- Research and Development Service, VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA
- Department of Neurosurgery, University of California, Los Angeles, California 90095, USA
Scott E. Krahl
Research and Development Service, VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA
Department of Neurosurgery, University of California, Los Angeles, California 90095, USA
DOI:10.4103/2152-7806.91610Copyright: © 2012 Krahl SE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Krahl SE. Vagus nerve stimulation for epilepsy: A review of the peripheral mechanisms. Surg Neurol Int 14-Jan-2012;3:
How to cite this URL: Krahl SE. Vagus nerve stimulation for epilepsy: A review of the peripheral mechanisms. Surg Neurol Int 14-Jan-2012;3:. Available from: http://sni.wpengine.com/surgicalint_articles/vagus-nerve-stimulation-for-epilepsy-a-review-of-the-peripheral-mechanisms/
Vagus nerve stimulation (VNS) is a unique epilepsy treatment in that a peripheral intervention is used to treat a disease that is entirely related to pathological events occurring within the brain. To understand how stimulation of the vagus nerve can be used to stop seizures, an understanding of the peripheral anatomy and physiology of the vagus nerve is essential. The peripheral aspects of the vagus nerve are discussed in this review, with an explanation of which fibers and branches are involved in producing these antiepileptic effects, along with speculation about the potential for improving the therapy.
Keywords: Epilepsy, vagus nerve stimulation, peripheral nerves
A series of experiments conducted by Zabara demonstrated that vagus nerve stimulation (VNS) could be used to stop experimentally induced seizures in dogs.[
Compared to other neurosurgical interventions in which the focus is surgically removed, VNS offers a lower-risk surgery with fewer complications.[
Stimulus parameters vary; however, studies suggest that maximum protection from seizures can be achieved with stimuli given periodically at 20–30 Hz.[
Side effects of VNS are generally limited to coughing and/or hoarseness of the voice. These side effects can be universally produced with sufficient VNS amplitude or pulse width, but they are not necessary to produce the therapeutic response. Often, these side effects will be elicited when the VNS settings are adjusted, but are usually transient, or can be eliminated immediately by reducing the relevant VNS parameters.
VNS is a unique epilepsy treatment in that a peripheral intervention is used to treat a disease that is entirely related to pathological events occurring within the brain. While it is often stated that VNS's therapeutic mechanisms have not been fully elucidated, it is clear from numerous studies that activation of vagal afferents through electrical stimulation directly and indirectly influences well-defined seizure-related circuitry within the brain.
To understand how stimulation of the vagus nerve can be used to stop seizures, an understanding of the peripheral anatomy and physiology of the vagus nerve and its central projections is critical. Only the peripheral aspects of the vagus nerve are discussed in this review, explaining which fibers and branches are involved in the antiepileptic effects of VNS. The central mechanisms of VNS will be discussed separately.
Vagus is the Latin term for “wandering.” The name alludes to the complexity of connections that the branches of this nerve form within the body. The vagus nerve is a composite of afferent sensory and efferent motor fibers traveling together in a common pathway, each with its own origin, destination, and activation threshold.
Despite the emphasis placed on the motor effects of the vagus nerve in most introductory texts, the sensory afferents far outnumber the motor efferents, comprising approximately 65–80% of all vagal fibers.[
The branchial motor fibers of the vagus nerve innervate the skeletal muscles of the neck and face. The cell bodies for these fibers are located in the nucleus ambiguus. The fibers leave the vagal trunk in three main branches. The pharyngeal branch provides most of the motor innervation of the pharynx and soft palate striate muscles and a portion of the tongue. The superior laryngeal branch supplies the inferior constrictor and cricothyroid muscles of the larynx, and the pharyngeal plexus. The recurrent laryngeal branch leaves the vagal trunk more distally than the others and follows a rather circuitous route to innervate all of the laryngeal muscles, except the cricothyroid. The left recurrent laryngeal branch passes under the aorta, while the right branch passes under the subclavian artery.
Visceral motor preganglionic fibers originate in the dorsal motor nucleus of the vagus, except for cardiomotor neurons which probably originate in the nucleus ambiguus.[
The pulmonary, esophageal, and cardiac motor branches leave the vagal trunks at various points within the neck and thorax, and synapse in ganglia within their target. Pulmonary branches leave the trunk in the thoracic cavity and form anterior and posterior pulmonary plexuses along with the fibers from the thoracic sympathetic trunk ganglia. These pulmonary branches innervate the bronchial smooth muscles. Esophageal plexuses are also formed from vagal branches in the thoracic cavity along the entire length of the esophagus. These fibers innervate the smooth muscles of the esophagus. The heart is served by several branches from each side: the superior and inferior cervical cardiac branches, which leave the main trunk in humans approximately at the level of the thyroid gland, and the thoracic cardiac branch, which exits as the vagal trunk passes near the heart. The left and right cardiac motor fibers innervate the heart asymmetrically, with fibers originating from the left vagus nerve supplying the atrioventricular (AV) node (causing decremental conduction) and those fr om the right vagus nerve innervating the sinoatrial (SA) node (reducing depolarization rates and producing bradycardia).[
The vast majority of vagal fibers are small unmyelinated afferents.[
The general sensory fibers have a much less extensive field than the vast visceral sensory system. General sensory fibers carry touch, pain, and temperature information from the ear and parts of the pharynx and larynx. Fibers of the auricular branch, which innervates the pinna and auditory canal, directly enter the jugular (superior vagal) ganglion without joining the vagal trunk. In contrast, general sensory fibers from the pharynx and larynx join the motor fibers in either the superior laryngeal or recurrent laryngeal branches, with their cell bodies located in the nodose (inferior vagal) ganglion. All of the general sensory fibers eventually synapse within the spinal nucleus of the trigeminal nerve.
Understanding the location of a VNS electrode on the vagal trunk and evaluating VNS-induced side effects can yield valuable information regarding the vagal branches and fiber types that are activated during clinical VNS. VNS electrodes are implanted on the left cervical vagal trunk, approximately 8 cm above the clavicle. With the exception of the recurrent laryngeal branch, the auricular, laryngeal, and pharyngeal branches are unlikely to be activated by VNS as they exit the main trunk proximal to the VNS electrodes. The same may be said of the superior and inferior cervical cardiac branches. The rest of the vagal branches and fibers described above, however, are present in the trunk at the level of the VNS electrode and, depending on the activation threshold as discussed below, may or may not be stimulated using normal therapeutic VNS parameters.
Small unmyelinated C-fibers make up the bulk of fibers in the cervical vagus nerve, activation of which should result in a host of clinical side effects that would include the cardiopulmonary and gastrointestinal systems. These side effects are rarely, if ever, observed in patients at therapeutically relevant VNS parameters, however, prompting some investigators to suggest that activation of vagal C-fibers probably does not occur.[
Early VNS work in rats indicated that recruitment of vagal C-fibers is necessary for seizure suppression.[
Selectively and non-invasively destroying specific vagal fiber types, thereby eliminating the effects of their activation, may be a more preferable method of determining which fiber types are involved in VNS-induced seizure suppression. In one such experiment, rats were pretreated systemically with either capsaicin, a selective C-fiber excitotoxin, or vehicle.[
These data are clinically important since A- and B-fibers have a much lower activation threshold as compared to C-fibers, thus reducing the amount of current necessary to produce the antiepileptic effects of VNS. Lack of C-fiber recruitment is also important since activation of these fibers would produce a host of unwanted side effects that are not seen in most patients and may have rendered the therapy intolerable.
Currently, VNS is applied only to the left cervical vagal trunk which contains fibers from the recurrent laryngeal, cardiopulmonary, and subdiaphragmatic vagal branches. Since these branches serve diverse functions, not all of the branches necessarily contribute to VNS-induced seizure suppression. In fact, evidence suggests that seizure suppression can be achieved with stimulation of lesser vagal branches. In one such study, a cuff electrode was implanted on the ventral (left) subdiaphragmatic vagal branch in rats.[
Kalia and Mesulam[
Fortunately, the anatomy of the cervical vagal trunk is different between dogs and humans. The cervical vagal trunk where the VNS electrodes are normally placed in humans does not include the superior or inferior cardiac branches, thereby minimizing clinically relevant cardiac side effects regardless of the side of implant. Only 0.1% of patients undergoing implantation of VNS electrodes on the left vagal trunk experience transient asystole during intraoperative testing.[
If right-sided VNS is safe, the question remains if it is effective. In animal models, the answer is yes. In one study, a cuff electrode was implanted on the left or right cervical vagus nerve in two groups of rats.[
This has now been demonstrated clinically in three separate studies. McGregor and colleagues[
The second clinical report of right-sided VNS involved another child who was originally receiving left-sided VNS that was subsequently removed due to postoperative infection.[
Finally, in a third case report, two adult patients received right-sided VNS after surgical complications precluded the use of left-sided VNS.[
Possible lateralization of vagus nerve stimulation effects
In an interesting study, patients with left-sided VNS were studied with surprising results.[
These case reports provide important clues that may have been long overlooked because of the reports from early animal research. Stimulation of the right-sided cervical vagus nerve appears to be feasible, both from a safety and efficacy perspective. Second, the laterality of VNS effects may be important for the ultimate goal of any epilepsy therapy: complete remission of seizures. This laterality hypothesis has yet to be systematically tested, but it is intriguing to speculate that right-sided or even bilateral VNS might be viable alternatives in patients receiving sub-optimal results from left-sided VNS.
The unique anatomy of the vagus nerve provides a convenient peripheral medium in which to influence the brain without the invasiveness of intracranial surgery. While clinical efficacy is often modest, VNS has been successful, due in large part to patient acceptability, safety, and a low incidence of side effects. Future studies exploring the possible laterality of VNS effects, possibly leading to bilateral VNS, and further understanding of fiber selectivity may lead to improvements of the therapeutic effect, not only for epilepsy, but also for major depression and other future VNS indications.
Publication of this manuscript has been made possible by an educational grant from
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