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Elinor Ben-Menachem
Vagus-nerve stimulation (VNS) is now an accepted treatment stimulators and were given intermittent stimulation of a 30 s
for patients with refractory epilepsy. There have been many train of impulses (on) every 5 min (off). The positive results of
studies suggesting that VNS affects the brain in such areas these pilot studies led to double-blind, low-dose, placebo-
as the thalamus and other limbic structures. In addition, controlled trials to elucidate further the efficacy of VNS in
there is some evidence that norepinephrine is important in partial seizures.17,18
the prophylactic antiseizure effects of VNS. The efficacy of
VNS has been established for partial seizure types, even in Anatomy
refractory patients who did not respond to surgical treatment Studies in cats have shown that the vagus nerve consists of
for epilepsy. There are also data, from open-label studies, 80% afferent fibres projecting from the viscera to the nucleus
that suggest efficacy in other seizure types. Therefore, VNS tractus solitarius.19 Efferent fibres provide parasympathetic
seems to be a broad-spectrum treatment for epilepsy. innervation primarily to the lungs, heart, and gastrointestinal
Improvement is not immediate but increases over 18–24 tract, and they also innervate the voluntary muscles in the
months of treatment. Most studies report subjective larynx and pharynx. These fibres originate from the
improvements in various quality-of-life measurements during paraganglionic neurons in the dorsal motor nucleus of the
treatment with VNS—objective trials have confirmed this vagus nerve. There is an asymmetrical innervation to the
observation. Side-effects are mainly stimulation related and heart—the right vagus nerve innervates the sinoatrial node
reversible and they tend to decrease over time. They are and the left innervates the atrioventricular node. In dogs,
generally mild to moderate and seldom necessitate the when the right vagus nerve is stimulated, bradycardia is
removal of the device. No idiosyncratic side-effects have elicited to a greater degree than when the left nerve is
been reported in 12 years of experience, and VNS does not stimulated.20 For this reason, VNS implants are placed on the
interact with antiepileptic drugs. Most adverse events are left side of the neck and not the right side. Afferent fibres arise
predictable and related to the specific stimulation regimen. from receptors in the lungs, heart, aorta, gastrointestinal tract,
VNS does not have cognitive and systemic side-effects and and aortic chemoreceptors, and a small group arise from the
can, therefore, be a valuable treatment approach even for concha of the ear. The afferent fibres have their cell bodies in
patients who have poor tolerance of antiepileptic drugs. the nodose and jugular ganglia and project to the nucleus
tractus solitarius as well as to the dorsal motor nucleus, area
Lancet Neurology 2002; 1: 477–82 postrema, and nucleus cunneatus. From the nucleus tractus
solitarius there are synaptic connections to higher centres in
Corning created the first, although crude and external, vagus- the brain such as the hypothalamus, dorsal raphe, nucleus
nerve stimulator (VNS) in the 1880s. He lowered the number of ambigus, dorsal motor nucleus of the vagus nerve, amygdala,
seizures in patients treated with cardioinhibitory vagal and thalamus, which in turn project to the insular cortex.21
stimulation to reduce cerebral blood flow.1 VNS was, however, Positron-emission tomography and functional magnetic
forgotten as a useful antiseizure therapy until Zabara2–4 began to resonance imaging of the effects of VNS in human beings have
analyse the effect of stimulation in chemically induced seizures confirmed the influence the vagus nerve on higher brain
in dogs. The results were striking, and the technique has become structures. These studies have shown increases and decreases
an accepted and registered form of treatment for epilepsy; in blood flow in response to VNS. In one of the first positron-
worldwide, more than 15 000 patients receive this therapy. emission tomography studies, Ko and co-workers22 found that
That peripheral stimulation of the vagus nerve can affect VNS increased blood flow to the right thalamus, the right
the brain and cause striking changes in electroen- posterior temporal cortex, the left putamen, and the left
cephalographic patterns has been described several times since inferior cerebellum. In positron-emission tomography studies
the 1930s.5–10 Most animal experiments were done in cats that by Henry and colleagues23,24 blood flow was increased to the
had been given strychnine; VNS lowered the frequency of
spiking activity in this model. VNS was later shown to inhibit
seizures in the maximum electroshock and pentylenetetrazol
EBM is at the Department of Clinical Neuroscience, Sahlgrenska
models in rats11 and monkeys.12 A recent study suggests that Academy, Göteborg University, Sweden.
VNS also inhibits spiking activity in human encephalograms.13 Correspondence: Prof Elinor Ben-Menachem, Department of
Results of the first trial of VNS in human beings were Clinical Neuroscience, Sahlgrenska Academy, Göteborg University,
published in 199014,15 and 1993.16 In this trial, 16 patients with 413 45 Göteborg, Sweden. Tel +46 31 3421000;
refractory partial-onset seizures received vagus-nerve fax +46 31 211552; email ebm@neuro.gu.se
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review Vagus-nerve stimulation
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Vagus-nerve stimulation
Review
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review Vagus-nerve stimulation
35
was 58·2% at 3 months (n=43) and 57·9% at 6 months
30 (n=24). By 6 months, there was a decrease of at least 50% in
25 58% of patients. The falling number of patients in this study
20 was due to study cut-off and not to patients’ dissatisfaction.
The number of atonic seizures was reduced by 55% at
15
3 months and by 88% at 6 months. In the five patients who
10 had had callosotomy, the number of seizures was reduced by
5 73% at 3 months and by 69% at 6 months.44 Other smaller
0 studies have shown similar results 45,46
In conclusion, the efficacy of VNS seems to be established
Patients with >50% seizure reduction (%)
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Vagus-nerve stimulation
Review
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review Vagus-nerve stimulation
provide evidence of efficacy in patients with less refractory with those for antiepileptic drugs. VNS does not have the
disease. VNS, therefore, is now a treatment for cognitive and systemic side-effects seen with the use of drugs
pharmacoresistant epilepsy. Although fewer than 10% of and therefore can be a valuable treatment modality for
patients were reported as seizure-free from the clinical trials, patients who have poor tolerance of effective antiepileptic
this proportion is similar to that seen with antiepileptic drugs drugs.61
in a population with similarly intractable epilepsy.50
Most paediatric neurologists and neurosurgeons also Conflict of interest
agree that VNS should be offered to patients before The author has previously received research grants from Cyebronics,
the company that manufactures vagus-nerve stimulators.
callosotomy because VNS is less invasive and seems to be
effective in patients who would be considered for surgery. Role of the funding source
VNS is well tolerated—side-effects tend to diminish over No funding source was involved in the preparation of this review or the
time, and continuation rates for VNS compare favourably decision to submit it for publications.
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For personal use. Only reproduce with permission from The Lancet Publishing Group.