Vagus nerve stimulation for the treatment of medically intractable seizures. Results of a 1-year open-extension trial. Vagus Nerve Stimulation Study Group.

BACKGROUND: Chronic vagus nerve stimulation (VNS) continues to be evaluated as an adjunctive treatment for medically intractable seizures. A previous randomized controlled trial of 114 patients demonstrated a significant decrease in seizure frequency during 3 months of VNS at effective stimulation levels. OBJECTIVE: To evaluate the efficacy of 1 year of VNS therapy for the treatment of medically refractory partial seizures and the relationship between initial and long-term response. PATIENTS AND METHODS: All patients exiting the randomized controlled study of VNS for treatment of medically refractory partial seizures were offered indefinite treatment extension as part of an open-label trial. One hundred (88%) of 114 patients completed 12 months of VNS treatment at effective stimulation levels. Fourteen patients discontinued VNS treatment prior to 1 year, principally because of the treatment's lack of efficacy. These 14 patients were retained in the present analysis using an intent-to-treat approach. Antiepileptic drug use was monitored throughout the trial. Seizure frequency was analyzed in 4 sequential 3-month treatment periods. RESULTS: Compared with pretreatment baseline, there was a significant decrease in seizure frequency during each of the 3-month treatment periods. Seizure frequency was reduced by a median of 20% during the first 3 months of VNS treatment and by 32% during stimulation months 10 through 12. Response during the first 3 months of VNS treatment was a statistically significant predictor of response at months 10 through 12. The observed reduction in seizure frequency was not explained by overall changes in antiepileptic drug use. CONCLUSIONS: The results indicate that VNS remains an effective adjunctive therapy for medically refractory partial seizures over a period of at least 1 year. Response during the first 3 months of treatment is predictive of long-term response.

Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial.

OBJECTIVE: To determine the efficacy and tolerability of tiagabine, a new antiepileptic drug (AED) that inhibits gamma-aminobutyric acid (GABA) uptake, at 3 dose levels vs placebo as adjunctive therapy in patients with intractable complex partial seizures (CPS). DESIGN: Randomized, double-blind, placebo-controlled study with a parallel-group, add-on design, starting with a 12-week unblinded baseline phase followed by a 20-week double-blind treatment phase. SETTING: Twenty-one US medical centers. PATIENTS: Patients (N = 297) aged 12 to 77 years, previously diagnosed as having CPS and receiving stable regimens of 1 to 3 hepatic enzyme-inducing AEDs; divalproex sodium or valproic acid was allowed in combination with any of these drugs. INTERVENTIONS: Placebo or tiagabine 4 times a day at 16, 32, or 56 mg daily. MAIN OUTCOME MEASURES: Median change in 4-week CPS frequency and adverse events. RESULTS: Median decreases in 4-week CPS frequency for the 32-mg (-2.2) and 56-mg (-2.8) tiagabine groups were significantly greater than for the placebo (-0.7) group (P = .03 and P < .03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a 50% or greater reduction in the frequency of CPS vs 4% in the placebo group (P = .002 and P < .001, respectively). Adverse effects were similar for placebo and tiagabine except for a significantly greater incidence of dizziness in the 32-mg tiagabine group, tremor in the 32- and 56-mg groups, abnormal thinking (usually mental lethargy or difficulty concentrating) in the 56-mg group, and depressed mood in the 16- and 56-mg groups. CONCLUSIONS: Tiagabine is efficacious and well tolerated as adjunctive therapy for CPS; there is a clear dose-response relationship.

Intramuscular use of fosphenytoin: an overview.

Phenobarbital, diazepam, lorazepam, and phenytoin are all currently used for the treatment of acute seizures, including status epilepticus. None of these drugs is considered ideal. Fosphenytoin is a new phenytoin prodrug that fulfills many of the properties of an ideal anticonvulsant drug. The safety, tolerance, and pharmacokinetics of intramuscularly administered fosphenytoin have been evaluated in three clinical trials involving patients requiring loading or maintenance doses of phenytoin. These investigations demonstrated that fosphenytoin is rapidly and completely absorbed after injection into muscle and is quickly converted to produce therapeutic phenytoin plasma concentrations within 30 min of administration. Plasma concentrations of phenytoin achieved with i.m. fosphenytoin exceeded those associated with an equimolar dose of oral phenytoin. i.m. fosphenytoin was well tolerated both locally and systemically. Only mild and transient reactions occurred at the injection site. The most common systemic adverse events reported--somnolence, nystagmus, dizziness, and ataxia--are side effects commonly seen with phenytoin and tended to be mild. Preexisting seizure disorders remained stable. Combination treatment with i.v. diazepam or lorazepam to attain rapid seizure control and i.m. fosphenytoin to maintain the anticonvulsant effect theoretically offers many advantages for control of acute seizures and should be studied.

Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine.

The finding of increased activity of the enzyme extracellular superoxide dismutase in four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type (PME-UL) prompted the addition of antioxidants to these patients' treatment regimen. After 6 months treatment with vitamin E, selenium, riboflavin, and zinc, there was some improvement in patient awareness and speech. N-acetylcysteine (NAC) is a sulfhydryl antioxidant that increases cellular glutathione and the activity levels of several antioxidant enzymes and has additional actions that contribute to its demonstrated efficacy in preventing or decreasing damage in models of neuronal toxicity. We treated the affected siblings with 4 to 6 grams a day of NAC in addition to the other antioxidants and magnesium. There has been a marked decrease in myoclonus and some normalization of somatosensory evoked potentials with NAC treatment. The patients were treated with NAC for up to 30 months with continued beneficial effects. NAC may prevent further deterioration in the clinical course of patients with PME-UL and may be indicated in other neurodegenerative conditions where excess free radical activity may contribute to disease progression.

Anosognosia and confabulation during the Wada test.

Feinberg et al. proposed that right-hemisphere-damaged stroke patients with anosognosia for hemiplegia (AHP) confabulate seeing stimuli on the left side but those without AHP admit to having inadequate visual information. This study examines the relationship between AHP and confabulation using selective anesthesia of the cerebral hemispheres. Seventeen patients with intractable epilepsy were tested during intracarotid methohexital infusion. For half of the trials, subjects were stimulated on their paretic hand with a material (sandpaper, metal, or cloth), and for the remaining trials they were not stimulated. The subjects were trained to use a pointing response to indicate if they been stimulated and the type of material they had felt. Admission of uncertainty was defined as pointing to a question mark. Confabulation was defined as any material response to a no-touch trial. During anesthesia of either hemisphere, subjects with and without AHP confabulated responses. The AHP and non-AHP groups did not differ in admission of uncertainty. Our results support the postulate that confabulation and AHP are independent disorders, and therefore confabulation cannot fully account for AHP.

Treatment of epilepsy by stimulation of the vagus nerve.

We treated 14 patients with medically refractory partial seizures by stimulation of the vagus nerve in two single-blind pilot studies. Patients received stimulation through an implantable, programmable NeuroCybernetic Prosthesis, consisting of a pulse generator and a lead-electrode assembly. The mean reduction in seizure frequency after 14 to 35 months of vagal stimulation was 46.6%. Of the 14 patients, five (35.7%) had a 50% or greater reduction in seizure frequency. Two patients, one of whom had had 10 to 100 seizures per day before stimulation, have been seizure-free for over 1 year. Adverse events were primarily limited to initial hoarseness and a tingling sensation at the electrode site in the neck when the device was activated. Most patients tolerated the device and stimulation well. There were no permanent adverse events. Some cases of medically refractory partial seizures are improved by vagal stimulation.

Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.

This study evaluated gabapentin monotherapy in 275 patients with medically refractory complex partial or secondarily generalized seizures who were taking one or two antiepileptic drugs (AEDs). Following an 8-week baseline, patients received randomized dosages of gabapentin (600, 1,200, or 2,400 mg/d) during a 26-week double-blind phase comprising 2 weeks gabapentin add-on therapy, an 8-week AED taper, and a 16-week gabapentin monotherapy period. Patients exited the study if they experienced a protocol-defined exit event. Results of outcome measures, including time to exit, completion rate, and mean time on monotherapy, showed no significant differences among dosage groups. Possible reasons for this lack of a dose-response relationship include withdrawal seizures and the limited range of gabapentin dosages studied. Overall, 20% of patients completed the study. Completion rates were higher among patients who had discontinued one AED (23%) than two AEDs (14%), and higher among patients who were not withdrawn from carbamazepine (27%) than among those who were (16%).

Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial.

OBJECTIVE: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. BACKGROUND: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. METHODS: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. RESULTS: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. CONCLUSIONS: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

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.

Absence of cortical white matter changes in three patients undergoing long-term vigabatrin therapy.

Chronic administration of the experimental antiepileptic drug vigabatrin (gamma-vinyl GABA) to animals has been shown to cause dose-dependent neuropathological changes characterized by a microvacuolation in specific white matter tracts. This finding has led to some concern as to whether similar pathologic changes might occur in patients taking this medication. Here we report on analysis of tissue specimens taken during neurosurgery from three patients undergoing chronic vigabatrin therapy (4 g/day). The first patient, a 34-year-old woman, had taken vigabatrin for 2 years prior to surgery, the second, a 50-year-old man, had taken the drug for 1 year, and a 34-year-old man had taken the drug for 5.3 years. For comparison, similar specimens were taken from three other patients not taking vigabatrin who were undergoing surgery for intractable epilepsy. Specimens from each subject were prepared in an identical manner and examined with light and electron microscopy. All specimens were examined in a blinded fashion. There was some minor nonspecific myelinic splitting seen in both controls and vigabatrin-treated patients but there was no evidence for any drug-induced lesions similar to that seen in experimental animals.

Intramuscular fosphenytoin (Cerebyx) in patients requiring a loading dose of phenytoin.

Fosphenytoin (Cerebyx), is a water soluble prodrug that is rapidly and completely converted to phenytoin. This study reports the injection-site tolerance and safety of intramuscular fosphenytoin (> 10 mg/kg doses) in 60 patients requiring a phenytoin loading dose. Patients received injections at single or multiple sites with volumes ranging from 4 to 30 ml per injection site. The majority of patients had no irritation (erythema, swelling, tenderness, bruising) or complaints of discomfort related to fosphenytoin injection either after injection (95%) or at follow-up (88%). Irritation, when reported, was mild in all cases. Forty of 60 patients (67%) reported transient side effects, primarily involving the central nervous system, such as nystagmus, dizziness or ataxia, which are commonly associated with phenytoin therapy. All patients received prescribed doses; no patient had an injection(s) stopped due to intolerance or side effects. No serious adverse events occurred with intramuscular fosphenytoin. In this study, intramuscular fosphenytoin was demonstrated to be a safe and well tolerated, and in many instances, a preferable alternative to other means of phenytoin loading.

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)

Vagus nerve stimulation for seizures.

It is agreed that 1% of the general population is afflicted with epilepsy and close to 30% of epilepsy patients are intractable to medications. In spite of a recent increase in the number of new medications that are available on the market, many patients continue to have seizures or their seizures are controlled at the expense of intolerable side effects. Resection epilepsy surgery is an alternative; however, not every intractable patient is a good candidate for this surgery. Additionally, it is only offered to a small fraction of these patients due to the lack of an adequate number of comprehensive epilepsy programs and financial support for such surgeries. Vagus nerve stimulation (VNS) is a novel adjunctive therapy that has recently become commercially available for intractable epilepsy. It is indicated as an add-on treatment for seizures of partial onset with or without secondary generalization in patients 12 years of age or older. The VNS system is comprised of a battery generator that delivers regular intermittent electrical stimuli programmed via menu-driven software and an interrogating wand. The generator is implanted in the left upper chest and connected to the left cervical vagus nerve via a pair of semi-circular helical electrodes wound around the vagus nerve and wires tunneled under the skin. Surgery is normally completed within 2 h under general anesthesia and the patient can go home within a few hours postoperatively. Experiments in humans began in 1988 with two single-blind pilot studies that demonstrated the feasibility and safety of this unconventional therapy. Following these studies, two multicenter, active-control, parallel, double-blind protocols showed a statistically significant reduction in partial onset seizures with reasonable and well-tolerated side effects. Adverse events related to VNS included voice alteration and a tingling sensation in the throat during stimulation only and a decrease in intensity over several weeks. Coughing during stimulation occurred normally when therapy was initiated and shortness of breath occurred mainly during exertion. Long-term follow-up suggests that reduction in seizure frequency and intensity is maintained over time. VNS is a novel adjunctive anti-epilepsy therapy that offers patients a better-tolerated option than medications in general and that is less invasive and extensive than resection surgery. Its efficacy may compare to novel potent anti-epilepsy drugs; however, VNS does not replace resection epilepsy surgery in selected patients in whom chances of seizure-free results are high (70-90%).

Gabapentin: pharmacokinetics, efficacy, and safety.

Gabapentin is a new antiepileptic drug (AED) with an attractive pharmacokinetic profile. It is absorbed by an active and saturable transport system, and has a high volume of distribution. Gabapentin is not bound to plasma proteins, does not induce hepatic enzymes and is not metabolized. At steady state, it has a half-life of 6-8 h, and is eliminated unchanged by renal route with a plasma clearance proportional to the creatinine clearance. It is devoid of significant drug-drug interactions when administered with the established AEDs or with oral contraceptives. Gabapentin used as an add-on AED significantly reduced the frequency of partial seizures and secondarily generalized tonic-clonic seizures in three large double-blind, placebo-controlled, parallel-group clinical trails. It is well tolerated, with transient somnolence and dizziness being the most frequent adverse effects. Although the mechanism of action of gabapentin is not fully established, there is strong evidence to suggest a novel mechanism of action. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy and is a welcome addition to the armamentarium of currently available AEDs for the treatment of patients with seizures of partial onset.

Abnormalities of antioxidant metabolism in a case of Friedreich's disease.

We report a patient with Friedreich's disease (FD) who exhibited abnormalities of antioxidant metabolism, including decreased levels of glutathione peroxidase, glutathione reductase, and selenium, and an increased lipid peroxide index. These abnormalities became normal after treatment with N-acetylcysteine, selenium, and low-dose vitamin E therapy. Treatment was associated with a decreased rate of clinical decline. FD is a neurodegenerative disorder that may be related to disturbed antioxidant metabolism; the disorder may be treatable with antioxidant compounds.

Calcified cystic lesions in a patient with epilepsy and progressive dementia.

A 67-year-old woman had intractable epilepsy and developed a progressive dementia with upper motor neuron signs over the last 6 years. Magnetic resonance imaging (MRI) revealed multiple areas of large calcified cysts, which increased in number and size over the last 3 years. Discussion includes the appearance of these lesions radiologically and pathologically, as well as their differential diagnosis and clinical significance, focusing on the increasing detection of these lesions with current imaging techniques.

Chaotic activity during iron-induced "epileptiform" discharge in rat hippocampal slices.

Low-dimensional chaotic dynamics have been suggested in the rat hippocampal slice during iron-induced epileptiform activity. The dimensionality of this chaotic activity has been found to be similar in slices bathed in the same ionic extracellular medium. Some slices also displayed a drop in dimensionality prior to the onset of seizure-like activity. We suggest that techniques of nonlinear dynamical analysis are a useful reverse-engineering tool for studying the in vitro brain slice. We further conclude that neuronal circuits capable of displaying chaotic activity could exist at the level of the in vitro brain slice.

Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy. METHODS: A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. Following a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin 600 mg/day administered twice daily (BID) or three times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing > or =50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population. RESULTS: Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID (p < or = 0.0001) and 44% for pregabalin BID (p < or = 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo (p < or = 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia. CONCLUSIONS: Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.

New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.

OBJECTIVE: To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared to carbamazepine (CBZ) in older patients with epilepsy. METHODS: This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. RESULTS: Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 +/- 4.83 microg/mL, LTG 2.87 +/- 1.60 microg/mL, CBZ 6.79 +/- 2.92 microg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% (p = 0.0002). Significant paired comparisons: LTG vs CBZ: p < 0.0001; GBP vs CBZ: p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% (p = 0.001). Significant paired comparisons: LTG vs CBZ: p < 0.0001; LTG vs GBP: p = 0.015. There were no significant differences in seizure free rate at 12 months. CONCLUSIONS: The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.

Emergency management of seizures: an overview.

The drugs currently used in the emergency management of seizures are chiefly phenytoin, phenobarbital, diazepam, lorazepam, and paraldehyde. The combination of intravenous phenytoin and lorazepam has the advantages of rapid onset of action, sustained efficacy, and freedom from drug interactions. The intermittent oral or rectal administration of diazepam is especially useful for acute home treatment of recurrent seizures. Phenytoin prodrug (ACC-9653), an investigational new drug, is promptly absorbed after intramuscular injection. Unlike phenytoin, it does not require propylene glycol and high alkalinity for solubility and therefore does not produce soft-tissue injury after parenteral administration. It appears to be close to an ideal drug for the emergency management of seizures.