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Vagus Nerve Stimulation for Refractory Epilepsy

Boon, Paul; Vonck, Kriste; Vandekerckhove, Tom; De Reuck, Jacques; Calliauw, Luc

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Left-sided vagus nerve stimulation (VNS) is a relatively new and efficacious neurophysiological treatment for patients with refractory epilepsy who were rejected for resective epilepsy surgery or who have had insufficient benefit from such a treatment. Animal experiments have shown that electrical stimulation of the vagus nerve can reduce the occurrence and duration of electrically and chemically induced seizures. The precise mechanism of action remains unclear. In 1988 the first vagus nerve stimulator was implanted in humans. Currently more than 7500 patients have been implanted world-wide. Randomized controlled clinical studies have shown a more than 50% reduction in seizure frequency in one third of the patients. Results on long-term treatment indicate that VNS remains effective over time and a trend towards improved seizure control with longer use of VNS was observed. VNS seems equally efficient in children. Hoarseness or voice change during stimulation are the most common side effects. VNS requires a substantial financial investment. Cost-efficacy studies have shown that these costs can easily be payed back by savings in epilepsy related direct medical costs in patients treated with VNS.

Epilepsy Monitoring Unit, Department of Neurology, and Department of Neurosurgery, University Hospital Gent, Belgium

Supported by grant BOZF 01105399 from the University of Gent. Dr Vonck is sponsored by the a junior research (“aspirant”) grant from the Fund for Scientific Research–Flanders. Dr Boon is sponsored by grant 1.5.236.99 from the Fund for Scientific Research–Flanders. Address correspondence and reprint requests to: L. Calliauw, MD, Acta Neurochiurgica, The European Journal of Neurosurgery, Kroonlaan 20, B-1050 Brussels, Belgium.

Epilepsy is second only to stroke as the most common chronic neurologic disorder and affects approximately 0.5%–2% of the population. 1 Seventy percent of patients can be efficiently treated with one or more antiepileptic drugs (AEDs). 2 Despite adequate antiepileptic treatment, 30% of patients continue to have seizures or experience unacceptable pharmacologic side effects.

For patients with “medically refractory” epilepsy, surgery is a therapeutic alternative. Resective surgery is a curative therapy when the epileptogenic zone can be identified and renders 60%–90% of patients seizure free. 3 Presurgical evaluation requires a thorough patient selection; in a substantial number of patients the epileptogenic zone cannot be identified or is located in a functional brain area.

Unsuitable candidates for resective surgery have few options left. Administration of a new antiepileptic drug will lead to seizure freedom in a maximum 7% of patients. 4 Electrical stimulation of the vagus nerve (VNS) is a recently available and efficacious neurophysiologic treatment of patients with refractory epilepsy who are unsuitable candidates for curative resective surgery or who have experienced insufficient benefit from such a treatment.

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HISTORY

The first vagus nerve stimulator was implanted in humans in 1988. However, the historical basis of peripheral stimulation for treating seizures dates back centuries. In the sixteenth and seventeenth centuries physicians described using a ligature around the limb in which a seizure commenced to arrest the seizure's progress. This method comes from Pelops, for whom this observation was proof that epileptic fits originated from the limb itself. This hypothesis was reviewed in the beginning of the nineteenth century when Odier and also Brown-Séquard 5 showed that ligatures are equally efficacious in arresting seizures caused by organic brain disease, such as a brain tumor. At the end of this century Gowers 6 attributed these findings to a raised resistance in the sensory and motor nerve cells in the brain that correspond with the involved limb. This would in turn arrest the spread of the epileptic discharge. Gowers also reported several other ways in which sensory stimulation could prevent seizures from spreading, such as pinching of the skin and inhalation of ammonia. Almost 100 years later, Rajna and Lona 7 demonstrated that afferent sensory stimuli can abort epileptic paroxysms in humans.

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ANATOMICAL BASIS

The vagus nerve is a mixed cranial nerve that consists of ∼ 80% afferent fibers originating from the heart, aorta, lungs, and gastrointestinal tract and of ∼ 20% efferent fibers that provide parasympathetic innervation of these structures and innervation of the voluntary striated muscles of the larynx and the pharynx. 8—10 Somata of the efferent fibers are located in the dorsal motor nucleus and nucleus ambiguus. Afferent fibers originate in the nodose ganglion and primarily project to the nucleus of the solitary tract. The nucleus of the solitary tract has widespread projections to numerous areas in the forebrain as well as the brainstem, including important areas for epileptogenesis such as the amygdala and the thalamus. There are direct neural projections into the raphe nucleus, which is the major source of serotonergic neurons and indirect projections to the locus coeruleus and A5 nuclei that contain noradrenegic neurons. Finally, there are numerous diffuse cortical connections.

The diffuse pathways of the vagus nerve mediate important visceral reflexes such as coughing, vomiting, swallowing, control of blood pressure, and heart rate. Heart rate is mostly influenced by the right vagus nerve, which has dense projections primarily to the atria of the heart. 11

The current rationale for vagus nerve stimulation as treatment for epileptic seizures is that stimulation of its diffuse connections to the brain can have a widespread influence on numerous central nervous system (CNS) structures. There is substantial evidence that the nucleus of the solitary tract as well as the locus coeruleus are involved when the vagus nerve is stimulated. 12,13 Evoked potentials during stimulation of the vagus nerve were registered in the cerebral cortex, hippocampus, thalamus, and cerebellum. 14

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ANIMAL EXPERIMENTS

The first animal experiments mainly investigated VNS-induced electroencephalograph (EEG) effects. Depending on the stimulus parameters used, vagus nerve stimulation can induce EEG synchronization, EEG desynchronization, rapid eye movement, and sleep or slow wave sleep in animals. 15,16 This was explained by the fact that different types of nerve fibers in the vagus nerve are activated when different stimulus parameters (frequency and intensity) are used. Synchronization of the EEG was observed when weak stimuli activating myelinated A- and B-fibers were used. Desynchronization resulted when stimuli with higher output and frequency activated unmyelinated C-fibers. 17–19 Because epilepsy is characterized by a paroxysmal abnormal synchronicity of EEG, it was believed that vagus nerve stimulation could suppress seizures by desynchronizing the EEG.

The effect of vagus nerve stimulation on clinical behavior and electroencephalographic epileptic activity in different animal models was studied. VNS blocks interictal spike activity induced by strychnine applied to the cortex of a cat. 15 Zabara 20 found that generalized seizures in dogs induced by pentylenetetrazol and strychnine were inhibited by vagus nerve stimulation and made an estimation about optimum stimulation parameters. Woodbury and Woodbury 21 established the anticonvulsant efficacy of VNS in rats after induction of seizures with pentylenetetrazol, mercaptoproprionate and maximal electroshock, which are validated animal models for simulating human epilepsy. According to their research the anticonvulsant effect is directly related to the fraction of unmyelinated C-fibers that are stimulated. Chronic VNS also reduced the frequency of recurrent spontaneous seizures in monkeys with alumina gel foci. 22 Results of these animal studies led to the development of an implantable device for human use and the first human trials for VNS as treatment of epilepsy.

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NEUROCYBERNETIC PROSTHESIS DEVICE AND SURGICAL PROCEDURE

In humans, stimulation of the vagus nerve is facilitated by implantation of the Neurocybernetic Prosthesis (NCP) System (Cyberonics Inc., Houston Texas), which comprises a pulse generator and bipolar helical lead with an integral tether. The surgical procedure requires two incisions. The first, for the pulse generator, is approximately 8 cm wide and 2 cm beneath the left clavicle and the other approximately 10 cm wide at the anterior border of the left sternocleidomastoid muscle. The connectors of the lead are tunneled from the neck incision to the upper chest incision, leaving the helical electrodes at the neck. Once exposed within the carotid sheath, the vagus nerve is freed for a minimum of 3 cm so that the bipolar helical electrodes and the integral tether support may be carefully placed around the vagus nerve. The electrode is stabilized using tie downs and then passed over the sternocleidomastoid muscle where a loop is placed and fixed to the fascia, again with a tie down. The connectors are fitted into the header of the pulse generator. A test of the integrity of the implanted lead and pulse generator combination is performed before closure. The operative procedure is usually performed under general anesthesia, with the patient remaining in hospital overnight. Some centers are, however, turning to regional anesthesia and day care surgery.

Programming is facilitated with a radio frequency telemetry wand connected to an IBM-compatible computer loaded with the NCP® software. The programmable parameters, together with their ranges, are shown in Table 1.

TABLE 1

TABLE 1

Stimulation can be initiated immediately after the procedure is completed with the lowest level of output current, 0.25 mA, and reprogrammed to patient tolerance on the following day. The advantage of this method is to mask any initial discomfort from the stimulation by pain caused by the surgical incision. An alternative approach is to initiate stimulation only when the patient has fully recovered from the surgery. In either case the output current is subsequently increased according to patient tolerance.

The patient may also be provided with a magnet. Usually it is better to wait for 6 to 8 weeks and allow the patient to accommodate to the programed stimulation before providing and giving instruction on the functions of the magnet. The magnet allows additional stimulation to be commanded by the patient or caregiver in case of an aura or a seizure. Additional stimulation is facilitated by holding the magnet over the pulse generator for 1 to 2 s. The magnet may also be used to inhibit stimulation by keeping it over the generator. The pulse generator may be programmed off using the telemetry wand and the programer by selecting 0 mA for the programed output current.

The system can be removed by explanting the generator and lead. Fibrous tissue may encapsulate the electrode, and care needs to be taken not to damage the vagus nerve. Alternatively, the lead may be cut off in the neck and capped, leaving the helical electrodes on the nerve.

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CLINICAL TRIALS

Acute Effects and Side Effects

Five (EO1–EO5) acute-phase clinical studies involving the NCP® System have been conducted in a total population of 454 patients. The purpose of the studies was to determine whether adjunctive use of electrical stimulation of the left vagus nerve could reduce seizure frequency in patients with refractory epilepsy. 23–26 The EO1 and EO2 studies were two pilot studies that enrolled 15 patients with refractory partial epilepsy, 14 of whom received stimulation. In one patient the NCP® device was explanted because of a surgical complication resulting in unilateral vocal cord paralysis that resolved 9 months later. The degree of response ranged from no improvement to complete cessation of seizures, with a mean reduction of 46.6%. In none of the patients did the seizure disorder appear to be exacerbated by VNS. Of 14 patients, 5 reported a reduction in seizure frequency of at least 50%. None of the patients reported transient or permanent serious side effects. The most common side effects were noted only during actual stimulation of the nerve and consisted of hoarseness and local neck/throat paresthesia. These effects became milder after a few months of stimulation. No negative cardic or gastrointestinal effects were observed on electrocardiogram monitoring and measurements of gastric acid output.

The EO3 (114 patients) and EO5 (196 patients) studies were both randomized, blinded, active control trials in which patients with refractory partial epilepsy were randomly assigned into two treatment groups. Patients assigned to treatment with “high” stimulation parameters (30 Hz, 30 seconds on, 5 minutes off, 500-μs pulse width) were believed to receive therapeutic treatment. Treatment with “low” stimulation parameters (1 Hz, 30 seconds on, 90–180 minutes off, 130-μs pulse width) was considered to be nontherapeutic. The primary efficacy endpoint was the percentage reduction in seizure rate measured over a period of 12 weeks. Adverse events were assessed at each patient visit. In the high stimulation groups there was a mean reduction in seizure frequency of 24% in the E03 study and 28% in the EO5 study. This is a statistically significant decrease in seizure frequency when compared with baseline seizure frequency (p < 0.05;p < 0.0001) and seizure frequency reduction in the low stimulation groups (6% in the EO3 study and 15% in the EO5 study), p ≤ 0.02; p < 0.02. The most common treatment-related adverse events were attributable to vagal innervation of the larynx during current “on” periods and consisted of voice alteration, coughing, throat paresthesia and discomfort, and dyspnea. Treatment was well tolerated, with 97% of patients continuing in the long-term follow-up phase of the study. Surgery-related complications included left vocal cord paralysis in two patients, lower facial muscle paresis in two patients, and fluid accumulation over the generator that required aspiration in one patient. All these complications resolved. Infection around the device occurred in three patients. VNS had no effect on concurrent AED serum levels or on body chemistry. Rigorous blinded collection of autonomic measures revealed no effect on weight, serum gastrin, or cardiac and pulmonary function tests. Electrical stimulation of the left vagus nerve has no demonstrable effects on visceral functions when administered at levels that do not exceed comfort.

The EO4 study was an open study in which 116 patients with all types of epilepsy and patients under 12 years of age were stimulated. In this study 29% of the implanted patients had a seizure reduction of more than 50%.

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Long-term Efficacy and Safety

Long-term data (> 3 months) were collected on all available EO1 through EO4 study patients. These long-term follow-up data are uncontrolled because they come from an open-label protocol in which both the AED medications and NCP device settings were allowed to be changed. Patients initially randomized to low stimulation parameters were changed to high stimulation parameters. George et al. 27 reported 18 months efficacy analysis in 50 patients exiting the EO3 study and Salinsky et al., 28 reported efficacy data in 100 of 114 patients from the EO3 study who were treated for 1 year. Results indicated that VNS remains effective over time, and a trend toward improved seizure control with longer use of VNS was observed. Response during the first 3 months of treatment is predictive of long-term response. Chronic side effects were identical to those observed during the randomized trials and consisted mainly of mild hoarseness during stimulus delivery.

Several other reports on long-term treatment with VNS confirm these findings. In our own study, up to 10% of patients became seizure-free for a period of 12 months or longer. 29 A trend toward improved seizure control with longer use of VNS was observed. Response during the first 3 months of treatment seemed predictive of long-term response. Ben-Menachem et al. 30 recently published data on 64 patients with follow-up of up to 5 years. The study included patients with partial seizures, Lennox-Gastaut syndrome, and primary generalized seizures. A large reduction in seizure frequency and severity over long periods of time was experienced by 44% of patients. VNS seems equally efficacious for Lennox-Gastaut syndrome and primary generalized seizures but results from larger patient groups are necessary. Two patients became pregnant and have given birth to healthy babies.

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Experience in Children

Experience with VNS in children is less extensive than it is in adults, but results seem promising. Two studies report seizure frequency reductions of ≥60% in 80% of children and ≥50% in 38% of children. 31,32 The most recent study in 60 children with mean age of 15 years reported a reduction in seizure frequency similar to that in adults. Median reduction of seizure frequency was 44%. A gradual increase in efficacy up to 18 months postoperatively was observed. The predominant seizure type in this study was complex partial (57%), followed by generalized tonic-clonic seizures (27%). No particular seizure or epilepsy type appeared usually sensitive or resistant to VNS. Adverse events during stimulation included fever, coughing, colds and voice alteration. No patients dropped out, and side effects subsided over time. 33

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MECHANISMS OF ACTION

Like in many other antiepileptic therapies, elucidation of the neural mechanisms of VNS lags behind the knowledge of its clinical efficacy. Over 9,000 patients worldwide have been implanted with a vagus nerve stimulator, but no clear predictive factors for positive outcome or guidelines for stimulation regimens have been published. Insight in the mode of action may help to identify epileptic seizures or syndromes that respond better to VNS and guide the search for optimal stimulation parameters. Improvement of clinical efficacy may result from this.

Research on the mode of action of VNS in humans remains a challenge because of safety concerns, the large number of patients required, and the widespread distribution of small patient series. Neurochemical studies were conducted by Hammond et al. 34 and Ben-Menachem et al., 35 who quantified amino acid and neurotransmitter metabolite concentrations in CSF samples before and after VNS. The first study revealed selective increases in 5-hydroxyindoleacetic acid and homovanillic acid, metabolites of serotonin and dopamine respectively; also a significant decrease in aspartate was found. The second study revealed increased GABA levels. It remains to be clarified whether these are epiphenomena or findings directly related to vagus nerve stimulation.

Investigation of VNS-induced EEG changes and evoked potentials in humans have also been performed. There is no significant VNS-induced change of background waking EEG rhythms. 36–38 Subtle changes, however, may be missed by visual analysis but detectable when quantitative methods are used. This is currently under investigation. Cortical evoked potentials were detected parietally but did not prove to play a role in mode of action. Prolongation of cervicomedullary to thalamocortical interpeak latency (N13/N19) during somatosensory evoked potentials performance in patients before and after intermittent VNS has been reported, suggesting VNS-induced alteration of neurotransmission in the forebrain. 39

Finally, the effect of VNS on human CNS structures has been studied with positron emission tomography. Various changes in cerebral blood flow supratentorially and in the cerebellum caused by acute and chronic VNS have been reported. Preliminary results in small patient populations suggest increased blood flow in contralateral gyrus pyriformis and bilateral thalamus correlate best with clinical response. 40–42 An acute SPECT study in patients receiving an initial stimulation train showed ipsilateral thalamic hypoperfusion. 43 Correlation with clinical efficacy after several months of treatment did not reveal significant findings.

Several mechanisms of action may be responsible for the antiepileptic effect of VNS. Desynchronization of the EEG was originally believed to be the key factor of the antiseizure effect of VNS. However, research in humans did not reveal the same EEG changes as observed in animals.

There is strong evidence that the nucleus of the solitary track and the locus ceruleus play a major role in the suppression of seizures by VNS. 12,13 Inhibition of the nucleus of the solitary tract is anticonvulsant and lesions of the locus ceruleus suppress the seizure-attenuating effects of VNS.

Previous research has suggested that VNS acts through a release of inhibitory neurotransmitters, such as GABA and glycine in widespread brain structures. Because several AEDs have a similar mode of action, a synergistic effect between VNS and AEDs is possible.

Investigation of VNS-induced changes in cerebral blood flow suggest suppression of seizures by modulation of thresholds in structures known to play an important role in epileptogenicity. It is unclear whether activation of inhibitory neurons or increase in inhibitory neurotransmitters is responsible for this.

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COST–EFFICACY CONSIDERATIONS

Vagus nerve stimulation is a costly treatment. Few cost–efficacy data are available. Two recent studies showed that there is a significant decrease in epilepsy-related direct medical costs after implantation with the vagus nerve stimulator. 44,45 This decrease is mainly due to an important decrease in the number of hospital admission days after implantation. It is estimated that the cost of the device can be paid back by savings in epilepsy-related direct medical cost after 2.5 years. Battery life now exceeds 4 years.

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CURRENT PRACTICAL MANAGEMENT

In many epilepsy centers VNS is a routinely-performed treatment for patients who are unsuitable candidates for epilepsy surgery or who have had insufficient benefit from such treatment. When patients with refractory epilepsy are referred to our epilepsy center they are initially included in a presurgical evaluation protocol including video-EEG monitoring, optimum magnetic resonance imaging, positron emission tomography, and neuropsychologic examination. Results of these examinations are discussed in the epilepsy surgery meeting by a multidisciplinary team. Patients who are considered unsuitable candidates for resective surgery can be included in phase-III drug trials with new AEDs or they can be offered implantation with a vagus nerve stimulator. Absolute contraindications for implantation of a vagus nerve stimulator are limited to previous left or bilateral cervical vagotomy. A stimulator will not be implanted when there is evidence of progressive intracerebral disease. Other conditions that need special attention are cardiac arrhythmias, respiratory diseases such as asthma, and pre-existing hoarseness, gastric ulcers, vasovagal syncope, and coexisting neurologic diseases other than epilepsy. Patients who were evaluated for epilepsy surgery several years ago when treatment with a vagus nerve stimulator was not yet routinely available are reconsidered at the epilepsy surgery meeting and are reevaluated with magnetic resonance imaging or other investigations when necessary.

Patients are extensively informed about the efficacy, side effects, implantation procedure, and ramping up procedure. After informed consent is obtained they are admitted to a neurosurgical unit for 48 hours. The surgical procedure is performed under general anesthesia and lasts about 1 hour. Patients leave the hospital with the stimulator unprogrammed. During a clinic visit 2 to 4 weeks after the operation, the vagus nerve stimulator is programmed to continuous intermittent stimulation, starting with an initial 0.25–0.50 mA output current, depending on individual patient tolerance. Every 2 to 4 weeks the stimulation output current is gradually ramped up by 0.25–0.50 until clinical efficacy or patient tolerance is reached. When patients are used to the electrical stimulation they are provided with the magnet. At every clinic visit seizure frequency and side effects are assessed. AEDs remain unchanged during ramping up. Tapering of AEDs may be considered when seizure freedom is achieved. After ramping up patients are seen every 3 to 4 months.

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CONCLUSION

Vagus nerve stimulation is an efficacious but palliative treatment of patients with refractory epilepsy. The current consensus on efficacy is that one third of patients have a considerable improvement in seizure control, with a reduction in seizure frequency of at least 50%, and one third of patients experience a worthwhile reduction of seizure frequency between 30% and 50%. In the remaining 30% of the patients there is little or no effect. Efficacy has a tendency to improve with longer duration of treatment, up to 18 months postoperatively. There is only limited information on patients becoming seizure free. VNS seems equally effective for children. Analysis of larger patient groups and insight into the mode of action may help to identify patients with epileptic seizures or syndromes that respond better to VNS and guide the search for optimal stimulation parameters. Further improvement of clinical efficacy may result from this.

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Acknowledgments:

M. D'Have and S. O'Connor are acknowledged for their continuous editorial support.

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Keywords:

Epilepsy; Refractory seizures; Vagus nerve stimulation; Epilepsy surgery; seizure frequency; Efficacy

© 2001 Lippincott Williams & Wilkins, Inc.