Vagus nerve is the longest mixed cranial nerve associated structurally with the post olivary sulcus of the medulla oblongata. The literal translation of the vagus is 'wanderer,' which aptly represents its widespread interfacing of cortex, brainstem, hypothalamus, and the body. Its afferent and efferent pathways comprise about 80% and 20%, respectively. With a premise that venous hyperemia caused seizures, James Corning, a 19th-century neurologist from New York, devised instrumented carotid compression along with vagus nerve stimulation as a treatment intervention for seizures. His observations were not put to the test until the latter part of the 20th century. In the 1980s, various observational studies emerged in the cybernetic use of a vagus nerve stimulator (VNS) in refractory epilepsy.
Currently, VNS is a Food and Drug Administration (FDA) approved treatment for various conditions like chronic epilepsy, refractory epilepsy, and depression. It is also being investigated in various other conditions like autoimmune and chronic inflammatory disorders.
Vagus nerve connects many visceral organs with the brainstem and the cortex given its widespread course and distribution compared to the rest of the cranial nerves through the autonomic nervous system interface. It originates in the medulla oblongata as eight to ten rootlets from four nuclei, namely:
The vagus nerve, after originating from the medulla oblongata, exits the cranium through the jugular foramen and travels down the neck within the carotid sheath along with the common carotid artery and the internal jugular vein.
The premise of the vagal nerve stimulation is to activate various neurochemical coordinates arising from the NTS to different parts of the brain. The FDA approved indications are:
Other Investigational Clinical Applications:
Vagus nerve plays an important role in conveying information about peripheral proinflammatory cytokines in the body to the brain (NTS) as the vagal afferents are sensitive to the presence of interleukins and prostaglandins. In turn, NTS relays this information to various levels like the hypothalamus, limbic lobe, and the pituitary leading to activation of the hypothalamo-pituitary adrenal (HPA) axis leading to the release of cortisol from the adrenal cortex. The anti-inflammatory role of the vagal efferents is mediated through the vagovagal reflex, where vagal afferents activate the vagal efferents. The vagal cholinergic output from the dorsal motor nucleus inhibits the release of cytokines like TNFα from the macrophages, and this is commonly termed as the cholinergic anti-inflammatory pathway. These anti-inflammatory abilities of the vagus nerve make it a target for modulation by VNS to affect the inflammatory conditions of the gut like the inflammatory bowel disease (IBD), and also other non-gut inflammations like rheumatoid arthritis (RA), diabetes mellitus (DM), sepsis, cardiovascular diseases, Alzheimer disease, and chronic pain.
Commonly used vagus nerve stimulator devices consist of an implantable, non-rechargeable battery-powered VNS therapy pulse generator and the VNS therapy lead. There is also an external programming system that is used to change the stimulation setting according to the requirement. They require new batteries in about six years. The VNS therapy lead is placed surgically around the left vagus nerve in the carotid sheath and connected to a subcutaneous programmable pacemaker device that is placed over the left chest wall.
Electrical signals generated from the pulse generator are transmitted to the vagus nerve via the VNS therapy lead. The patients can deactivate (turn OFF) or give an additional burst of stimulation on demand by placing or swiping the magnet provided to them over the pulse generator, respectively. The previously programmed stimulation resumes after the magnet is removed. The device has three modes, manual, automatic, and chronic.
Vagus nerve stimulator device ideally should be implanted by a surgeon, neurosurgeon, vascular surgeon, or an ear-nose-throat surgeon trained in this procedure. It involves an interprofessional team to determine the eligibility of the patient for the procedure (screening) and a close long-term follow-up and education after the procedure for good outcomes. The settings of the device would require periodic adjustments as necessary to result in an optimal response for the indicated clinical indication.
Randomized controlled trials observed the following early complications (in descending order):
But generally, the patients show improved tolerance over a period of time. Intraoperative complications are rare and may include the following:
Vagus nerve stimulation is an effective antiseizure treatment, albeit without significant treatment-related side effects. Based on the evidence from randomized controlled trials, VNS therapy is an adjunctive treatment aimed towards a maximal reduction in seizure frequency with reduced use of antiepileptic medications. The general trend in patients, both children, and adults, with chronic epilepsy treated with VNS therapy, has been increased quality of life. At the same time, this effect is most significant in those with the highest seizure frequency reduction. Besides the antiseizure effect, VNS therapy leads to improved mood symptoms.
According to the American Psychiatric Association (APA) adjuvant long term VNS therapy is specified by FDA in treatment-refractory depression, either unipolar or bipolar, with a history of failure to respond to at least four antidepressant medications. Better efficacy of electroconvulsive therapy (ECT) for treatment-resistant depression should be discussed with the patient and should be considered before the use of the VNS.
The extensive interface of the vagus nerve, between mind, body, gut, and brain, opens a plethora of therapeutic possibilities from seizures and depression to immune modulation. As Dacher Keltner puts it: "The vagus nerve is one of the great mind-body nexuses in the human nervous system."
Overall, an interprofessional team effort involving multiple specialists (neurologist, epileptologists, neurosurgeons, psychiatrists) and medical staff personnel are essential to provide and enhance patients care to achieve good outcomes. Patient education is crucial since these devices require an active involvement when there is a need to intervene and provide on-demand stimulation.
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