by Richard S. McLachlan, MD
 That epilepsy is usually a relatively benign and easily treated disorder can be lost sight of by those who manage the 20-30% of people with seizures that are intractable. Even in these individuals, considerable improvement or even complete control of seizures can be achieved when new antiepileptic drugs become available or epilepsy surgery is performed. Despite these measures, there remains a group, possibly up to 10%, of epilepsy patients in whom seizures continue to be disabling. Thus, proposals have been made for other forms of treatment such as biostimulation to control seizures, including cerebellar stimulation1, thalamic stimulation2,3,4 and most recently, vagus nerve stimulation (VS) in the neck.5,6
Dr. Jacob Zabara, a neurophysiologist working in Philadelphia, was the first to suggest in the mid 1980s that electrical stimulation of the vagus nerve might be effective in preventing seizures7. This novel approach was based on previous observations extending back 50 years on the profound effect of electrical stimulation of the vagus nerve on central nervous system (CNS) activity. Bailey and Bremer8 were the first to demonstrate that stimulation of the cephalic end of the severed vagus nerve in the neck changed cortical electro-encephalographic (EEG) activity in cats. Since then, further studies have demonstrated both desynchronization9,10 and increased synchrony11 of background rhythms in the EEG of experimental animals, depending on the intensity of VS. Since seizures reflect an abnormal degree of EEG synchronization, the hypothesis was formulated that VS could be used to treat epilepsy.
Anatomy
The cervical component of the [vagus or] 10th cranial nerve transmits primarily sensory information that is important in the regulation of autonomic activity by the parasympathetic system. General visceral afferents [that transmit impulses from the periphery toward the central nervous system] constitute ~80% of the fibers of the [vagus] nerve12,13 and thus it is not surprising that VS can profoundly affect CNS activity. These afferents originate from receptors in the heart, aorta, lungs, and gastro-intestinal system14 and project primarily to the nucleus of the solitary tract which extends throughout the length of the medulla oblongata [the inner part of the hind-brain].15
The 20% of vagal nerve fibers that are special or general visceral efferents innervate the larynx via the recurrent laryngeal nerve, the pharynx, esophagus, heart, and gastro-intestinal structures.
Stimulating Device
On the basis of the promising animal studies, an implantable stimulator similar to a cardiac pacemaker was developed 16,17 consisting of a constant current pulse generator and bipolar platinum stimulating electrodes. The device, which weighs 65 grams and measures 5.5 cm. in diameter by 1.3 cm. in depth is implanted in the anterior chest wall and can be programmed externally by using a programming wand and software running from a standard personal computer. It is powered by a lithium thionyl chloride battery and must be replaced every 1.5 - 5.0 years, depending on the stimulation parameters. A 2-mm lead wire (molychrome, nickel, cobalt alloy) 43 cm long runs subcutaneously to the silicone rubber-imbedded platinum electrodes that are implanted around the left vagus nerve in the neck through a standard incision using microvascular techniques to avoid mechanical damage to the nerve.18,19 The surgery is carried out with patients under general anesthesia and requires ~2 hours.
The stimulating electrode is made of flexible and biocompatible platinum ribbon with an open helical design allowing the electrode to conform to the shape of the nerve, thus minimizing mechanical trauma. Extensive studies of peripheral nerves from cats and dogs following electrical stimulation with similar devices suggest that the parameters of stimulation used in human VS should provide an adequate margin of safety against nerve injury.20 However, this has yet to be confirmed in humans.
The optimal stimulation parameters have yet to be determined and may vary from patient to patient. Based on animal studies, empirical information from the first few patients, and expectations of battery life, the following settings have been used most often: 1.0-2.0 milliamperes, 0.5 millisecond, 20-30 Hz, 30 seconds on, 5 min off, 24 hours a day. However. the range of possible settings for the pulse generator is 0-3 5 milliamperes, 0.13-1.0 milliseconds, 1-143 Hz, 7-270 seconds on, 12 seconds -180 minutes off, allowing other stimulation strategies to be utilized. One paradigm that has been used with some success, if the standard protocol fails to improve seizure control, is called rapid cycling, in which a 5- to 7-second stimulus alternates with either 14 second or 30 second off. Other methodologies, including longer duration stimulus on times up to 1 min, are being explored. The original concept for VS to control seizures was to use the ictal [seizure] EEG from chronically implanted recording electrodes to trigger the pulse generator and thus stop the seizure in the same way feedback from the ECG can be used to trigger an implanted cardiac pacemaker. This avenue has not been pursued, but on demand stimulation triggered by an external hand-held magnet can be given in an attempt to abort a seizure.
Clinical Trials
In 1989, a patient of Dr. Kiffen Penry at Bowman Gray School of Medicine was the first to have an implant of a vagus nerve stimulator21. Subsequently, two single-blind pilot studies were carried out with 14 patients who had uncontrolled partial seizures.22,23 Seizure frequency in 36% of patients was reduced by $50% after 14-35 months of' stimulation, and two patients became seizure free for 1 year.
A multicenter, randomized controlled trial involving 114 patients was then undertaken.24,25 Patients were > 11 years of age and had >5 partial seizures per month, with or without secondary generalization. Following 12 weeks of baseline assessment, patients were randomized into a high-stimulation or a low stimulation group, the latter presumed to be of subtherapeutic intensity and thus the control arm of the parallel design study. Since virtually all patients feel the stimulation when it is on, this was an attempt to double blind the patient and the study coordinator to treatment groups. Only those in the high-stimulation group received VS with manual activation of the device. Following 14 weeks of stimulation, patients entered an open extension phase when those from the control group were offered full VS.
Collectively, seizure frequency decreased by 24.5% in the high-stimulation group compared with 6.1% in the low stimulation group. Seizure frequency decreased by at least 50% in 31% of the high-stimulation group compared with 13% in the low-stimulation group, a difference that was statistically significant (p=0.02), but no patient became seizure free. Magnet activation of the device that produced stimulation only in the high-stimulation group resulted in a significant difference in the percentage of seizures that could be aborted: 20.7% in the high group and 8.8% in the low group26. VS appeared to be most effective in reducing simple partial seizures, and the effect on seizure severity or duration was not described. Thus, the results indicate a modest influence of VS on seizure frequency over a relatively brief 14-week period. The findings of this study might be an underestimate since there is some evidence that the therapeutic effect of VS increases with longer periods of stimulation. George et al.27 described the follow-up at 18 months of 50 patients from the above study who continued with VS. In the high-stimulation group, a 50% decrease in seizure frequency occurred in 52% at 18 months compared with 31% after 3 months of stimulation. These results should be interpreted cautiously. If these results represent a true effect of VS, then the possibility of all influence on neuroplasticity÷ what could be described as a form of' "reverse kindling" must be considered. A placebo effect cannot be ruled out in either group, nor, on the other hand, can a therapeutic effect of low stimulation in the control group.
Children
A small number of children have been implanted with vagal nerve stimulators. Murphy et al.28 treated 12 children of age 4-16 years with VS for 2-14 months using both slow and fast cycling stimulation paradigms. Three patients reported >90% reduction in seizures at last follow-up, and a general improvement in overall function was noted, in part related to reduced medication. However, possibly related to the small population size, no significant difference in the overall number of seizures per month before and after VS was seen in the 12 patients. In a later brief follow-up of 20 children by the same group, 12 of the 20 had >50% reduction in seizures.29 Additional brief reports on three children30 and 16 children31 provide further suggestive evidence of VS efficacy in this age group. In the latter study, children were 4-19 years of age and were followed up 6 months after VS. Seizure frequency decreased by 50% in six of the 16, and one became seizure free. A reduction in seizure severity and an improved quality of life were also noted. All of the reports on children have included VS for both partial and generalized seizure disorders, with generalized tonic clonic seizures, and Lennox-Gastaut syndrome in particular, responding well to VS32; however. there is little information on typical absence or myoclonus.
Side Effects and Adverse Events
Side effects are common during the 5-30 seconds when the stimulator is on, with virtually all patients experiencing some form of pain or discomfort in the throat and/or alteration in the voice. Since these effects are directly related to the intensity of stimulation, the settings can be reduced to a lower level if a patient finds the symptoms too uncomfortable. Coughing, dyspnea [difficult breathing], paresthesias [abnormal sensations] of the throat, and muscle pain in the neck were additional, less frequent occurrences during the stimulation. Nausea, tinnitus, and tooth pain have also been reported. Despite these symptoms, >90% of patients elect to continue stimulation for >1 year. Those that discontinue tend to do so for lack of efficacy, with only ~2% discontinuing due to side effects.
Pulse generator malfunction in one patient resulted in continuous high-intensity VS for ~4 hours, caused by a short circuit.33 The patient developed a permanent paralysis of the left vocal cord. Another patient developed paralysis of the left diaphragm. One patient developed a duodenal ulcer 3 months after stimulation onset.
A total of 14 patients have died while having VS (data from Cyberonics): five of the deaths were attributed to possible sudden unexplained death in epilepsy. This results in mortality of ~10 per 1,000 patient years, comparable to that from other studies of similar intractable patients34,35.
Postoperative infection occurs in ~3% of cases, requiring removal or the device in ~1%. There is occasional transient postoperative hoarseness, three patients have had a lower left facial weakness from a severed facial nerve, and the pulse generator has migrated under the skin in five cases.
Mechanism
The mechanism by which VS might exert its influence is unknown. An early hypothesis suggested that VS utilizes the relatively specific projections from the nucleus of the solitary tract to limbic structures to inhibit partial seizures. Afferent VS at the onset of a partial seizure could abort the seizure; however, chronic intermittent stimulation may also produce an alteration in limbic circuitry that outlasts the stimulus and decreases epileptogenesis or limits seizure spread.
Another possible mechanism that is being explored to explain an anti-seizure effect of VS is activation of the brainstem noradrenergic nuclei, locus ceruleus and A5.36 Finally, a nonspecific alteration of activity in the brainstem reticular system with subsequent arousal must be considered.37,38
Conclusions
The efficacy of VS at this point compares favourably with that of some of the new antiepileptic drugs for intractable epilepsy, but these treatment modalities have not been directly compared. Furthermore, no criteria have yet been determined to indicate which patients will respond to VS. The indication for consideration of VS currently would appear to be disabling partial or generalized seizures unresponsive to antiepileptic medication in patients who are not suitable candidates for epilepsy surgery or have failed to improve following surgery. Patients with intolerable side effects from antiepileptic drugs who are not surgical candidates might also be considered for VS since, clearly, such individuals would be better off having an implanted electronic device to control seizures if their medication could be reduced. Little information is available on antiepileptic drug withdrawal during VS, nor is it clear how many patients become seizure free. Preliminary work on the effect of VS on patient-perceived efficacy and quality of life has suggested a favourable response, but more studies are required in this regard. Although the technical challenge in children is somewhat greater (small chest for subcutaneous implant and lead-wire failure from growth), VS has achieved encouraging results in children as young as 4 years of age. The safety and tolerability of VS have been demonstrated in >800 patients, but the criteria for selection for VS have not been elucidated because the clinical features that predict a favourable prognosis have yet to be determined. Whether certain seizure types or epilepsy syndromes will respond better to VS than others is unknown, and there are no descriptions of the effect of VS in individuals with symptomatic epilepsy from progressive neurologic disease such as tumour, chronic encephalitis, or progressive myoclonic epilepsy. Assuming further studies support the efficacy of VS, it is unlikely that it will ever be considered an alternative to resective epilepsy surgery, at least in patients with temporal lobe epilepsy. Caution is still warranted in treating epilepsy patients who have cardiac, respiratory, or gastro-intestinal problems. Although there are still unanswered questions and a number of issues remain unresolved with respect to VS, there is a sound rationale based on animal studies and the promising clinical evidence for further investigation of VS as an alternative treatment for intractable seizures. Further clinical experience and future research studies will determine whether VS stands the test of time in the management of epilepsy.
References*
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*NOTE: This is an abridged version of the longer paper ãVagus Nerve Stimulation for Intractable Epilepsy: A Reviewä that first appeared in the Journal of Clinical Neurophysiology, Vol. 14, No. 5, 1997.
Reprinted with kind permission of the author, Dr. Richard S. McLachlan, Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
FACT SHEET ON VAGUS NERVE STIMULATION
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