Vagus Nerve Stimulation for Epilepsy

May 2000; Volume 3; 53-56

By V. Jane Kattapong, MD, MPH

Illness is not something a person has. It’s another way of being.

Jonathan Miller

The Body in Question

Epilepsy wreaks havoc in people’s lives; patients with epilepsy have to get used to another way of life. They give up much of their independence. They often have to give up driving. They cannot swim alone. They frequently miss school and work. They must always remember to bring their medications with them when they are away from home, and to take their medications regularly. Children may have difficulty in school. Severely affected individuals may be completely disabled and unable to work at all because of the seizures themselves, post-ictal symptoms of lethargy or confusion, or the sedation from multiple seizure medications. Thus, living with epilepsy may amount to another way of being.

A decrease in seizure frequency or severity may enable people with refractory epilepsy to achieve some semblance of normality in their lives.1 Effective treatment of epilepsy may lessen the disability that patients experience. Vagus nerve stimulation (VNS) is one treatment modality that may decrease frequency and severity of seizures, as well as decrease the amount of sedating medications that patients must take.

Background

Epilepsy is generally defined as recurrent, unprovoked seizures.2 Epilepsy occurs commonly; the risk of developing epilepsy by age 80 has been reported to be 4%,3 and it affects 0.5-1.0% of the population.4 Epilepsy causes significant disability: Up to 50% of epilepsy patients experience either inadequate seizure control or disabling side effects of medication such as drowsiness, poor coordination, or poor concentration. Thus, disability from epilepsy occurs commonly.

Seizures are broadly classified as either generalized or partial in onset. Generalized seizures begin bilaterally in both hemispheres of the brain. Partial seizures have a localized onset and may evolve into generalized seizures.

What are the two broad classifications of seizure types?

a. Psychomotor and motor

b. Generalized and partial

c. Childhood and adult


Procedure

In VNS, intermittent stimulation is administered to the left vagus nerve in the neck. The VNS is delivered via the NeuroCybernetic Prosthesis (NCP®), a vagal nerve stimulation device developed by Cyberonics, Inc. (Houston, Texas) for the treatment of epilepsy.5 (See Figure 1.)

The device is a programmable signal generator which is implanted as an outpatient, or during an overnight admission, in the upper left chest. The generator is connected to a stimulating coil placed in close proximity to the left vagus nerve. Patients typically receive vagal nerve stimulation for 30 seconds every five minutes.6 Since the device is programmable, signal duration and frequency can be modified as needed. In 1997, FDA approved the device for use as adjunctive treatment for partial-onset seizures for people over 12 years of age.

Mechanism of Action

The mechanism of action of VNS for seizure control is not well understood. The vagus nerve normally supplies parasympathetic innervation to the pharynx, esophagus, trachea, bronchi, lungs, heart, stomach, small intestine, ascending and transverse colon, liver, and pancreas,7 and has an integral role in regulation of respiratory, digestive, and cardiac function.8

In addition, the vagus nerve provides the brain with visceral sensory information from the head, neck, thorax, and abdomen.2,9 The cell bodies of the vagus nerve sensory axons are contained in the nodoose ganglion. These cell bodies relay information to the nucleus of the solitary tract (NTS).2 One pathway of the NTS provides an ascending projection conveying visceral sensory information to the forebrain.10 This communication with the thalamocortical system may be the mechanism whereby VNS modulates seizure activity.

Vagus Nerve Stimulation in Adults

Long-term safety, tolerability, and efficacy of VNS were assessed in an open-label study of 454 patients with refractory epilepsy.3 All patients had had continued seizures despite medical therapy. All patients had an NCP implanted in the anterior chest.

During the study, patients continued using antiepileptic drugs (AEDs) as needed. About half of the study participants were male and half were female. The average age of participants was 31 years, and the average duration of epilepsy was 21 years. The average number of seizures per day at baseline was about two, and the average number of AEDs used was two. Significant (P < 0.0001) seizure reductions were seen at predetermined time intervals, including three months, one year, two years, and three years.

To minimize the potential bias resulting in patient attrition, a "last-visit-carried-forward" analysis was performed, considering the status at the last visit to be the current condition. At three years, 43% of patients remaining in the study had experienced a > 50% decrease in seizure frequency. At three years, the most common side effects reported were hoarseness (19.3%) and cough (5.9%). Serious adverse events were limited to severe hoarseness in three individuals and shortness of breath in three individuals. There were no deaths of study participants believed to be related to the VNS.

The total cost of VNS, including surgery and follow-up visits, is about $20,000 (personal communication, Cyberonics). This compares favorably with traditional epilepsy surgeries, such as temporal lobectomy, which can range from $20,000 to $100,000. Contraindications include the presence of a bilateral vagotomy or left cervical vagotomy.

The NeuroCybernetic Prosthesis (NCP®) delivers electrical stimulation to:

a. the right and left vagus nerves.

b. the right vagus nerve.

c. the left vagus nerve.

d. alternating right and left vagus nerves.


Vagus Nerve Stimulation in Children

Evidence is starting to accumulate suggesting that VNS may be efficacious in children. The Pediatric VNS Study Group evaluated the use of intermittent left vagal nerve stimulation in children with medication-resistant epilepsy.11

In this study, essentially a meta-analysis of two double-blind, controlled trials of VNS efficacy, 60 children between 31/2 and 18 with uncontrolled epilepsy were followed for up to 18 months. At 12 months, seizure reduction of 35% was found in 51 patients; and at 18 months, seizure reduction of 42% was found in 46 patients. Twenty-seven percent of patients had generalized tonic-clonic seizures, and 73% had partial-onset seizures. Differences in numbers between study enrollees and patients still enrolled at 18 months occurred because of patient dropout. However, an intent-to-treat analysis revealed little difference between analyses involving the entire group vs. the patients enrolled at the end of 18 months.

Of the group of patients who did not complete the study, three left because of lack of efficacy, one left because the device eroded through the skin, and one died of aspiration pneumonia (unrelated to the device). The study authors concluded that VNS is a safe, effective adjunctive therapy for children with intractable epilepsy.

Side Effects

Relatively few side effects have been reported in association with vagus nerve stimulation. Side effects that have been reported include hoarseness, cough, paresthesias, headache, and shortness of breath.3 In a blinded study of 254 epilepsy patients, no serious adverse events were found to be related to VNS.12 One post-marketing case report described a 56-year-old man with mild mental retardation, right hemiparesis, and refractory partial seizures who developed bradycardia and transient asystole during lead diagnostic testing. The patient recovered completely with brief cardiopulmonary resuscitation. The manufacturer has stated that the occurrence of similar arrhythmias is expected to occur in about 0.1% of patients.13

The American Academy of Neurology’s Assessment of Vagus Nerve Stimulation

The American Academy of Neurology’s Subcommittee on Therapeutics and Technology Assessment reviewed the existing evidence in 199914 and found that the degree of improved seizure control attributed to VNS was comparable to that of the new AEDs. The subcommittee found that VNS for epilepsy was both effective and safe. Nevertheless, neurologists may be reluctant to offer VNS because it utilizes neither traditional pharmaceutical nor traditional surgical means of treatment.

Common side effects of vagus nerve stimulation for epilepsy include:

a. nausea.

b. jaw pain.

c. hoarseness.

d. vomiting.


Conclusion

VNS appears to be a safe, effective alternative to multi-pharmacy for patients with refractory epilepsy. Although current FDA approval covers usage for people over 12 years of age, it appears to be of benefit for younger children as well.

Recommendation

VNS may be beneficial as an adjunctive therapy in refractory epilepsy. This device is a nonpharmacologic treatment option that should be considered for epilepsy patients.

Dr. Kattapong is a board-certified neurologist and principal in Medicat Consulting, a health services consulting firm in Tucson.

References

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13. Asconape JJ, et al. Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: A rare complication of intraoperative device testing. Epilepsia 1999;40:1452-1454.

14. Fisher RS, Handforth A. Reassessment: Vagus nerve stimulation for epilepsy: A report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 1999;53:666-669.