Vagus nerve stimulation for epilepsy, clinical efficacy of programmed and magnet stimulation.

RATIONALE: Vagus nerve stimulation (VNS) by intermittent and programmed electrical stimulation of the left vagus nerve in the neck, has become widely available. It is an effective treatment for patients with refractory epilepsy. Patients can be provided with a magnet that allows to deliver additional stimulation trains. Since earlier studies have demonstrated the persistence of a stimulation effect after discontinuation of the stimulation train, we evaluated the clinical efficacy of VNS both in the programmed intermittent stimulation mode and magnet stimulation mode. METHODS: A group of 30 patients (16 F, 14 M) with medically refractory partial epilepsy, who were unsuitable candidates for resective surgery, were included in the study. The patients, their companions and caregivers were instructed on how to administer additional stimulation trains using a hand-held magnet when an aura or a seizure onset occurred. Patients or caregivers could recognize habitual seizures and were able to evaluate sudden interruption of these seizures. Using seizure diaries, detailed accounts of magnet use and regular clinic follow-up visits, data on seizure frequency and severity and number of magnet applications were collected. Patients who provided unreliable information were excluded from the analysis. RESULTS: Forty-seven percent of all patients had an improvement in seizure control with a reduction in seizure frequency of more than 50% during a mean follow-up of 33 months (range: 4-67 months). More than half of the patients used the magnet and provided reliable information. In 63% of patients who were able to self-administer or receive additional magnet stimulation, seizures could be interrupted, be it consistently or occasionally. More than half of the patients who reported a positive effect of magnet stimulation became responders. In most cases the magnet was applied by a caregiver. CONCLUSIONS: To our knowledge, this study is the first to explore the efficacy of magnet-induced vagus nerve stimulation. Results suggest that the magnet is a useful tool that provides patients and mainly caregivers with an additional means of controlling refractory seizures. Additional controlled studies comparing programmed stimulation and magnet-induced stimulation in monitoring conditions are warranted.

Direct medical costs of refractory epilepsy incurred by three different treatment modalities: a prospective assessment.

PURPOSE: More than 20% of epilepsy patients have refractory seizures. Treatment options for these patients include continued polytherapy with/without novel antiepileptic drugs (AEDs), epilepsy surgery (ES), or vagus nerve stimulation (VNS). The purpose of this study was prospectively to compare epilepsy-related direct medical costs (ERDMCs) incurred by these different treatment modalities. METHODS: Eighty-four patients underwent a complete presurgical evaluation protocol at our institution. As a result, 24 (29%) patients were treated with continued AED polytherapy only; 35 (40%) underwent ES; and 25 (30%) had VNS. In each patient, annual costs in the 2 years preceding the therapeutic decision (ERDMC-pre) and during the follow-up afterward (ERDMC-post) were prospectively calculated. Furthermore, frequency of complex partial seizures with/without secondary generalization (CPS+/-SG), dosage and number of AEDs, number of hospital admission days, clinic visits, and laboratory tests before and after the therapeutic decision also were prospectively assessed. ERDMC-pre and ERDMC-post were compared in and among the three treatment groups. RESULTS: In patients conservatively treated with AEDs, mean frequency of CPSs decreased from 12 per month to nine per month, whereas mean ERDMCs decreased from $2,525 U.S. to $2,421 U.S. In surgical patients, mean seizure frequency decreased from six to fewer than one per month; mean ERDMCs per year decreased from $1,465 U.S. preoperatively to $1,186 U.S. postoperatively. In the VNS group, mean seizure frequency decreased from 21 per month to seven per month. ERDMCs in this subgroup decreased from $4,826 U.S. to $2,496 U.S. Mean seizure frequency changes were significant when conservatively treated patients were compared with surgically treated and VNS patient groups (chi2 test, p<0.001 and p=0.0019, respectively). ERDMC changes in conservatively treated patients also were statistically significant when compared with surgically treated and VNS patients (chi2 test, p=0.0007 and p=0.0036, respectively). No statistically significant differences were found in ERDMC changes between the surgical and VNS groups (chi2 test, p=0.387). CONCLUSIONS: Ongoing daily treatment of patients who underwent resective surgery costs significantly less than conservative treatment. For patients in whom resective surgery is not an option, ERDMC show a significant decrease in VNS-treated patients compared with conservatively treated patients.

Vagus nerve stimulation for refractory epilepsy.

Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Since the first human implant in 1989, more than 10 000 patients have been treated with VNS. Two randomized controlled studies have shown a statistically significant decrease in seizure frequency during a 12-week treatment period versus a baseline period when 'high stimulation' mode was compared with 'low stimulation' mode. The efficacy appears to increase over time. In general, one third of the patients show a >50% reduction of seizure frequency; one third show a 30-50% seizure reduction, and one third of patients show no response. Few patients become seizure-free. Side effects during stimulation are mainly voice alteration, coughing, throat paraesthesia and discomfort. When studied on a long-term basis, VNS is an efficacious, safe and cost-effective treatment not only in adults but also in children and the elderly. The precise mechanism of action remains to be elucidated. In recent years much progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in animals and patients treated with VNS. Further elucidation of the mechanism of action of VNS may increase its clinical efficacy and our general understanding of some physiopathological aspects of epilepsy. Finally, VNS may become an alternative treatment for other conditions such as depression and pain.

The mechanism of action of vagus nerve stimulation for refractory epilepsy: the current status.

Vagus nerve stimulation (VNS) is a neurophysiologic treatment for patients with medically or surgically refractory epilepsy. Since the first human implant in 1989, more than 10,000 patients have been treated with VNS. The precise mechanism of action remains to be elucidated. Animal experiments with VNS were initially performed to demonstrate efficacy and safety preceding the clinical trials in human patients. Mechanism of action research involving animal experiments can provide essential clues. Animal experiments are often labor-intensive even in the hands of experienced researchers, however, and the results remain only a reflection of the complicated pathophysiologic systems of the human brain. Mechanism of action research in human patients treated with VNS is particularly challenging because of safety concerns, the large number of patients required, and the heterogeneous nature of various small patient series. This study provides an overview of the progress that has been made in the past 10 years through neurophysiologic, neuroanatomic, neurochemical, and cerebral blood flow studies in animals and patients treated with VNS. Further elucidation of the mechanism of action of VNS may increase its clinical efficacy. It may also provide inspiration for the development of new therapeutic modalities for refractory epilepsy.

Deep brain stimulation of the globus pallidus pars interna in advanced Parkinson's disease.

Pallidotomy is now widely performed for the treatment of advanced Parkinson's disease (PD). Preliminary reports of the effect of globus pallidus pars interna deep brain stimulation (GPi DBS) have also been promising. We have analyzed a cohort of 22 consecutive patients enrolled in a multicenter study. Surgery was bilateral in 17 and unilateral in five patients. At 6-month follow-up, the bilaterally GPi-implanted patients demonstrated a marked improvement when examined after drug withdrawal ("off") and under optimal medication ("on") using the Unified Parkinson's Disease Rating Scale (UPDRS). The benefit induced by the stimulation in the "off" medication condition in the total motor score was 31% and in the activities of daily living (ADL) scores was 39%. During the "on" medication period, the reduction in the total "on" dyskinesias score was 66% and in the ADL score was 32%. A similar pattern of improvement was seen in the group of patients with unilateral GPi stimulation, although a second cohort of 12 patients not included in the multicenter study showed greater improvements in "on" motor functioning. Although the effect of DBS is predominantly reversible, electrode insertion alone resulted in measurable clinical effects in the absence of stimulation. Thus, at 6-month follow-up, the benefit observed without stimulation was up to 44% in the "on" dyskinesias score and 29% in timed tapping scores undertaken in the "off" medication state. Complications among 34 patients from all centers included perioperative infection (n=3), hardware fracture (n=2), and premature battery failure (n=3). These results show a positive antiparkinsonian effect of pallidal DBS. No specific complications were observed with bilateral procedures.

99Tc(m)-ECD SPET perfusion changes by internal pallidum stimulation in Parkinson's disease.

High-frequency stimulation of the internal pallidum is an effective surgical approach for patients with advanced Parkinson's disease suffering from motor fluctuations and L-dopa induced dyskinesia. To study the acute effects of internal pallidum stimulation, changes in cerebral blood flow were measured by means of a single-day split-dose protocol using 99Tc(m)-ECD SPET. Nine patients with advanced Parkinson's disease and with a clinical picture predominated by tremor and drug-induced dyskinesia, were imaged before and immediately after electrostimulation. Brain perfusion data were mirrored to the same electrode side (five left and four right implants), co-registered and analysed statistically on a voxel-by-voxel basis (Statistical Parametric Mapping) and by an automated volume-of-interest approach. Acute stimulation of the internal pallidum induced a significantly decreased perfusion in the ipsilateral thalamus and striatum, as well as in the right parietal cortex. For the subgroup of seven patients with effective motor score improvements, a significant correlation between thalamic and striatal perfusion changes and UPDRS III motor score was present (P = 0.04). These results suggest that effective stimulation of the internal globus pallidus may produce symptom relief through decreased activity in pallido-thalamo-cortical circuits.

Vagus nerve stimulation for medically refractory epilepsy; efficacy and cost-benefit analysis.

INTRODUCTION: Vagus nerve stimulation is a novel treatment for patients with medically refractory epilepsy, who are not candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. To date only studies with relatively short follow-up are available. In these studies efficacy increased with time and reached a maximum after a period of 6 to 12 months. Implantation of a vagus nerve stimulator requires an important financial investment but a cost-benefit analysis has not been published. PATIENTS AND METHODS: Our own experience with VNS in Gent comprises 15 patients with mean age of 29 years (range: 17-44 years) and mean duration of epilepsy of 18 years (range: 4-32 years). All patients underwent a comprehensive presurgical evaluation and were found not to be suitable candidates for resective epilepsy surgery. Mean post-implantation follow-up is 24 months (range: 7-43 months). In patients with follow-up of at least one year, efficacy of treatment in terms of seizure control and seizure severity was assessed one year before and after the implantation of a vagus nerve stimulator. Epilepsy-related direct medical costs (ERDMC) before and after the implantation were also compared. RESULTS: A mean reduction of seizure frequency from 14 seizures/month (range: 2-40/month) to 8 seizures/month (range: 0-30/month) was achieved (Wilcoxon signed rank test n = 14; p = 0.0016). Five patients showed a marked seizure reduction of > or = 50%; 6 became free of complex partial seizures, 3 of whom became entirely seizure free for more than 12 months; 2 patients had a worthwhile reduction of seizure frequency between 30-50%; in 2 patients seizure frequency reduction has remained practically unchanged. Seizure freedom or > or = 50% seizure reduction was achieved within the first 4 months after implantation in 6/11 patients. Before the implantation, the mean yearly epilepsy-related direct medical costs per patient were estimated to be 8830 US$ (n = 13; range: 1879-31,129 US$; sd = 7667); the average number of hospital admission days per year was 21 (range: 4-100; sd = 25.7). In the 12 months after implantation, ERDMC had decreased to 4215 US$ (range: 615-11,794 US$; sd = 3558) (Wilcoxon signed rank test n = 13; p = 0.018) and the average number of admission days to 8 (range: 0-35) (Wilcoxon signed rank test n = 13; p = 0.023). CONCLUSION: VNS is an effective treatment of refractory epilepsy and remains effective during long-term follow-up. Cost-benefit analysis suggests that the cost of VNS is saved within two years following implantation.

Changes in quality of life following unilateral pallidal stimulation in Parkinson's disease.

Twenty patients with Parkinson's disease (age range 38-70 years) completed the Sickness Impact Profile (SIP) 2 months before and 3 months after long-term high-frequency electrostimulation of the globus pallidus internus to improve clinical symptoms. The SIP provides an estimate of perceived quality of life on 12 health-status categories. Neurological assessment with the Hoehn and Yahr scale and the Unified Parkinson's Disease Rating Scale revealed a significant postoperative reduction in clinical symptomatology (p<0.001). The patients experienced a general improvement in self-reported quality of life that exceeded the purely motor and physical aspects of quality of life. The significant postoperative drop in perceived impairment of communication skills can be considered the most important subjective improvement. Longitudinal research on a larger sample of patients is necessary to evaluate the durability of the subjective improvement in quality of life after unilateral pallidal stimulation.

Cognitive outcome after unilateral pallidal stimulation in Parkinson's disease.

OBJECTIVES: Chronic high frequency electrostimulation of the globus pallidus internus mimics pallidotomy and improves clinical symptoms in Parkinson's disease. The aim of this study was to investigate the cognitive consequences of unilateral deep brain stimulation. METHODS: Twenty non-demented patients with Parkinson's disease (age range 38-70 years) were neuropsychologically assessed 2 months before and 3 months after unilateral pallidal stimulation. The cognitive assessment included measures of memory, spatial behaviour, and executive and psychomotor function. In addition to group analysis of cognitive change, a cognitive impairment index (CII) was calculated for each individual patient representing the percentage of cognitive measures that fell more than 1 SD below the mean of a corresponding normative sample. RESULTS: Neurological assessment with the Hoehn and Yahr scale and the unified Parkinson's disease rating scale disclosed a significant postoperative reduction in average clinical Parkinson's disease symptomatology (p<0.001). Repeated measures multivariate analysis of variance (using right/left side of stimulation as a between subjects factor) showed no significant postoperative change in cognitive performance for the total patient group (main effect of operation). The side of stimulation did not show a significant differential effect on cognitive performance (main effect of lateralisation). There was no significant operation by lateralisation interaction effect. Although the patients experienced significant motor symptom relief after pallidal stimulation, they remained mildly depressed after surgery. Analysis of the individual CII changes showed a postoperative cognitive decline in 30% of the patients. These patients were significantly older and took higher preoperative doses of levodopa than patients showing no change or a postoperative cognitive improvement. CONCLUSIONS: Left or right pallidal stimulation for the relief of motor symptoms in Parkinson's disease seems relatively safe, although older patients and patients needing high preoperative doses of levodopa seem to be more vulnerable for cognitive decline after deep brain stimulation.