Intraoperative human vagus nerve compound action potentials.

OBJECTIVE: Although electrical stimulation of vagus nerve is used widely for treatment of epilepsy the electrophysiological properties of human vagus nerve are not well characterized. Our objective was to measure compound action potentials of human vagus nerve fiber groups intraoperatively by stimulation using a commercially available generator and electrode system (Neurocybernetic Prosthesis System, NCP). MATERIAL AND METHODS: During NCP implantation we recorded compound action potentials evoked by stimulating the left vagus nerve through the NCP bipolar lead. Current intensities were varied from 0.25 to 3.0 mA. RESULTS: Vagus nerve compound action potential components conducting in the A, Adelta, and C velocity ranges could be elicited using either the NCP pulse generator or by a standard evoked potential instrument. A fiber potentials were recordable in all nerves, and were activated by very low stimulus currents. Adelta and C fibers were less reliably elicited, with C fibers requiring the highest currents. CONCLUSIONS: Three clearly identified fiber populations can be identified using therapeutic electrical stimulation of the human vagus. Intraoperative measurements of NCP-induced action potentials may potentially provide a marker for therapeutic stimulation and better insight into mechanisms of vagus nerve stimulation (VNS) efficacy.

Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures.

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. METHODS: Patients with six or more complex partial or generalized tonic-clonic seizures enrolled in the pivotal EO5 study were prospectively evaluated for 12 months. The primary outcome variable was the percentage reduction in total seizure frequency at 3 and 12 months after completion of the acute EO5 trial, compared with the preimplantation baseline. Subjects originally randomized to low stimulation (active-control group) were crossed over to therapeutic stimulation settings for the first time. Subjects initially randomized to high settings were maintained on high settings throughout the 12-month study. RESULTS: The median reduction at 12 months after completion of the initial double-blind study was 45%. At 12 months, 35% of 195 subjects had a >50% reduction in seizures, and 20% of 195 had a >75% reduction in seizures. CONCLUSIONS: The efficacy of VNS improves during 12 months, and many subjects sustain >75% reductions in seizures.

Revision and removal of stimulating electrodes following long-term therapy with the vagus nerve stimulator.

BACKGROUND: A significant concern about vagus nerve stimulation therapy has been the disposition of the spiral stimulating electrodes once treatment is considered ineffective or is no longer desired. Because the electrodes are wrapped around the vagus nerve, there is the potential for nerve injury during their removal. METHODS: We attempted removal of the spiral stimulating electrodes from 10 patients who received long-term vagus nerve stimulation therapy for drug-resistant epilepsy. In some patients, replacement with electrodes was also performed for poorly functioning leads. RESULTS: The mean duration of electrode implantation was 3.7+/-2.2 years (range 1.1-7.3 years). In seven patients, the old electrodes were removed completely from the nerve. No adverse events occurred intraoperatively or postoperatively. CONCLUSIONS: Our results indicate that the spiral electrodes may be safely removed from the vagus nerve, even after the electrodes have been implanted for several years. The reversibility of lead implantation may enhance the attractiveness of vagus nerve stimulation therapy for patients with medically-intractable epilepsy.

Enhanced recognition memory following vagus nerve stimulation in human subjects.

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.

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.

Vagus nerve stimulation induces a sustained anticonvulsant effect.

PURPOSE: Stimulation of the vagus nerve can effectively abort several types of experimentally induced seizures in animals when administered near the time of seizure onset. Indirect evidence from human trials and animal studies suggests that the anticonvulsant effects of vagus nerve stimulation (VNS) extend beyond the duration of stimulation. We used the pentylenetetrazol model to determine whether VNS exerts a persistent anticonvulsant effect. METHODS: VNS (1 mA, 30 Hz, 500 microseconds pulse width) was administered continuously for 0.1, or 60 min, or intermittently (30 s on, 5 min off) for 60 min, to awake and freely moving animals. After the end of stimulation, pentylenetetrazol (50 mg/kg i.p.) was administered to induce seizures. Time-course studies were also performed, consisting of 60 min of VNS followed by pentylenetetrazol injection after 0, 3-, 5-, and 10-min intervals. RESULTS: The greatest anticonvulsant effect occurred after 60 min of continuous VNS, which prevented convulsions in four of 12 rats and reduced significantly seizure duration, the total number of seizures, and number of tonic seizures. Intermittent VNS was less effective than continuous stimulation for 60 min, but more effective than that for 1 min. The anticonvulsant effect declined in a time-dependent fashion after discontinuation of VNS, with return to nonstimulated control values by 10 min. CONCLUSIONS: The results of this study verify a persistent VNS-induced anticonvulsant effect and indicate that its efficacy is dependent on the cumulative stimulus duration.

Chronic vagus nerve stimulation increases the latency of the thalamocortical somatosensory evoked potential.

The Neurocybernetic Prosthesis (NCP) is a pacemaker-like device that has been designed to provide chronic intermittent vagus nerve stimulation. It is currently under study for the treatment of refractory partial onset epilepsy, and preliminary studies have indicated that partial onset seizures are improved by this therapy. The mechanisms by which it exerts its antiepileptic effect are not well understood. Although there are extensive pathways to the forebrain from the nuclei of the vagus nerve, the evidence that the NCP alters neural transmission outside the vagal system is limited. We prospectively examined somatosensory and brain stem auditory evoked potentials (BAEPs) in three patients receiving NCP implantation to determine if changes in these studies occur as a result of chronic vagus nerve stimulation. The results demonstrate a significant prolongation of the cervicomedullary to thalamocortical potential (N13-N20) interval on somatosensory evoked potential (SSEP) studies following activation of the device. No other significant changes were seen on SSEP or BAEP in the NCP implanted patients or normal controls. The findings suggest that chronic vagus nerve stimulation does alter neuronal networks outside of the brain stem vagus system, and may potentially provide a means to clinically monitor and titrate this therapy.

Repetition of audiogenic seizures in genetically epilepsy-prone rats induces cortical epileptiform activity and additional seizure behaviors.

Repetition of seizures appears to increase severity in a number of seizure models, but the nature of these severity increases has not been elucidated in naturally occurring genetic epilepsy models. The genetically epilepsy-prone rat (GEPR) is highly susceptible to many seizure provoking stimuli, and high intensity acoustic stimuli induce audiogenic seizures (AGS). The role of forebrain structures in AGS in the GEPR has not been clear, and the presence of cortical epileptiform EEG activity in the GEPR is controversial. The present study examined the effects of 21 daily AGS repetitions on behavior and EEG activity recorded from the cortex of two GEPR substrains that exhibit moderate (GEPR-3) or severe AGS (GEPR-9). The results indicated that AGS repetition induced seizure severity increases in both GEPR substrains and resulted in prominent cortical epileptiform EEG activity. The AGS behavioral patterns remained distinctly different in the two substrains throughout seizure repetition. In each substrain a different additional behavioral phase was expressed; the GEPR-9 exhibited post-tonic clonus, and the GEPR-3 exhibited facial and forelimb clonus. These findings indicate that seizure repetition results in expansion of the neuronal network subserving AGS to involve forebrain structures. The medial geniculate body and amygdala appear to be part of this expanded network, and long-term potentiation, which was reported in the pathway between the latter brain structures, may be involved. These data suggest that recruitment of forebrain structures into the AGS neuronal network appears to be essential for production of the additional ictal behaviors evoked by AGS repetition.