V. De Herdt

Early seizures in intracerebral hemorrhage Incidence, associated factors, and outcome

Objective: In patients with spontaneous intracerebral hemorrhage (ICH), the occurrence of early seizures (ES) may be a prognostic marker. Therefore, we aimed to identify incidence, associated factors, and influence on outcome of ES in patients with ICH. Methods: Between November 2004 and March 2009, we prospectively recruited 562 consecutive adults with a spontaneous ICH (Prognosis of InTra-Cerebral Hemorrhage cohort). Patients with previous seizures (n = 40) were excluded. ES were defined as seizures occurring within 7 days of stroke onset, and their associated factors were identified with Cox regression. For a subgroup of onset seizures, we used logistic regression. Data influencing outcome (mortality at day 7 and month 6 and functional outcome at month 6) were studied using survival analyses. Results: ES occurred in 71 (14%; 95% confidence interval [CI] 11–17) of 522 patients (274 male; median age 72 years, interquartile range 58–79 years). The only factor associated with ES was cortical involvement of ICH (odds ratio [OR] = 2.06; 95% CI 1.28–3.31). Regarding onset seizures (n = 38) (7%; 95% CI 5–10), associated factors were previous ICH (OR = 4.76; 95% CI 1.53–14.84), cortical involvement (OR = 2.21; 95% CI 1.11–4.43), younger age (OR = 0.97 per 1 year increase; 95% CI 0.95–0.99), and severity of the neurologic deficit at admission (OR = 1.03 per 1 point increase in the National Institutes of Health Stroke Scale score; 95% CI 1.01–1.06). ES did not influence vital or functional outcome. Conclusions: ES are a frequent complication in patients with spontaneous ICH; however, their occurrence does not influence outcome at 6 months.

Vagal nerve stimulation--a 15-year survey of an established treatment modality in epilepsy surgery.

Neurostimulation is an emerging treatment for neurological diseases. Electrical stimulation of the tenth cranial nerve or vagus nerve stimulation (VNS) has become a valuable option in the therapeutic armamentarium for patients with refractory epilepsy. It is indicated in patients with refractory epilepsy who are unsuitable candidates for epilepsy surgery or who have had insufficient benefit from such a treatment. Vagus nerve stimulation reduces seizure frequency with > 50% in 1/3 of patients and has a mild side effects profile. Research to elucidate the mechanism of action of vagus nerve stimulation has shown that effective stimulation in humans is primarily mediated by afferent vagal A- and B-fibers. Crucial brainstem and intracranial structures include the locus coeruleus, the nucleus of the solitary tract, the thalamus and limbic structures. Neurotransmitters playing a role may involve the major inhibitory neurotransmitter GABA but also serotoninergic and adrenergic systems. This manuscript reviews the clinical studies investigating efficacy and side effects in patients and the experimental studies aiming to elucidate the mechanims of action.

Clinical experience with vagus nerve stimulation and deep brain stimulation in epilepsy

Patients with refractory epilepsy present a particular challenge to new therapies. Vagus nerve stimulation (VNS) for the control of intractable seizures has become available since 1989. VNS is a relatively noninvasive treatment. It reduces seizure frequency by > or =50% in 1/3 of patients; an additional 1/3 of patients experience a worthwhile reduction of seizure frequency between 30 and 50%. In the remaining 1/3 of the patients there is little or no effect. Efficacy has a tendency to improve with longer duration of treatment up to 18 months postoperatively. Deep brain stimulation (DBS) or direct electrical stimulation of brain areas is an alternative neurostimulation modality. The cerebellum, various thalamic nuclei, the pallidum, and, more recently, medial temporal lobe structures have been chosen as targets. DBS for epilepsy is beyond the stage of proof-of-concept but still needs thorough evaluation in confirmatory pilot studies before it can be offered to larger patient populations. Analysis of larger patient groups and insight in the mode of action may help to identify patients with epileptic seizures or syndromes that respond better either to VNS or to DBS. Randomized and controlled studies in larger patient series are mandatory to identify the potential treatment population and optimal stimulation paradigms. Further improvements of clinical efficacy may result from these studies.

Increased rat serum corticosterone suggests immunomodulation by stimulation of the vagal nerve

The role of the vagal nerve within the immune system has not been fully elucidated. Vagal afferents connect to several central nervous system structures, including the hypothalamus. We investigated the effect of vagal nerve stimulation (VNS) on serum corticosterone levels in rats. Corticosterone levels were measured following 1 h of high frequency (30 Hz) or low frequency (1 Hz) VNS in awake animals. There was a significant increase (p < 0.05) in serum corticosterone levels following 30 Hz VNS compared to 1 Hz VNS or sham stimulation. These results suggest an immediate effect of VNS on the hypothalamic pituitary-adrenal (HPA) axis and support the role of the vagal nerve in immunomodulation.

Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures

De Herdt V, De Waele J, Raedt R, Wyckhuys T, El Tahry R, Vonck K, Wadman W, Boon P. Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures. 
Acta Neurol Scand: 2010: 121: 271–276.
© 2009 The Authors Journal compilation

Intensity-dependent modulatory effects of vagus nerve stimulation on cortical excitability

Vagus nerve stimulation (VNS) is an effective treatment for refractory epilepsy. It remains unknown whether VNS efficacy is dependent on output current intensity. The present study investigated the effect of various VNS output current intensities on cortical excitability in the motor cortex stimulation rat model. The hypothesis was that output current intensities in the lower range are sufficient to significantly affect cortical excitability.

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.

Serial day rapid kindling is an effective tool in screening the anti-epileptic properties of topiramate

INTRODUCTION In this study, a serial day rapid kindling protocol was used to fully kindle rats in a matter of days. Subsequently, the anticonvulsant profile of a relatively new anti-epileptic drug, topiramate, was evaluated in a cross-over design to further validate this rapid kindling model. METHODS Rats were kindled during three consecutive days, according to the serial day rapid kindling protocol. Topiramate was tested at a dose of 100mg/kg, i.p., over the next 2 days using a cross-over design. The stability of the kindled state was evaluated in all rats during two retest paradigms. During the drug-testing procedure, rats received a single i.p. injection of either topiramate or verhicle. Starting 1 h later the rats received additional kindling stimulations during which their response was measured. RESULTS Serial day rapid kindling induced a long lasting and stable fully kindled state that allowed for the anti-epileptic drug screening procedure. Topiramate reduced both the afterdischarge duration and ameliorated seizure semiology in the kindled rats. DISCUSSION Serial day rapid kindling provided a tool to rapidly kindle rats in 3 days. Using a cross-over design, clear indications on anti-epileptic activity of a given drug can be determined using few laboratory animals.

Amygdalohippocampal Deep Brain Stimulation (Ah-DBS) for Refractory Temporal Lobe Epilepsy

Four patients had a left-sided focal medial temporal lobe onset. Three patients had a right-sided regional medial temporal lobe onset. One patient had a bilateral regional temporal lobe onset with predominant involvement of the left side. Two patients had a leftsided regional medial temporal lobe onset. Nine out of 10 patients had a >50% reduction of interictal spikes during the initial AH-DBS trial period. In one patient who showed very infrequent spiking, seizure frequency that had significantly decreased, was used as a criterion for implantation. One patient did not meet the chronic implantation criterion and underwent a selective amygdalo-hippocampectomy. Nine out of 10 patients were implanted with an internal generator. The mean follow-up in these patients was 16 months (range: 9–25 months). One patient has been free of complex partial seizures (CPS) for 2 years and has been tapered off 2 anti-epileptic drugs (AEDs). Another patient has become seizure-free in the past 9 months; 3/10 patients have a >50% reduction in seizure frequency; 3/4 patients have been taIntroduction

The effect of neuropeptide FF in the amygdala kindling model.

Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are differentially distributed throughout the central nervous system. NPFF reduces cortical excitability in rats when administered intracerebroventricularly (i.c.v.), and both NPFF and NPFF1R antagonists attenuate pilocarpine‐induced limbic seizures. In this study, our aim was to determine whether NPFF exerts anticonvulsant or anti‐epileptogenic effects in the rat amygdala kindling model for temporal lobe seizures.