer AD latency during application of stimulation.

Cell therapy in models for temporal lobe epilepsy

For patients with refractory epilepsy it is important to search for alternative treatments. One of these potential treatments could be introducing new cells or modulating endogenous neurogenesis to reconstruct damaged epileptic circuits or to bring neurotransmitter function back into balance. In this review the scientific basis of these cell therapy strategies is discussed and the results are critically evaluated. Research on cell transplantation strategies has mainly been performed in animal models for temporal lobe epilepsy, in which seizure foci or seizure propagation pathways are targeted. Promising results have been obtained, although there remains a lot of debate about the relevance of the animal models, the appropriate target for transplantation, the suitable cell source and the proper time point for transplantation. From the presented studies it should be evident that transplanted cells can survive and sometimes even integrate in an epileptic brain and in a brain that is subjected to epileptogenic interventions. There is evidence that transplanted cells can partially restore damaged structures and/or release substances that modulate existent or induced hyperexcitability. Even though several studies show encouraging results, more studies need to be done in animal models with spontaneous seizures in order to have a better comparison to the human situation.