by Michael Wong, MD, PhD
Dr. Wong is an Assistant Professor of Neurology at Washington University School of Medicine and an epileptologist in the Pediatric Epilepsy Center at St. Louis Children’s Hospital.
The vagal nerve stimulator (VNS) was approved by the FDA in 1997 for use in patients with intractable epilepsy. Mechanistically, the VNS is unlike any other previous treatment for epilepsy. VNS is generally used in patients with intractable epilepsy, who have failed to respond adequately to other available treatments, mainly consisting of multiple antiepileptic drugs. After appropriate evaluation, a patient may undergo surgical implantation of a VNS, usually performed at a specialized epilepsy program at a tertiary care center. This article will review the technical aspects, postulated mechanisms of action, data on clinical efficacy, and side effects of the VNS.
Surgical implantation of a VNS routinely takes place in an outpatient surgery setting or with an overnight inpatient stay. The surgery can be performed either under local or general anesthesia. A stimulating electrode is wrapped around the vagus nerve in the neck and a programmable pulse generator and battery pack are implanted in the anterior chest wall. The VNS is always placed on the left, due to the higher risk of cardiac arrhythmias with stimulation of the right vagus nerve. The battery does need to be replaced surgically every few years.
The pulse generator is externally programmable through the skin using a magnetic wand. Parameters of stimulation that can be programmed include current amplitude, pulse width, pulse train frequency, and pulse train on and off times. It usually takes several weeks to “ramp up” the pulse parameters to effective settings, after which further adjustments can be made in attempts to optimize efficacy. The patient can also be shown how to use a magnet to activate a pulse train at the onset of a seizure to try and abort the seizure. The cost of the equipment and surgery is about $7000.
Mechanism of Action
The precise mechanism of action of VNS is unknown. Despite incomplete understanding of the mechanism, electrical stimulation of various areas of the brain and peripheral nervous system is receiving increasing attention for potential treatment of a variety of neurological disorders, such as epilepsy and movement disorders. VNS is the first approved use of electrical stimulation for patients with epilepsy.
Unlike seizure medications, which activate specific cellular receptors that control electrical excitability of the brain, VNS has been hypothesized to have more diffuse effects on neural circuits in the brain. The vagus nerve is perhaps the most complicated of the cranial nerves and carries both afferent (incoming) and efferent (outgoing) fibers to and from the brain that control motor, sensory, and visceral function. The afferent inputs of the vagus directly or indirectly affect diverse and widespread areas of the brain, such as the reticular formation, hypothalamus, thalamus, limbic system, and neocortex. Given the extensive anatomical connections of the vagus nerve, it is easy to imagine multiple regions of the brain where vagus nerve stimulation may exert an antiepileptic effect. Theoretically, electrical stimulation could directly activate inhibitory circuits in relevant cortical regions to suppress seizure activity. Supporting this idea, vagus nerve stimulation has been shown to cause significant changes in EEG synchronization in animals, but curiously VNS seems to have minimal effect on the EEG of people. In animal models, VNS can also induce changes in gene expression, such as in the nuclear protein Fos, suggesting that VNS causes long-term changes in neural circuitry and function. However, the specific cellular and physiological mechanism(s) by which the antiepileptic effect occurs remains a mystery.
A number of different clinical trials of VNS have been performed in patients with epilepsy. The best evidence of efficacy of VNS comes from two large, multicenter, randomized, active-control trials in patients with intractable partial epilepsy. These trials consisted primarily of adults with frequent partial seizures (complex partial, secondarily generalized tonic-clonic) that had not been controlled on multiple antiepileptic drugs. After implantation of the VNS, patients were randomized to either a “low” or “high” stimulation group. The results of both trials were quite similar, reporting a ~25-30% mean decrease in seizure frequency with “high” stimulation compared to ~10-15% reduction in seizures with “low” stimulation over a three month period. Approximately 20-30% of patients with “high” stimulation had a >50% reduction in seizure frequency, compared to ~15% of patients with “low” stimulation. Almost no patients with intractable epilepsy became seizure-free with VNS. Overall, the results of these controlled clinical trials with VNS are comparable to what is seen with many of the new antiepileptic drugs in intractable epilepsy patients, but are not as favorable compared to traditional resective epilepsy surgery.
Long-term follow-up of patients with VNS suggests that efficacy may improve with continued use, although this conclusion is based on uncontrolled, “open-label” studies that are subject to certain biases limiting interpretation of the data. Patients with VNS for three years were reported to have a median reduction in seizure frequency of ~40-45%. Similarly, there was an improvement in the percentage of patients with >50% reduction in seizure to about 45%.
Although VNS has most thoroughly been tested in adults with intractable partial seizures, there is some evidence that VNS is effective in patients with primary generalized seizures and in children. Furthermore, VNS may be particularly useful in children with certain severe seizure types and epilepsy syndromes, such as drop attacks in Lennox-Gastaut syndrome.
Overall, VNS has been shown to be relatively safe with few side effects. In fact, although the efficacy of VNS may not be any greater than a new antiepileptic drug, a major advantage of the VNS may be that it allows a patient’s medications to be reduced, thus decreasing the side effects from those medications. General risks associated with any surgery exist with implantation of the VNS but are rare, including infection, bleeding, and problems with anesthesia. Hoarseness and throat pain felt when the stimulation is on are the most common reported side effects, affecting up to a third of patients. Of theoretical concern are cardiac side effects, but there has been no evidence of significant effects on the heart.
VNS represents a novel treatment for patients with epilepsy, the mechanism of action of which is poorly understood. It has been used most extensively in adults with intractable partial epilepsy, but may also have a role in other types of epilepsy. The efficacy of VNS is probably comparable to that of most antiepileptic drugs. VNS is unlikely to make an intractable patient completely seizure-free. However, the relative lack of side effects may make VNS advantageous over antiepileptic drugs in some situations.
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