Page 466 - ILAE_Lectures_2015

Chapter 48

Vagus nerve stimulation

ARJUNE SEN1, RICHARD SELWAY2 and LINA NASHEF2

1Oxford Epilepsy Research Group, NIHR Biomedical Research Centre, John Radcliffe
Hospital, Oxford, and 2King’s College Hospital, London
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Overview

Vagal nerve stimulation (VNS) was first delivered to patients over 25 years ago with the first
patient being implanted in 1988. European Community approval was granted in 1994 and
USA (FDA) commercial approval in 19971. VNS currently has a licence in Europe and the
UK for the adjunctive treatment of epilepsy refractory to antiepileptic medication. The UK
NICE Guidelines for Epilepsy (2012) suggest VNS is indicated ‘for use as an adjunctive
therapy in reducing the frequency of seizures in adults (and children) who are refractory to
antiepileptic medication but who are not suitable for resective surgery’. NICE specifies that
VNS is indicated for patients in whom focal or generalised seizures predominate. The US
licence is for refractory focal epilepsy in patients over the age of 12.

VNS is implanted to reduce the frequency and severity of seizures. That the VNS magnet can
be used to administer an extra stimulation at the onset of the seizure can be additionally
beneficial in some patients. Since its initial implantations for epilepsy, VNS has been trialled
in a variety of other medical conditions. In particular, the observation that co-existing
depression in epilepsy patients seemed to improve with VNS led to VNS now also being
licensed for treatment-resistant depression in adults and the American Academy of
Neurology recently recommended that VNS may be considered for improving mood in adults
with epilepsy2. Other potential therapeutic roles in anxiety, dementia, tremor, heart failure,
obesity and even rheumatoid arthritis are being explored.

Mechanism of action

Theories as to how VNS mediates its effect include direct activation, neurotransmitter and
neuropeptide modulation influencing ictal discharge, pre-ictal changes and arousal3,4. As
many as 80% of vagus fibres are afferent and the parameters used in clinical practice
preferentially stimulate these smaller fibres over the efferents. Afferent pulses reach the
nucleus tractus solitaris (NTS), synapsing bilaterally. The NTS projects to the thalamus,
hypothalamus, locus coeruleus, reticular activating system, midline raphe, limbic system and
secondarily to the cortex. In a kindling model of epilepsy, VNS was shown to prevent
lowering of seizure threshold compared to control animals5, while in rodents treated with
kainic acid VNS promoted neurogenesis in the dentate gyrus of the hippocampus. In a
maximal electroshock rat epilepsy model, VNS therapy was no longer effective as an
anticonvulsant when noradrenergic pathways were depleted by lesioning of the locus
coeruleus. A cat amygdala kindling seizure model suggested a partial anti-epileptogenic
effect of VNS. Positron emission tomography (PET) scanning showed increased blood flow
in the thalamus, hypothalamus, and the insular cortex with decreased blood flow in the
amygdala, hippocampus, and posterior cingulate. VNS induced forebrain Fos, a nuclear
protein expressed under conditions of high neuronal activity. Further, VNS has also been