eMedicine Specialties > Neurology > Seizures and Epilepsy

Vagus Nerve Stimulation

Author: Diego Rielo, MD, Staff Physician, Department of Neurology, Memorial Hospital West, Memorial Hospital Pembroke, Memorial Healthcare
Coauthor(s): Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Contributor Information and Disclosures

Updated: Feb 14, 2007

Introduction

An estimated 1% of the general population has epilepsy. In close to 30% of these patients, the epilepsy is intractable to medications, and many others have their seizures controlled at the expense of unacceptable adverse effects from pharmacotherapy. Before vagus nerve stimulation (VNS) became available, the only nonpharmacologic treatment option for refractory epilepsy was surgery. However, not all patients with medically refractory epilepsy are candidates for surgery. In addition, surgery is not always an option for medically refractory seizures.

On the other hand, VNS appears to have some effects in others disease processes such as treatment-resistant depression and cerebellar tremor in multiple sclerosis.

Historical Background

In 1934, before clinical EEG became available, Soma Weiss proposed that compression of the carotid sinus produced a direct cerebral response, causing syncope in human beings that is distinct from the effects of this stimulation on blood pressure or heart rate and not caused by loss of carotid artery blood flow. In 1938, Bailey and Bremer reported that vagal stimulation causes EEG changes. In 1951, Dell and Olson studied the route taken by the ascending influence from the nucleus of tractus solitarius (NTS). By stimulating the proximal end of the cut cervical vagus nerve, they identified evoked responses in the ventroposterior complex and intralaminar regions of the thalamus. Thus, for many years investigators have known the effects of vagal stimulation in the brain. Many subsequent experiments confirmed the effects of VNS on EEG (ie, low-frequency stimulation causes synchronization, high-frequency stimulation causes desynchronization).

In 1985, Zabara reported the effects of VNS on seizure control in animal studies. In 1988, Penry, Wilder, Ramsay, and colleagues performed the first implant of a vagal stimulating device into a human. Two pilot studies (E01, E02) were performed with 15 patients who each had a programmable stimulating device (the NeuroCybernetic Prothesis [NCP]) implanted. Follow-up was performed on 14 patients (one excluded because of surgical complications) for 14 and 35 months. The mean percentage of reduction in seizures was 46.6%. Adverse effects were limited to hoarseness and tingling in the neck when the vagus nerve was stimulated.

Because of these encouraging results, a randomized active control study (E03) was performed in 1992. In 1994, the European Community approved the use of VNS for seizure prevention and control. Other controlled studies were performed, including the pivotal E05. On July 16, 1997, the US Food and Drug Administration (FDA) approved the use of VNS as an adjunctive treatment for refractory partial-onset seizures in adults and adolescents older than 12 years. To date, probably more than 8000 people have been treated with VNS.

Mode Of Action

The precise mode of action of VNS, like that of the antiepileptic drugs (AEDs), is not known.

Areas possibly activated by VNS include the medulla, cerebellum, parabrachial nucleus, locus ceruleus, hypothalamus, thalamus (including the intralaminar and ventroposterior parvocellular nuclei), amygdala, hippocampus, cingulate gyrus, and contralateral somatosensory cortex.

VNS inhibits seizures in multiple animal models of epilepsy, including the maximum electroshock, penicillin, pentylenetetrazol, and 3-mercaptopropionic acid (an inhibitor of GABA synthesis and release) models. In animals, the anticonvulsant effect of VNS requires stimulation of C fibers, which is achieved with high-intensity, high-frequency stimulation; it produces desynchronization of the cortical EEG. Investigators have suggested that VNS increases seizure threshold by causing widespread release of GABA and glycine in the brain.

Ben-Menachem et al measured amino acid and neurotransmitter metabolite concentrations in cerebrospinal fluid (CSF) samples of patients on clinical trials of VNS before and 3 months after VNS placement. They found paradoxical results—patients assigned at random to low-frequency stimulation settings and patients whose seizures failed to respond to VNS had the greatest increase in free and total GABA levels in the CSF. On the other hand, free and total GABA levels were higher after long-term VNS; responders as well as patients who received VNS at high-stimulation settings showed increased ethanolamine concentrations.

In 1993, McLachlan posited that VNS decreased cortical epileptiform activity indirectly by influencing the reticular activating system. Krahl et al demonstrated that the anticonvulsant effect of VNS could be reduced experimentally by lesioning the locus ceruleus. Henry et al reported that VNS causes measurable changes in cerebral blood flow in the cerebellum, thalamus, and cortex and may activate inhibitory structures in the brain. As expected, the interpretations of these data are diverse.

Technical Aspects

The NeuroCybernetic Prosthesis (NCP; Cyberonics, Webster, Texas), a vagal nerve stimulator, is composed of a pulse generator; a bipolar VNS lead; a programming wand with accompanying NCP software for an IBM-compatible computer; a tunneling tool; and handheld magnets. The lead is attached to the left vagus nerve (midcervical portion) and delivers a biphasic current that continuously cycles between on and off periods. The programmable NCP generator is placed on the patient's chest (upper left side).

In the United States, the generator is set to 0 mA for the first 2 postoperative weeks, followed by an increase in the output current. Some centers initiate stimulation the day after implantation. Typically, the current output is adjusted to tolerance, using a 30-Hz signal frequency, with a 500-microsecond pulse width for 30 seconds of "on" time and 5 minutes of "off" time. These settings were used in double-blind controlled studies of patients who were assigned randomly to receive high levels of stimulation. The handheld magnets are used according to the patient's demand to interrupt or reduce the severity of an oncoming seizure. The patient or a companion may activate the generator by placing the supplied magnet on the patient's chest above the generator implant for several seconds.

The optimal range of device duty-cycles is poorly understood. A multicenter, randomized trial of 3 unique modes of VNS (7 seconds on and 18 seconds off [rapid cycle]; 30 seconds on and 30 seconds off; and 30 seconds on and 3 minutes off) indicates that the 3 duty-cycles were equally effective and supports the use of standard duty-cycles as initial therapy.

Clinical Data

Several short- and long-term studies of VNS have been performed. The results of 2 pilot studies (E01, E02) were mentioned already. The E04 study (1991) was a compassionate-use trial that included 116 patients with all seizure types, all intractable. Results included a 21.8% mean decrease in seizure frequency, with 29% having a reduction in seizure frequency of at least 50%.

The E03 and E05 studies were the first add-on, double-blind, active-control, and parallel-design trials. Both had similar population characteristics (ie, age >12 y, at least 6 seizures/mo, predominantly partial seizures, active treatment with 1 or 3 AEDs). In both studies, the treatment efficacy was assessed during 12 weeks.

The E03 study involved 114 subjects who were assigned randomly to receive either a high level of stimulation (n=54) or a low level of stimulation (n=60). The mean decrease in seizure frequency was 24% in the high-stimulation group and 6.1% in the low-stimulation (active control) group (P = 0.01). A reduction in seizure frequency of at least 50% was seen in 31% of the subjects in the high-stimulation group and 13% in the low-stimulation group (P = 0.02). The investigators of the E03 study noted that further improvements in efficacy might have occurred after the initial 3-month treatment period.

The pivotal E05 trial included 196 subjects who were assigned blindly to either the high-stimulation group (n=94) or low-stimulation group (n=102). The mean decreases in seizure frequency were 28% in the high-stimulation group and 15% in the low-stimulation group (P = 0.039). The reduction in seizure frequency was greater than 75% in 11% of patients in the high-stimulation group and in 2% of patients in the low-stimulation group (P = 0.01).

After completion of the acute phase of the E05 study, 195 patients were involved in a long-term prospective study in which the primary outcome was the percentage reduction in total seizure frequency at 3 and 12 months. Subjects originally randomized to the low-stimulation group were crossed-over to receive therapeutic stimulation, and the patients initially randomized to the high-stimulation group were maintained on high settings throughout the 12-month study. The median reduction in seizure frequency at 12 months after completion of the initial double-blind study was 45%. Of all the subjects, 35% had a reduction in seizures of at least 50%, and 20% had reduction in seizures of at least 75%. Other studies with 15-month follow-up (XE5 trial) and 5-year follow-up have been reported, with similar results.

More recently, Uthman et al in a 12-year retrospective review of the effectiveness of VNS in 48 patients with intractable partial epilepsy, found that the mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment.

The experience in children is limited, although a recent study by Saneto et al demonstrated the effectiveness of VNS in children younger than 12 years. They studied 43 children with medically intractable seizures (generalized, mixed, and partial) and achieved a median seizure reduction rate of 55%, of which 37% were at least a 90% reduction. All children but 5 were monitored for 12 months to more than 18 months.

Tolerability

The NCP device appears both mechanically and electrically safe. Electrical stimuli of no more than 14 V are delivered to the vagus nerve. The stimulation frequency that is used generally has not produced any tissue damage. Continuously holding the magnet over the generator turns off the stimulation. The NCP device is not affected by microwave transmission, cellular phones, or airport security systems.

In the E03 study, adverse effects experienced by more than 5% of patients in the high-frequency stimulation group were hoarseness (37%), throat pain (11%), coughing (7%), dyspnea (6%), paresthesia (6%), and muscular pain (6%). Only hoarseness occurred significantly more frequently with high stimulation than with low stimulation.

In the E05 study, adverse effects reported by more than 10% of the patients during the perioperative period were pain (29%), coughing (14%), voice alteration (13%), chest pain (12%), and nausea (10%). In the high-stimulation group, voice alteration/hoarseness, cough, throat pain, nonspecific pain, dyspnea, paresthesia, dyspepsia, vomiting, and infection were increased significantly from baseline.

These adverse effects have a negligible impact on the quality of life of treated patients and are reported as mild 99% of the time. The effects appear during stimulation and tend to diminish over time. Unlike AEDs, VNS has not been associated with adverse effects such as depression, fatigue, dizziness, insomnia, confusion, cognitive impairment, weight gain, or sexual dysfunction.

Indication

FDA indication: "... adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizure, which are refractory to antiepileptic medications."

Although the FDA indication for VNS excludes other types of epilepsy (ie, those without partial seizure), most epileptologists agree that the VNS indications are probably broader than that.

Conclusions

Studies have demonstrated that VNS is an effective therapy for medically refractory partial-onset seizures, with an approximate long-term decrease in mean seizure frequency of 40-50%, and a short-term decrease in mean seizure frequency of 20-30% in patients older than 12 years. Small studies in children also have demonstrated the effectiveness of VNS. Adverse effects (eg, hoarseness/voice changes, throat discomfort, cough, dyspnea) are mild, appear during stimulation, and tend to diminish over time. Thus, VNS can be described as a long-lasting, hassle-free, and on-demand therapy, with no interactions or black box warnings regarding potential life-threatening adverse effects.

Many questions remain unanswered, however, and a lot of work needs to be done. The mechanism of action of VNS is as well (or as poorly) understood as that of most AEDs. The available long-term studies are open-label studies, raising some doubts about their accuracy.

No studies have been performed in the following areas: monotherapy for milder or severe cases and identification of the most likely responder/perfect candidate for this type of therapy.

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.

Multimedia

(Enlarge Image)

Media file 1: The NeuroCybernetic Prosthesis (NCP) in place in the left chest wall. Image courtesy of Cyberonics, Inc.

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Media file 2: The NeuroCybernetic Prosthesis (NCP) generator, with the leads that are wrapped around the left vagus nerve. Image courtesy of Cyberonics, Inc.

Keywords

VNS, epilepsy, vagal nerve stimulation, vagus nerve stimulation, seizures, refractory epilepsy, seizure control, vagal nerve stimulator, vagal stimulating device, partial-onset seizures, vagus nerve stimulation treatment

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