Chapter 113 Treatment of Intractable Epilepsy by Electrical Stimulation of the Vagus Nerve

Epilepsy is estimated to affect approximately 50 million people worldwide,¹ with a higher incidence in children, estimated at 100 to 200 per 100,000 children per year, compared with 24 to 53 per 100,000 in adults.² While the overall prognosis of epilepsy is good, approximately 30% of patients do not respond adequately to antiepileptic drugs or ketogenic diet and suffer from medically intractable seizures.² More than half of these patients are not good candidates or are not controlled by resective surgery, subpial transection, or corpus callosotomy. The effect on health and quality of life, as well as impact on society, is enormous, so the establishment of a new surgical strategy for control of seizures is of significant interest to neurosurgeons. Vagus nerve stimulation (VNS) in the neck, approved since July 1997 by the Food and Drug Administration (FDA) and in much of the European community since 1994, has now been used to treat more than 20,000 patients in at least 26 countries.

Currently, the vagal nerve stimulator is labeled by the FDA for treatment of partial seizures in patients aged 12 years and older, and since 2005, for refractory depression. Many patients with generalized seizures and children younger than 12 years have also been treated “off label.” The distinction between “partial” seizures (i.e., ones with a presumed focal origin, even if rapidly generalizing), and primarily generalized epilepsy, also tends to be elusive. While this chapter focuses on epilepsy, the operative considerations would be similar for depression.

The history of vagal nerve stimulation is interesting. In the late 1930s, animal studies demonstrated that electrical stimulation of the vagus nerve altered electroencephalographic (EEG) activity. Over the next few decades, animal investigations verified the changes in the EEG and documented anticonvulsant activity. Human clinical trials were begun in the late 1980s, with the outcomes showing significant effects on seizure reduction and minimal side effects. A brief history of VNS follows, with discussion of possible mechanisms of action, current uses, efficacy, and safety profile, as well as surgical technique.

Background

The vagus nerve, or tenth cranial nerve, is composed of approximately 80% afferent visceral fibers ³ transmitting visceral sensory information from receptors in the heart, aorta, lungs, and gastrointestinal system to the central nervous system (CNS). Accordingly, it is not surprising that VNS can affect CNS activity. A small number of fibers pass directly to the spinal trigeminal nucleus and the reticular formation, but most vagal afferents originate from nodose ganglion neurons with projections primarily to the nucleus of the solitary tract, which has widespread projections to the cerebral cortex, basal forebrain, hypothalamus, dorsal raphe, and cerebellum,⁴ and important areas for epileptogenesis such as amygdala, hippocampus, and thalamus.

There is also a direct pathway with viscerotopic representation to the insular cortex via the parabrachial nucleus in the pons.⁵ This is probably the pathway that relays sensation from vagal stimulation to conscious perception.

Other axons from the parabrachial nucleus go to the thalamic intralaminar and midline nuclei, which have extensive and diffuse projections throughout the cerebral cortex. This pathway may represent the point at which vagal stimulation interacts with pathways traditionally believed to control cortical synchronization and desynchronization.

The parasympathetic nucleus lies beneath the floor of the fourth ventricle and receives afferent input from the hypothalamus and glossopharyngeal nerve (carotid sinus). The efferent output supplies involuntary muscles of the bronchi, esophagus, stomach, small intestine, part of the large intestine to the distal third of the transverse colon, and heart.

The motor nucleus of the vagus nerve is formed by the nucleus ambiguus in the reticular formation of the medulla and receives input from both cerebral hemispheres. This nucleus supplies the constrictor muscles of the pharynx and the intrinsic muscles of the larynx.

In addition to the anatomic studies of the vagus nerve showing the vast number of cortical projections, animal studies have demonstrated effects on the EEG with stimulation. Electrical stimulation of the vagus nerve in cats was first shown to cause EEG changes in 1938 by Bailey and Bremer.⁶ Further studies have shown that, depending on the stimulation intensity and frequency, the cortical EEG can be synchronized or desynchronized.⁷ Low frequency (1 to 16 Hz) and very high intensity synchronize (increase slow waves), and higher intensity and faster frequencies (greater than 70 Hz) desynchronize (arousal, rapid eye movement), as do high intensity and slower frequency (20 to 50 Hz).⁸^–¹⁰ This suggests that different afferent fibers are stimulated under different circumstances, affecting different pathways and connections, with ultimately differing effects on the cortical EEG.

Animal Studies

Based on studies showing that the vagus nerve has a wide “connectivity” to the CNS,^11,¹² various animal models have been used to investigate the effect of VNS on epilepsy. Some of the early studies in cats, dogs, rats, and monkeys showed reduction or prevention of seizures using a variety of chemically induced seizures. Study of the stimulation parameters required showed maximal anticonvulsant effect with C-fiber stimulation.¹³^–¹⁶

In addition, McLachlan ¹⁷ demonstrated reduction or abolition of interictal spike activity in an acute epilepsy model using rats. Secondarily generalized seizures were also reduced in duration, but only if VNS occurred within 3 seconds of the start of the seizure. After 3 seconds, VNS had no effect on duration. This was also borne out in studies by Woodbury and Woodbury,^14,¹⁵ who showed that the longer the delay in stimulating the vagal nerve, the longer the duration of a seizure. In the same study, it was also shown that the effect on interictal spiking was seen 1 to 2 seconds after the onset of VNS and could persist for 1 to 3 minutes beyond stimulation; therefore, the anticonvulsant effect appeared to outlast the stimulation. Koo¹⁸ showed that during stimulation at the frequency of 20 to 30 Hz, there is synchronization of the epileptiform activity during the time when the stimulus is on, and suggested that there may be desynchronization of EEG results during the time when the stimulator is off. This may contribute to the mechanism of intermittent stimulation of the VNS as opposed to continuous stimulation.

Other parameters for optimal stimulation were assessed and shown in animal studies to be a stimulation of 10 to 20 Hz with a pulse width of 0.5 to 1 millisecond.^14,^15,¹⁹ In practice, human stimulation is usually started with a pulse width of 0.25 millisecond (250 microseconds).

Human Studies and Efficacy

The first human implantation was in 1988, with FDA approval following five clinical studies, enrolling about 500 patients. These studies looked at efficacy, safety, stimulation frequency, and tolerability of VNS as an adjunctive treatment in refractory partial seizures in adults.

The data show that patients treated with high stimulation rates (≤5 minutes of “off time”) had a mean decrease in seizure frequency of almost 30% versus a mean decrease of 15% in the low-stimulation-rate group (180 minutes off, used as an “active control”). Results also show that the responder rate of at least a 50% reduction in seizure numbers was 30% in the group with the high stimulation rate. The responder rate in the low-stimulation-rate group was 13%, which suggests that VNS works at both rates but the higher stimulation rates are optimal. The use of such “active control” strategies has been critical in minimizing potential placebo effects when interpreting the results of this modality.^20,²¹

Long-term results from the first four studies reported a 95% continuation beyond the first year of implantation, with 82% and 69% beyond 2 and 3 years, respectively. Reduction in seizure frequency remained the same or improved over time, with pooled results showing a 40% reduction in seizures at 36 months. Thus it appears that the effects of VNS are cumulative without increased adverse effects.

There have been a few small studies suggesting that rapid-cycle (7 to 14 seconds on, 30 seconds off) stimulation may be effective in the patient who has not responded to slower cycling rates. This has shown some added efficacy in patients with Lennox-Gastaut syndrome and tuberous sclerosis.²²^–²⁴

A few studies have included children also.^25,²⁶ The numbers are small, but most children had a more than 50% reduction in seizure frequency and a significant number had more than 90% reduction.

A small number of patients with generalized seizures have been studied. These studies suggest that these patients may respond better, with a higher responder rate to VNS than patients with partial seizures. Of the 25 patients with generalized seizure, 11 had a more than 50% seizure reduction.

Since FDA approval of the stimulator device in 1997, over 400 children, adolescents, and adults have received implants and have been studied at our institutions. The age ranged from 2 to 68 years, and most had refractory mixed seizures and generalized seizures, with a few with partial-onset seizures. The children with generalized seizures have shown a greater than 50% reduction on seizure number in more than 50% of the group. The children with partial seizures have shown a 30% to 40% reduction in number in approximately one third of the group. In addition to reduction in seizure number, seizure severity and the postictal period are dramatically decreased in a large number of patients. Finally, the level of alertness and interaction improves significantly in many of these children according to parents’ impressions.

Mechanisms of Action

Chronic VNS induces many physiologic changes in the brain. Naritoku and colleagues ²⁷ have reported increases in neuronal fos expression with VNS. The increased activity was seen in areas of the medulla, hypothalamus, thalamus, amygdala, and cingulate with connectivity to the vagus nerve. The increased fos activity suggests increased neuronal activity.

Positron emission tomography scanning has also shown activation of CNS structures with VNS. Regional blood flow changes showing increases in the ipsilateral anterior thalamus and cingulate gyrus were reported by Garnett and co-workers,²⁸ and in another study, Ko and associates²⁹ found increased blood flow in the ipsilateral putamen and cerebellum with contralateral increases in the thalamus and temporal lobe.

In addition to reports of increased blood flow, concentrations of inhibitory neurotransmitters and amino acids have been shown to increase. The recent demonstration that magnetoelectroencephalography (MEG) can feasibly be performed on patients with VNS devices in place ³⁰ may suggest a direction to collect data to further understanding of the mechanism of action. A coherent understanding of the mechanism of understanding, which has not so far advanced beyond the vague concept of “desynchronization,”³¹ may help advance appropriate use of the devices.

Patient Selection

Selection criteria for VNS are broad and continue to evolve. Selected patients should have medically refractory epilepsy. VNS is not a first-line treatment for epilepsy and is thus reserved for patients who have already tried multiple treatments. In addition, a potentially curative surgical resection should be considered preferable to VNS, when possible. It is highly desirable that all patients undergoing consideration for vagal nerve surgery be evaluated by epileptologists and surgeons well versed in other surgical options. For many patients, stimulator implantation may be preferable to extratemporal surgery in an eloquent area, corpus callosotomy, or repeat craniotomy for those who have failed surgery before. The use of the stimulator in cases where a more risky surgical approach or a less effective procedure is the only option gives an alternative treatment option with low morbidity. The last inclusion criterion is that the patient’s body size allows implantation of the device.

Seizure type is not an inclusion criterion. Studies have shown that the efficacy of VNS in generalized seizures and Lennox-Gastaut syndrome is comparable with that in partial seizures.²²A clear definition of the best patients for use of this therapy is unknown. Initial studies focused primarily on patients with intractable partial epilepsy. Approximately 20% of the patients studied in this group had a 50% or greater reduction in the number of seizures, with another 50% of the patients having a significant decrease in seizure frequency of at least 20%. Many patients also reported a decrease in seizure intensity, which is more difficult to quantify.

Patients who have previously undergone left cervical or bilateral vagotomies are excluded. In addition, patients who have significant preexisting upper airway/pharyngeal, pulmonary, cardiac, or gastrointestinal problems, presence of a dysautonomia, history of vasovagal syncope, or concurrent brain stimulator should be approached with caution and may need more frequent follow-ups.

Once the patient has received the implant, the stimulator is activated at any time from surgery to 2 weeks postsurgery. There have been no adverse effects when activating the device on the day of surgery. At our institution, the device is routinely activated by the surgeon at the time of implantation with initial settings as follows: 0.25 mA output, 20 Hz, pulse width of 250 milliseconds, on time of 30 seconds, and off time of 5 minutes. These minimal settings allow the patient to acclimate to the stimulation. Follow-up for reprogramming can then take place as frequently as once a week to once every few months.

The current stimulator device gives options for telemetrically changing the current intensity in milliamps, pulse width, length of time for stimulus train, and off time or time between stimulus trains. Reprogramming the stimulus output is usually the first parameter to adjust, and it can be increased in increments based on the patient’s tolerance. Other parameters that are adjusted are stimulus on and off times, which can be shortened or lengthened. Changing the on time to as little as 7 seconds and the off time to as little as 30 seconds has been shown to improve seizure control in patients with Lennox-Gastaut syndrome who have shown no improvement with the usual settings.²²

Follow-up examinations serve not only as an opportunity to reprogram and interrogate the device, but to begin adjustment of medications. Tapering of medications usually begins within a reasonable period after improved seizure control is observed. If improvement in seizure control is not seen, continued reprogramming and medication adjustment can be done.

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