Vagus Nerve Stimulation

Steven C. Schachter

Paul Boon

Introduction

For patients with medically refractory seizures, the major nonpharmacologic options are limited to epilepsy surgery, the ketogenic diet, and vagus nerve stimulation (VNS). In 1997, the VNS Therapy System (Cyberonics, Inc.) was approved by the Food and Drug Administration (FDA) as adjunctive therapy for adults and adolescents over 12 years of age whose partial-onset seizures were refractory to antiepileptic drugs (AEDs), thereby becoming the first (and only) FDA-approved nonpharmacologic treatment for epilepsy. This chapter reviews the relevant anatomy, possible mechanisms of action, and clinical results in patients with epilepsy.

Relevant Anatomy

The cell bodies of the nodose ganglion relay afferent sensory information that is carried by the vagus nerve to the nucleus of the solitary tract (NTS). From there, one pathway ascends to the forebrain via the parabrachial nucleus, lateral to the locus coeruleus.⁹⁸ The parabrachial nucleus transmits sensations of visceral origin to the ventroposterior parvocellular nucleus of the thalamus, which then projects to the insular cortex.¹⁸ The parabrachial nucleus and NTS also project to the amygdala and basal forebrain. c-Fos mapping studies show activation of these nuclei and pathways by VNS,⁸⁴ and one intriguing animal study underlines the possible involvement of the locus coeruleus.⁵²

Because the right vagus innervates the cardiac atria more than the left vagus nerve and the left vagus nerve provides the predominant innervation of the ventricles,⁹⁷ electrical stimulation of the left vagus nerve has generally been used in clinical practice, though right-sided VNS has been reported safe in one case series⁷³ and is equally effective against seizures as left-sided stimulation in rat models of epilepsy.⁵³

Mechanism of Action

Neurophysiologic Studies

Early work showed that repetitive VNS either synchronizes or desynchronizes cortical activity in anesthetized animals, depending on stimulus frequency and current strength, which determines whether myelinated fibers are activated.²⁰^,²¹^,²² Desynchronization of cortical rhythms implied a possible anticonvulsant effect of VNS and prompted further animal experiments in a variety of models,⁶¹^,⁷⁴^,¹⁰⁴^,¹¹⁴^,¹¹⁵^,¹¹⁶ including a recent report in genetic absence epilepsy rats from Strasbourg that showed no effect of VNS.²³

Low-intensity trains of VNS (100 μA, 30 Hz, 500 μs, 20 seconds on time) have been found to hyperpolarize pyramidal neurons of rat parietal association cortex.¹¹⁷ Interestingly, low-intensity stimulation, which predominantly activates myelinated fibers, was more effective in this model in inducing long-lasting inhibitory effects than higher stimulus intensities, which also entrain nonmyelinated vagus fibers. Consistent with these findings, a study of transcranial magnetic stimulation in five patients treated with VNS for epilepsy showed significantly increased cortical inhibition associated with stimulation without any evidence of an effect on cortical excitability.²⁷ Further, in a limited series of patients whose seizures responded to VNS, Marrosu et al. found normalization of impaired neuronal inhibition.⁷¹ The same group has more recently shown decreased synchronization of theta frequencies and an increased gamma power spectrum and synchronization in 11 patients treated with VNS.⁷⁰ By contrast, Ebus et al. were unable to find a relationship between clinical response to VNS and a reduction of electroencephalographic (EEG) spike discharges after implantation compared to preimplantation.²⁸

Neuroimaging Studies

The intracranial effects of VNS have been evaluated with positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI) scanning. The findings on PET studies have variably demonstrated increased blood flow in the ipsilateral anterior thalamus and cingulate cortex³⁵ or the contralateral thalamus and temporal cortex, and ipsilateral putamen and cerebellum.⁵⁰ The group at Emory correlated the extent of bilateral thalamic changes in blood flow and reductions in seizure frequency.⁴¹

SPECT studies have generally shown decreased regional cerebral blood flow in the medial thalamic regions bilaterally,⁹³^,¹⁰⁹ without a relationship between the extent of these changes and clinical outcomes with VNS.¹¹¹ An exception is the study of Van Laere et al., which showed a correlation between long-term clinical efficacy and (a) initial stimulation changes in the right amygdala and (b) right hippocampal perfusion changes.¹⁰⁹

In a series of nonepileptic patients enrolled in a trial of VNS for depression, Bohning et al. assessed VNS-synchronized functional MRI (fMRI) and found changes in bilateral orbitofrontal and parieto-occipital cortices, the left temporal cortex, the hypothalamus, and the left amygdala.¹² The same group has shown that the pulse width of VNS determines the pattern of regional activation, and that a pulse width of 130 microseconds is insufficient for activation of some regions.⁷⁸ An fMRI study in four patients treated for epilepsy found that VNS activated the left superior temporal gyrus, inferior frontal gyrus (bilateral), medial portions of the superior frontal gyrus in the region of the supplementary motor cortex (bilateral), and posterior aspect of the middle frontal gyrus (bilateral).¹⁰³
Other fMRI studies reported activations in the thalami (left greater than right) and insular cortices⁸³ and positive correlations between thalamic activation and clinical response to VNS.⁶⁰

Short-term Efficacy Studies

The first patient with epilepsy was treated with VNS in 1988,⁹⁰ followed by two pivotal trials of patients with partial epilepsy, the E03 study⁸^,³⁷^,⁹²^,¹⁰⁷ and the E05 study.³⁸ Prior to approval, a compassionate-use trial evaluated VNS in 124 patients with intractable seizures (the E04 study).⁵⁶

The E03 and E05 studies were multicenter, blind, randomized trials that compared two different VNS stimulation protocols for partial-onset seizures: High stimulation (30 Hz, 30 seconds on, 5 minutes off, 500 microseconds pulse width) and low stimulation (1 Hz, 30 seconds on, 90 to 180 minutes off, 130 microseconds pulse width). Enrolled patients were at least 12 years of age, with at least six seizures per month treated with a mean of 2.1 AEDs at study entry.

In both studies, the primary measure of efficacy was the percentage change in seizure frequency during VNS treatment compared to the preimplantation baseline. Changes in seizure frequencies in the high- and low-stimulation groups were then compared in each study. The hypothesis was that the low-stimulation treatment was less effective than the high-stimulation treatment. In the E03 study, the high-stimulation group had a mean reduction in seizure frequency of 24.5%, versus 6.1% for the low-stimulation group (p = 0.01). Furthermore, 31% of patients receiving high stimulation had at least 50% reduction in seizures compared to 13% of patients in the low-stimulation group (p = 0.02). In the E05 study, the corresponding decreases were 28% and 15% for the high- and low-stimulation groups, respectively (p = 0.039), and 11% of patients in the high-stimulation group had at least a >75% reduction of seizures compared to baseline, versus 2% of patients in the low-stimulation group (p = 0.01). Thus, both studies showed that high stimulation was more effective than low stimulation.

Long-term Efficacy

Seizure control is maintained in long-term studies of VNS,²⁶^,³⁷^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁷⁶^,⁹⁵^,¹⁰⁸^,¹¹³ including in catastrophic childhood epilepsy,⁶⁷ but these results should be interpreted cautiously since long-term studies are not blinded, and stimulation parameters and AED dosages could be adjusted as clinically indicated. One retrospective study of 269 patients whose AEDs were kept constant for 1 year after VNS implantation found a 45% seizure reduction at 3 months postimplantation compared to preimplantation baseline, and 58% reduction at 12 months postimplantation.⁵⁷ On-demand stimulation with the supplied magnet can be an effective adjunct to chronic stimulation for attenuating or interrupting seizures in some patients.¹⁵

Efficacy in Other Seizure Types and in Children

A number of open case reports and uncontrolled studies of VNS have been published, suggesting possible benefits for patients with medically refractory generalized seizures; in children with intractable seizures, including Lennox-Gastaut syndrome⁴^,¹⁶^,³²^,⁴⁰^,⁴⁴^,⁶⁵^,⁷⁹^,⁸⁰^,⁸²^,⁸⁶^,⁸⁹; and in developmentally disabled or mentally retarded patients with epilepsy.³⁶^,⁴⁵ In one adult described in a case report, VNS apparently terminated status epilepticus.⁸⁸ Given the limitations of all these studies, randomized, controlled trials are needed to further evaluate VNS in these populations.

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