Dean K. Naritoku

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.

Prospective Long-Term Study of Vagus Nerve Stimulation for the Treatment of Refractory Seizures

Summary: Purpose: To determine the long‐term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short‐term double‐blind trials have demonstrated its safety and efficacy, and one long‐term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long‐term study of VNS to date.

Vagus Nerve Stimulation: Analysis of Device Parameters in 154 Patients during the Long-Term XE5 Study

Summary:  Purpose: To determine the effect of changes in device settings and duty cycle (on and off times) on the efficacy of vagus nerve stimulation (VNS) for refractory epilepsy. In the long‐term XE5 study of VNS for intractable epilepsy, the median reduction in seizure frequency improved significantly after 1 year of follow‐up. A central question is whether device changes improve efficacy. We analyzed the effects of device parameter changes on seizure frequency in 154 subjects who completed the study and who had complete data for analysis.

Vagus nerve stimulation therapy for epilepsy in older adults

Article abstract The authors assessed the efficacy, safety, and tolerability of vagus nerve stimulation (VNS) for refractory epilepsy in 45 adults 50 years of age and older. They determined seizure frequency, adverse effects, and quality of life. At 3 months, 12 patients had a >50% decrease in seizure frequency; at 1 year, 21 of 31 studied individuals had a >50% seizure decrease. Side effects were mild and transient. Quality of life scores improved significantly with time.

Intravenous loading of valproate for epilepsy.

Valproate is an antiepileptic drug that has broad spectrum activity against several types of seizure. Little information is available about the use of valproate for acute loading of patients when a rapid increase in serum level is needed. We describe the use of intravenous valproate in 20 adults with epilepsy. In each case, a loading dose was calculated by multiplying the patients body mass, desired change in serum level, and estimated volume of distribution. The mean dose (+/- SD) administered was 1420 +/- 440 mg (19.4 +/- 5.4 mg/kg). In four patients, the dose was infused at 20 mg/min; in all other patients, infusions were performed at 50 mg/min. The infusions were tolerated well and few clinical side effects were observed. Postinfusion levels were drawn and the apparent volume of distribution was calculated to be 0.22 +/- 0.04 L/kg. The results indicate that intravenous valproate may be used to quickly and efficiently increase serum levels in patients with epilepsy.

Acute vagus nerve stimulation does not suppress spike and wave discharges in genetic absence epilepsy rats from Strasbourg.

We evaluated the efficacy of vagus nerve stimulation (VNS) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a validated model for absence epilepsy. In the first experiment, we investigated whether VNS applied at seizure onset can interrupt spike and wave discharges (SWD). In the second experiment, we investigated whether SWD are suppressed or shortened in duration when VNS is applied several hours per day. Both control and VNS groups underwent EEG and VNS electrode implantation. For the first experiment, a randomized crossover design was used. Stimuli (amplitude: 3 V; frequency: 30 Hz; pulse duration: 500 micros) were given when an SWD occurred on the EEG. The experiment was repeated the next day. In the second experiment, treated animals were stimulated (amplitude: 1.5 mA; frequency: 30 Hz; pulse duration: 500 micros; on/off time cycle: 30 s / 5 min) for 3h per day, during five consecutive days. In the first experiment, the duration of the SWD was increased on day 1, (P < 0.05). There was no difference in SWD duration on Day 2. In the second experiment, no significant differences could be found in number, duration and EEG frequency of SWD. VNS applied at the onset of an SWD can prolong the duration of SWD in GAERS. As a 5-day stimulation protocol had no effect, long-term VNS might be necessary to affect SWD.

Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: A randomized double-blind clinical trial

Purpose:  To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new‐onset epilepsy.

Effect of Cotherapy Reduction on Tolerability of Epilepsy Add-On Therapy: A Randomized Controlled Trial

BACKGROUND: Adverse effects are the most common cause for failure of an antiepileptic drug (AED), especially when an AED is added to existing therapy. With the increased drug load, it may not be possible to titrate the newly added AED to effective doses. Reducing the dosage of AED cotherapy as the new drug is introduced may improve tolerability. OBJECTIVE: To evaluate reduction of AED cotherapy as a strategy to improve tolerability and patient retention when a new AED is added to existing therapy. METHODS: In a 20-week, randomized, open-label study, topiramate was initiated as add-on therapy in adults and adolescents (⩾12 y of age) with inadequately controlled partial-onset seizures. Patients were randomized to receive treatment in which adverse events could be managed by adjustments in AED cotherapy (flex-dose group) or treatment in which AED cotherapy dosages remained fixed (fixed-dose group). Topiramate could be adjusted as needed in both groups. In the flex-dose group, patients exited randomized treatment when topiramate was discontinued. In the fixed-dose group, patients exited when AED cotherapy was reduced due to adverse events or when topiramate was discontinued. The primary study outcome was the percentage of patients exiting randomized treatment due to adverse events. RESULTS: The flex-dose group comprised 297 patients; 302 patients were in the fixed-dose group. Significantly fewer patients in the flex-dose group exited the study due to adverse events (16% vs 23% in the fixed-dose group; p = 0.02). In the flex-dose group, 10% (17 of 168) of patients discontinued topiramate due to adverse events after AED cotherapy was reduced versus 22% (29 of 129) when AED cotherapy was not reduced. CONCLUSIONS: Reduction of AED cotherapy is a useful strategy to improve tolerability and retention when topiramate is initiated as adjunctive therapy.

Core elements of epilepsy diagnosis and management: expert consensus from the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty

ABSTRACT Background: Although epilepsy is relatively common, only a limited number of specialized epilepsy centers exist in the United States. Therefore, epilepsy diagnosis and management frequently occur in the community setting. This can complicate patient management and suboptimal care is a potential concern. Delayed recognition and inadequate treatment increase the risk of subsequent seizures, brain damage, disability, and death from seizure-related injuries. To identify core elements of epilepsy management that should be offered to all patients, the Leadership in Epilepsy, Advocacy, and Development (LEAD) faculty assessed current practical issues and identified practices to improve patient care and outcomes. Scope: This paper presents a consensus opinion formed from a survey of 26 current LEAD faculty members, who answered 105 questions about epilepsy diagnosis and patient evaluation, treatment decisions, lifelong monitoring, and the management of special patient subgroups. Consensus agreement was concluded when ≥50% of the faculty provided the same answer. The results were compiled and areas of consensus are included in this report. The recommendations provided in this commentary are limited by the scope of the survey. Findings: Consensus was reached on several minimum standard patient management practices. Primary among these minimum standards of care is the need for diagnosis including a detailed medical history, neurological examination, discussions with caregivers, and diagnostic tests including electroencephalograms and magnetic resonance imaging. As the overall goals of therapy include seizure freedom, minimizing side effects, and improving quality of life and long-term safety, therapy decisions should consider parameters that affect these goals, including potential adverse effects of therapy. Antiepileptic drug selection should consider coexisting conditions for possible exacerbation of disease and potential drug–drug interactions. Conclusions: The core elements of epilepsy management identified here suggest minimum standards that can be used across all settings to improve consistency and quality of epilepsy diagnosis and care.