Vagus nerve stimulation for treatment of seizures?
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Double-Blind Method↗
Biomedical subjects
E Ben-Menachem
Publications and source records attributed to E Ben-Menachem.
Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients.
Progressive myoclonic epilepsy (PME) syndromes are intractable to most antiepileptic drugs (AED). The course of these diseases, results in almost total dependency due to continuous myoclonias, repeated episodes of status epilepticus, ataxia and dementia. The need for new treatment strategies is therefore imperative. Zonisamide has previously been reported to be effective in two patients with PME. Case reports of seven patients (ages 19-42) with Unverricht-Lundborgs disease (ULD) and one Lafora Body Disease are presented. Zonisamide was given at doses of 100-600 mg/day for a period of 2 to 3 years. Concomitant AEDs were usually valproate and a benzodiazepine. Zonisamide dramatically reduced the amount of myoclonias and generalized seizures. In three of the cases, the initial dramatic effect on myoclonias wore off after 2-4 years of treatment but patients still experienced moderate efficacy for generalized tonic-clonic seizures. The dramatic reduction of stimulus sensitivity for light, touch and startle by zonisamide was sustained in all patients with ULD. Zonisamide may be a useful agent in the treatment of PME. Controlled clinical trials are warranted to further investigate the antiepileptic effects of this drug, in difficult to treat epileptic syndromes.
Adult↗
Clinical efficacy of topiramate as add-on therapy in refractory partial epilepsy: the European experience.
In three randomized, double-blind, placebo-controlled add-on European trials, target daily topiramate (TPM) dosages of 400, 600, and 800 mg/day (200, 300, and 400 mg bid) were evaluated in adults with refractory partial seizures with or without becoming secondarily generalized. Median reductions from baseline in monthly seizure rate were 41% with TPM 400 mg/day vs. 1% with placebo (n = 0.065), 46% with TPM 600 mg/day compared to -12% (a 12% increase) with placebo (p < or = 0.005), and 36% with TPM 800 mg/day versus -18% (an 18% increase) with placebo (p < 0.001). Differences between TPM and placebo with respect to percent responders (percent of patients demonstrating a 50% or greater reduction in seizures) significantly favored TPM (p < 0.05) at all three target dosages. Significant reductions in secondarily generalized tonic-clonic seizures compared to placebo were also observed with 400 mg/day (p = 0.002) and 800 mg/day (p < 0.05) of TPM. TPM appears to be a promising new antiepileptic drug for use as adjunctive therapy in adults with refractory partial epilepsy.
Adolescent↗
Topiramate: current status and therapeutic potential.
Topiramate (TPM) is a structurally unique, highly effective new antiepileptic drug (AED). Three mechanisms of action that may contribute to TPM anticonvulsant activity include modulation of voltage-dependent sodium channels, potentiation of gamma-aminobutyric acid (GABA)-induced chloride fluxes and blockade of kainate glutamate receptors. TPM is rapidly absorbed, has linear pharmacokinetics, a half-life of 20 - 30 h in the absence of hepatic-enzyme-inducing AEDs, and few pharmacokinetic interactions with other drugs. TPM is not extensively metabolised and is excreted renally. The most common adverse effects reported in controlled trials were mild to moderate in severity, mainly CNS-related, and occurred most frequently during the titration period when the TPM dosage was rapidly increased. Combined data from five double-blind, placebo-controlled trials showed TPM produced statistically significant reductions in seizures regardless of age, gender or baseline seizure frequency. Seizure control appears to be maintained with long-term TPM therapy; no evidence of tolerance was seen in patients receiving TPM for periods of up to 7 years. Preliminary findings on TPM as monotherapy for partial epilepsy and as adjunctive therapy for generalised tonic-clonic seizures of non-focal origin, Lennox-Gastaut syndrome, and partial epilepsy in children have been promising.
Journal Article↗
Cost analysis of epilepsy surgery and of vigabatrin treatment in patients with refractory partial epilepsy.
In this study the direct actual costs associated with epilepsy-related health care, treatment with the novel antiepileptic drug vigabatrin (gamma-vinyl GABA, GVG), epilepsy surgery evaluation (ESE) and epilepsy surgery were analysed in 52 patients with intractable partial epilepsy who were on a waiting-list for ESE while trying GVG. Sixty percent of the 52 patients obtained a reduction in seizure frequency of 50% or more with GVG. Of the twenty-one operated patients 57% became seizure free, 10% had more than 75%, 5% had 50-75% and 29% had less than 50% reduction of seizure frequency. Of the 17 patients who did not go through ESE (the "GVG responders"), the corresponding outcome was 6%, 59%, 29% and 6%. For the 14 patients who were neither operated nor GVG responders, the outcome was 0%, 0%, 36% and 64%. The mean yearly costs (expressed in 1991 prices) of epilepsy-related health care including antiepileptic drug treatment was US $1,594 the year before starting GVG therapy, and US $2959 the first year of GVG treatment including a mean yearly cost of GVG of US $1,572. The mean total cost for ESE and surgery was US $46,778 (N = 21), while the mean cost of ESE in patients evaluated but not accepted for surgery (N = 14) was US $24,054. Considering the costs for ESE and surgery in the whole patient series, the mean total cost of rendering one patient seizure free with surgery was US $110,000. Surgery is the most effective treatment option in selected cases of severe partial epilepsy. If its costs are distributed over the patient's expected lifetime, the yearly cost is comparable to the present yearly cost of medication with GVG. However, since many patients achieve satisfactory seizure control with GVG, and considering the risks of surgery, we consider it a rational policy to let patients try this drug (or another of the new generation of antiepileptic drugs) before entering ESE.
Adult↗
Double-blind, placebo-controlled study of topiramate in patients with refractory partial epilepsy.
The efficacy and safety of topiramate 400 mg/day as adjunctive therapy to traditional antieleptic drugs for partial onset seizures with or without secondary generalization were assessed in a double-blind, parallel-group, placebo-controlled trial. Forty-seven patients with at least one seizure per week during an 8 week baseline were randomly assigned to topiramate (N = 23) or placebo (N = 24) double-blind treatment for a 3 week titration and an 8 week stabilization period. Median percent reduction from baseline in monthly seizure frequency during the double-blind phase was not significantly greater in the topiramate group than in the placebo group (41% vs. 1%; P = 0.065). Nevertheless, other efficacy variables evidenced statistically significant differences in favor of topiramate: a greater number of treatment responders (> or = 50% reduction in seizures; 35% vs. 8%; P = 0.033); better investigator (P = 0.002) and patient (P = 0.021) global assessments; and greater reductions in secondarily generalized seizures compared to placebo (P = 0.002). The most commonly reported topiramate treatment-emergent adverse events were somnolence, fatigue, abnormal vision, weight decrease, and anxiety. Most adverse events were mild or moderate in severity. Among 7 withdrawals due to limiting adverse events, 6 were CNS-related (in 5 topiramate-treated patients). Results of this trial strongly suggest that topiramate 400 mg/day is effective and well tolerated in the treatment of refractory partial epilepsy.
Adolescent↗
Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial seizures.
In a double-blind, randomized, parallel-group trial, we compared topiramate (TPM) with placebo as add-on therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b.i.d)] or to the maximal tolerated dose if lower. Twenty-eight (28) patients were randomized to each treatment group. In the intent-to-treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo-treated patients and 43% of the patients treated with TPM experienced > or = 50% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75-100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentration, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM-treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefit/risk ratio of TPM in resistant partial epilepsy.
Adolescent↗
Expanding antiepileptic drug options: clinical efficacy of new therapeutic agents.
Results of double-blind, placebo-controlled, add-on trials of topiramate (TPM), lamotrigine (LTG), and vigabatrin (VGB) in refractory partial epilepsy were reviewed. In three European multicenter studies of TPM, the clinical efficacy of 400-, 600-, and 800-mg/day target dosages was demonstrated. In a similarly designed United States trial, LTG was significantly superior to placebo at a 500-mg/day dosage but not at a 300-mg/day dosage. A meta-analysis of a number of smaller trials of VGB suggests that a > or = 50% reduction in seizures is observed in approximately 45% of patients with refractory partial epilepsy. All of these newer antiepileptic drugs have shown efficacy in well-controlled trials and should contribute significantly to our ability to manage partial epilepsy.
Anticonvulsants↗
Modern management of epilepsy: Vagus nerve stimulation.
Vagus nerve stimulation (VNS) was first tried as a treatment for seizure patients in 1988. The idea to stimulate the vagus nerve and disrupt or prevent seizures was proposed by Jacob Zabarra. He observed a consistent finding among several animal studies which indicated that stimulation of the vagus nerve could alter the brain wave patterns of the animals under study. His hypothesis formed the basis for the development of the vagus nerve stimulator, an implantable device similar to a pacemaker, which is implanted in the left chest and attached to the left vagus nerve via a stimulating lead. Once implanted, the stimulator is programmed by a physician to deliver regular stimulation 24 hours a day regardless of seizure activity. Patients can also activate extra 'on-demand' stimulation with a handheld magnet. Clinical studies have demonstrated VNS therapy to be a safe and effective mode of treatment when added to the existing regimen of severe, refractory patients with epilepsy. Efficacy ranges from seizure free to no response with the majority of patients (> 50%) reporting at least a 50% improvement in number of seizures after 1.5 years of treatment. The side-effect profile is unique and mostly includes stimulation-related sensations in the neck and throat. The mechanism of action for VNS is not clearly understood although two theories have emerged. First, the direct connection theory hypothesizes that the anticonvulsant action of VNS is caused by a threshold raising effect of the connections to the nucleus of the solitary tract and on to other structures. The second is the concept that chronic stimulation of the vagus nerve increases the amount of inhibitory neurotransmitters and decreases the amount of excitatory neurotransmitters. Additional research into the optimal use of VNS is ongoing. Animal and clinical research have produced some interesting new data suggesting there are numerous ways to improve the clinical performance of vagus nerve stimulation as a treatment for refractory patients.
Adult↗
Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures.
Electrical stimulation of the vagus nerve (VNS) is a new method for the treatment of patients with medically intractable epilepsy. Sixteen patients, ten of whom participated in a larger multicenter double-blind trial on the efficacy of VNS in epilepsy, and six who participated in pilot studies, consented to participate in the present study. Ten patients received HIGH stimulation and six patients LOW stimulation for the 3-month trial. Cerebrospinal fluid (CSF) samples (16 ml) were collected both before and after 3 months of VNS. Amino acid and neurotransmitter metabolites were analyzed. Four patients responded to VS with more than a 25% seizure reduction after 3 months. Mean and median concentrations of phosphoethanolamine (PEA) increased in responders and decreased in nonresponders. Free GABA increased in both groups but more so in the nonresponders. After 9 months of VS (6-9 months on HIGH stimulation) 4 of 15 patients had more than 40% seizure reduction. There were significant correlations between seizure reduction and increases in asparagine, phenylalanine, PEA, alanine and tryptophan concentrations. Comparison between patients with HIGH or LOW stimulation showed a significant increase in ethanolamine (EA) in the HIGH group and a decrease in glutamine in the LOW group. All patients regardless of response or stimulation intensity showed significantly increased total and free GABA levels. A decrease in CSF aspartate was marginally significant. Other trends were decreases in glutamate and increases in 5-hydroxyindoleacetic acid. Chronic VNS appears to have an effect on various amino acids pools in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Seizure frequency and CSF parameters in a double-blind placebo controlled trial of gabapentin in patients with intractable complex partial seizures.
Gabapentin (GBP) is a non-protein-bound gamma amino acid which is not subjected to metabolic degradation in man. As part of a placebo-controlled double-blind study, patients suffering from intractable complex partial seizures with or without secondary generalization were followed with lumbar punctures at baseline and after three months of GBP treatment (900 mg/day or 1200 mg/day). Cerebrospinal fluid (CSF) was analyzed for concentrations of GBP, amino acids including GABA, homovanillic acid (HVA), and 5 hydroxyindoleacetic acid (5-HIAA). The results indicate that there were no changes in the selected amino acids, HVA, or 5-HIAA after GBP treatment. At steady state the CSF/plasma ratios of GBP ranged from 0.056 to 0.34, indicating that there may be some type of active out-transport of GBP across the blood-brain barrier. No linear relationship was observed between plasma and CSF levels in these patients.
Acetates↗
Vigabatrin.
gamma-Aminobutyric acid (GABA) was first proposed as a putative inhibitory neurotransmitter by Elliot and van Gelder in 1958. Since then, numerous efforts have been made to find ways to increase GABA at its receptor sites, based on the findings that decreased GABA results in convulsions in animals and that agents enhancing GABA-mediated functions can have antiepileptic effects. However, the relationship between GABA levels and seizures is not simple. Seizures can occur even in the presence of elevated GABA levels. Indeed, it is possible that regional biochemical differences in the brain can be important. The antiepileptic effects of GABA depend on the mechanism whereby GABA-mediated inhibition is enhanced. Since the 1970s, several compounds have been developed that are designed to act in some manner on the GABA system. These compounds affect GABA-mediated inhibition at different levels and appear to have varied effects, depending on their mechanism of action. To date, specific antiepileptic drugs (AEDs) with potential GABA-inhibitory effects have been designed either to have GABA agonist properties, to inhibit GABA catabolism, to inhibit GABA uptake, or to facilitate GABA release or facilitate GABAA receptor activity. Vigabatrin (VGB) was designed specifically to inhibit GABA transaminase and thereby increase the availability of GABA in the brain. Study data and clinical experience over the past 14 years have demonstrated VGB to be an effective AED.
Animals↗
International experience with tiagabine add-on therapy.
Tiagabine (TGB) hydrochloride is a novel antiepileptic drug (AED) that is a potent and specific inhibitor of gamma-aminobutyric acid (GABA) uptake into glial and neuronal elements. In accordance with medical and regulatory standards, the clinical development program for TGB as an AED has assessed the value of TGB in add-on treatment, focusing mainly on partial seizures, including secondarily generalized seizures. Five add-on, placebo-controlled trials and six noncomparative, open-label, long-term multicenter trials have been or are being conducted in Australia, Europe, and the U.S.A. The results of these trials, involving 2,261 patients, indicate that TGB has efficacy as add-on therapy in patients with epilepsy difficult to control with existing AEDs. Efficacy of TGB is also sustained with long-term treatment. A clear dose-response has been demonstrated, and the minimal effective dose level is 30 mg. TGB is also tolerated, and with long-term therapy no new or more severe types of adverse events develop. These studies have included a wide age range of patients, including adolescents and the elderly.
Adolescent↗
Airway effects of direct left-sided cervical vagal stimulation in patients with complex partial seizures.
Airway nerves have been implied in obstructive lung diseases for many years. In experimental animals, vagal stimulation produces several features of asthma, including airflow obstruction and airway plasma exudation. Vagal stimulation is a novel and effective therapy in patients with refractory epilepsy. We evaluated the airway response to left-sided cervical electrical stimulation using 1 Hz (low stimulation: 30 s, once every 90 min) and 30 Hz (high stimulation: 30 s, every 5 min) in a randomized double-blinded fashion for 3 months in epileptic patients participating in a phase two efficacy study. In eight patients with high stimulation and six with low stimulation, no effect on FEV1 (forced expiratory volume in 1 s) was seen over 3 months chronic stimulation. In a follow-up, up to 9 months, no further deterioration of lung function was observed. Of five patients without concomitant lung disease who consented to more extended experiments, one patient produced a reduction of FEV1 with variable frequency and current stimulation (10-87 Hz and 0.5-2.5 mA respectively). In one patient with obstructive lung disease, however, increased frequency and current stimulation led to a stimulation-dependent decrease in FEV1. After the addition of inhaled ipratropium bromide (160 micrograms, dry powder) to this patient, there was a clear improvement of baseline FEV1, but only a slight improvement of the stimulation-induced deterioration of FEV1. We conclude that long-term vagal stimulation in patients without concomitant lung disease does not induce any significant changes in FEV1. However, in patients with obstructive lung disease, intense vagal stimulation can cause a deterioration of lung function.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of long-term vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system--a case study.
A 32 year old patient with refractory complex partial seizures was treated with vigabatrin for 3.5 years. Before starting treatment and at 42 months, lumbar punctures were done and the CSF analyzed for amino acids including GABA. Although the patient experienced a 50% seizure reduction, he underwent a left sided temporal lobectomy, and the tissue sample was also analyzed for amino acid content. It was found that vigabatrin caused a three-fold increase in total and free GABA in both the tissue sample and CSF. There were no other significant changes in the other amino acids analyzed. Seizure reduction seen initially was maintained over the long-term observation period. The finding of a specific increase of GABA in brain tissue and CSF of this patient treated with vigabatrin provides additional support to the concept that the primary effect of vigabatrin is as a selective enzyme activated irreversible inhibitor of GABA transaminase.
Adult↗
Neurochemical effects of vagus nerve stimulation in humans.
An implanted stimulating device chronically stimulated the left cervical vagus nerve in epileptic patients. Cerebrospinal fluid concentrations of free and total gamma-aminobutyric acid, homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, glutamate, asparagine, serine, glutamine, glycine, phosphoethanolamine, taurine, alanine, tyrosine, ethanolamine, valine, phenylalanine, isoleucine, vasoactive intestinal peptide, beta-endorphin, and somatostatin were measured before and after 2 months of chronic stimulation in six patients. Significant increases were seen in homovanillic acid and 5-hydroxyindoleacetic acid in three patients, and significant decreases in aspartate were seen in five patients. These changes were associated with a decrease in seizure frequency.
Adult↗
Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin.
Gabapentin (GBP) is a neutral amino acid and a GABA analog which in animal experimental models has shown a broad anticonvulsant spectrum. To evaluate the penetration of GBP into the CSF in humans as well as its possible effects on free and total GABA, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), a special investigation was performed as part of a placebo controlled add-on study of GBP in partial epilepsy. At the end of the 3-month double-blind period, 5 patients on placebo were given a single oral dose of GBP. Four patients received 600 mg and 1 patient 1200 mg GBP. CSF was collected immediately before and at 6, 24 and 72 h after the single dose. 5 ml of plasma was collected at 1, 2, 3, 6, 12, 24, 48 and 72 h. Plasma concentrations and plasma elimination half-life (4-6 h) of GBP were in agreement with the results of previous studies. The CSF/plasma concentration ratio of GBP 6 h after drug was 0.1. After 24 h, GBP could only be recovered in the CSF of the patient given 1200 mg. The CSF/plasma ratio at that time was 0.3. Free and total GABA concentrations did not change, but CSF 5-HIAA and HVA increased at 24 and 72 h post dose. The CSF/plasma ratio of gabapentin is similar to that of other amino acids.
Acetates↗
Neurovascular microdysgenesis in a case of Unverricht-Lundborg's disease.
An 18 year old female presented with a characteristic clinical course of Unverricht-Lundborg's disease. She was treated with several antiepileptic drugs but never with phenytoin. This patient died quietly during sleep. Coronal sectioning of the fixed brain revealed a 10 mm large red-brown solid cortical-subcortical lesion in the mesial part of the right frontal lobe and a similar alteration measuring 4 mm in the centromedian nucleus of the left thalamus. Histologically the lesions displayed supernumerary irregularly oriented vessels, mainly capillaries, and, in the cortex, a markedly disturbed neuronal orientation and lamination. Numerous heterotopic nerve cells were found in the subcortical white matter, especially under the calcarine cortex. A similar vascular malformation was found in the pons. The neuropathological changes in Unverricht-Lundborg's disease have been described as non-specific atrophy of various neuronal populations, especially medial thalamic nuclei and Purkinje cells. The present case shows that the same clinical picture may be associated with multiple cerebral microvascular malformations and a disturbance in neuronal migration and organization which may be more generalized than appears in light microscopical sections.
Adolescent↗