Vagus nerve stimulation

Vagus nerve stimulation or vagal nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. It is used as an adjunctive treatment for certain types of intractable epilepsy and treatment-resistant depression.

Vagus nerve action

Vagus, the tenth cranial nerve, arises from the medulla and carries both afferent and efferent fibers. The afferent vagal fibers connect to the nucleus of the solitary tract which in turn projects connections to other locations in the central nervous system. Little is understood about exactly how vagal nerve stimulation modulates mood and seizure control but proposed mechanisms include alteration of norepinephrine release by projections of solitary tract to the locus coeruleus, elevated levels of inhibitory GABA related to vagal stimulation and inhibition of aberrant cortical activity by reticular activation system.[1]

Approval and endorsement

In 1997, the US Food and Drug Administration’s neurological devices panel met to consider approval of a vagus nerve stimulator (VNS). The manufacturer, Cyberonics, said it could prevent or reduce seizures in patients with partial onset epilepsy who did not respond to drug treatment. The device consists of a generator the size of a matchbox that is implanted under the skin below the patient’s clavicle. Lead wires from the generator are tunnelled up to the patient’s neck and wrapped around the left vagus nerve at the carotid sheath, where it delivers electrical impulses to the nerve lasting about 30 seconds every 3–5 minutes.

Representatives from Cyberonics offered no definitive explanation during the FDA meeting of how the device stopped or reduced seizures, but they had three studies, E03, E04, and E05, to show its safety and efficacy.

Two of the studies, E03 and E05, involved 313 patients with treatment resistant partial seizures randomised to high or low dose stimulation. The low stimulation arm was intended to avoid the problem of an unblinded placebo arm because all patients would be implanted and told they were receiving stimulation. The studies did not include a medical treatment arm for comparison, leaving unanswered the question of whether either treatment arm was superior to existing care. Researchers reported that 25% of patients in the high stimulation arms of the trials achieved the primary end point: a 50% reduction in seizure frequency from baseline. However, 20% of patients in the high stimulation arm had more seizures.[2][3]

Although the use of VNS for TRD has been endorsed by the American Psychiatric Association, the FDA's approval of VNS for TRD remains controversial. According to Dr. A. John Rush, vice chairman for research in the Department of Psychiatry at the University of Texas Southwestern Medical Center at Dallas, results of the VNS pilot study showed that 40 percent of the treated patients displayed at least a 50 percent or greater improvement in their condition, according to the Hamilton Depression Rating Scale.[4][5] Many other studies concur that VNS is indeed efficacious in treating depression. However, these findings do not take into account improvements over time in patients without the device. In the only randomized controlled trial VNS failed to perform any better when turned on than in otherwise similar implanted patients whose device was not turned on.[6]

Patients

Charles E. Donovan, a study subject in the investigational trial of vagus nerve stimulation therapy for treatment-resistant depression, wrote Out of the Black Hole: The Patient's Guide to Vagus Nerve Stimulation and Depression.[7] Dennis Fegan, subject of the Reader's Digest article Medical Devices That Can Kill. [8]

Other uses

Because the vagus nerve is associated with many different functions and brain regions, research is being done to determine its usefulness in treating other illnesses, including various anxiety disorders, Alzheimer's disease, migraines,[9] fibromyalgia,[10] obesity,[11] and tinnitus.[12]

  • Alcohol addiction[13]
  • Atrial fibrillation[14][15]
  • Autism[16]
  • Bulimia nervosa[17]
  • Burn-induced organ dysfunction[18]
  • Chronic heart failure[19]
  • Chronic intractable hiccups[20]
  • Comorbid personality disorders[21]
  • Coronary artery disease[22]
  • Dravet syndrome[23]
  • Drop-attacks[24]
  • Heatstroke[25]
  • Heroin seeking behavior[26]
  • Intestinal epithelial barrier breakdown[27]
  • Lennox-Gastaut syndrome[28]
  • Memory[29]
  • Mood disorders in elderly population[30]
  • Multiple sclerosis[31]
  • Myocarditis[32]
  • Obsessive compulsive disorder[33]
  • Peripheral arterial occlusion disease[34]
  • Postoperative cognitive dysfunction in elderly patients[35]
  • Rasmussen's encephalitis[36]
  • Severe mental diseases[37]
  • Sepsis[38]
  • Spinal trigeminal neuronal[39]
  • Transient focal cerebral ischemia[40]
  • Trauma-hemorrhagic shock[41]
  • Traumatic brain injury[42][43]
  • Vaginal-Cervical self-stimulation in women with complete spinal cord injury[44][45]
  • Vegetative States After Traumatic Brain Injury[46]
  • Visceral pain-related affective memory[47]

Other brain stimulation techniques used to treat depression include Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES). Deep brain stimulation is currently under study as a treatment for depression. Transcranial magnetic stimulation (TMS) is under study as a therapy for both depression and epilepsy.[48] Trigeminal Nerve Stimulation (TNS) is being researched at UCLA as a treatment for epilepsy.[49]

Adverse events

The value of the FDA’s MAUDE database as an early warning system is undermined by two key problems: underreporting of the numerator (the number of adverse events), and the lack of a denominator (the total number of exposures). One cause of underreporting is that manufacturers do not have to report serious adverse events, including deaths, if they decide that the event is not related to the device. Jerome Hoffman, an expert in clinical epidemiology at the University of California, Los Angeles, is critical of the FDA’s policy of allowing manufacturers to make that determination. “The manufacturer has a powerful motive to find an alternative explanation for an adverse event. There’s always the possibility of a separate cause.” Dr Hoffman says that the agency should insist on independent adjudication of serious adverse events.

The database’s value could be further improved, says Dr Hoffman, by including denominator data. “It’s often claimed that even when bad events occur, they have to be relatively rare, given the huge number of exposures. That certainly may be true in some cases. But it’s hard to know for sure in any individual instance, because the FDA doesn’t track the number of exposures. It shouldn’t be that hard … considering that WalMart can apparently track every head of lettuce they sell, at every point of its existence. Of course the FDA would have to require that companies submit data on the quantity of devices sold, and in use.”

Ultimately, says Dr Hoffman, the process of ensuring device safety will continue to be compromised unless the thorny problem of interference from politicians and industry is tackled. “None of this occurs in a vacuum, of course. If we want to see fewer of these debacles in the future, it seems only logical that we’re going to have to look to root causes, such as how campaigns are financed, and how the wealthy and powerful get to have so much more influence on laws, regulations and policies, than do scientists and others who would advocate for making the public health more important than corporate profit.”

However, it is not clear that Dr Hoffman’s wish that scientists have greater influence on regulation than industry is likely to be realised any time soon. President Obama has appointed Margaret Hamburg as FDA commissioner. She has said she will step down as director with Henry Schein—the largest supplier of medical devices in North America and Europe. Hamburg and her husband, who is a hedge fund executive, reported their 2008 income at $10m.17 [50][51]

Cardiac

Cardiac arrhythmia during implantation [52][53] along with multitudes of late onset cardiovascular events have been reported.[54][55][56][57][58][59]

Sleep apnea

Intermittent decrease in respiratory flow during sleep has consistently been demonstrated in patients with VNS implants.[60] This seems to be due to an increase in vagal tone,[61] a measure of the control the vagus nerve has over the heartbeat.[62] Clinically significant sleep disordered breathing associated with VNS has been described in pediatric[63] and adult[64] patient populations. Most patients undergoing VNS treatment experience an increase of apnoea hypopnoea index (AHI) post treatment,[64] up to approximately one third develop mild obstructive sleep apnoea post treatment,[64] and a minority of patients develop severe obstructive sleep aponea related to VNS therapy.[63] These obstructive events can be alleviated by decreasing the frequency or intensity of VNS stimulation,[60] by having the patient sleep in non-supine position or by applying positive airway pressure.[64]

Screening for obstructive sleep apnoea (OSA) in patients with a seizure disorder who are undergoing a VNS implant is also important because adequate treatment of previously undiagnosed and untreated OSA is likely to result in better seizure control in these patients.[65]

Other

VNS causes stimulation of the superior and recurrent laryngeal nerves and is associated with problems ranging from alteration of voice(66%), coughing(45%), pharyngitis(35%) and throat pain(28%)[63] and hoarseness (very common) to frank laryngeal muscle spasm and upper airway obstruction (rare).[66] "Increased muscle tension," presumably in the upper body, may be experienced during the stimulation period.[67] The left vagus has proportionally lesser number of cardiac efferent fibers and placing the stimulator on this side potentially limits the arrhythmogenic effects of vagal stimulation but reversible bradyarrhythmias associated with vagal nerve stimulators have been well described.[68] Other nonspecific symptoms include headache, nausea, vomiting, dyspepsia,[68] dyspnea and paresthesia.[48]

In the treatment of epilepsy, randomized control trials conducted in the United States indicated that one-third of the patients had some type of an increase in seizures, with 17 percent having greater than a 25 percent increase. In each of the studies, there were patients who had greater than a 100 percent increase. In the E05 study, the range went up to a 234 percent increase, while in the E04 study, it went even higher, to a 680 percent maximum range.[69][70]

Anti-inflammatory activities of vagus nerve stimulation

The discovery by Kevin J. Tracey that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production has led to significant interest in the potential to use this approach for treating inflammatory diseases ranging from arthritis to colitis, ischemia, myocardial infarction, and congestive heart failure.[71] Action potentials transmitted in the vagus nerve activate the efferent arm of the Inflammatory Reflex, the neural circuit that converges on the spleen to inhibit the production of TNF and other pro-inflammatory cytokines by macrophages there.[72] This efferent arc is also known as the Cholinergic anti-inflammatory pathway[73] Because this strategy targets the release of TNF and other pro-inflammatory cytokines, it may be possible to use vagus nerve stimulation instead of anti-inflammatory antibodies (e.g., Remicade or Enbrel) to treat inflammation.

A recent study published in Science[74] demonstrated the existence of acetylcholine-synthesizing T-cells in the spleen that respond to vagal stimulation, resulting in suppression of inflammatory response / TNF-alpha via macrophages.

Methods of stimulation

Direct vagus nerve stimulation

This is currently the only widely used method of therapeutic VNS. It requires the surgical implantation of a stimulator device The Cyberonics VNS devices consist of a titanium-encased generator about the size of a pocket watch with a lithium battery to fuel the generator, a lead wire system with electrodes, and an anchor tether to secure leads to the vagus nerve. The battery life for the pulse generator is "between 1 [and] 16 years, depending on the settings [ie how strong the signal being sent is, the length of time the device stimulates the nerve each time, and how frequently the device stimulates the nerve]."[75]

Implantation of the Cyberonics VNS device is usually done as an out-patient procedure. The procedure goes as follows: an incision is made in the upper left chest and the generator is implanted into a little "pouch" on the left chest under the clavicle. A second incision is made in the neck, so that the surgeon can access the vagus nerve. The surgeon then wraps the leads around the left branch of the vagus nerve, and connects the electrodes to the generator. Once successfully implanted, the generator sends electric impulses to the vagus nerve at regular intervals.[76] The left vagus nerve is stimulated rather than the right because the right plays a role in cardiac function such that stimulating it could have negative cardiac effects.[48] The device is currently only made by Cyberonics, Inc.

Transcutaneous vagus nerve stimulation (t-VNS)

"Wearable" devices are being tested and developed that involve transcutaneous stimulation and do not require surgery. Electrical impulses are targeted at the aurical (ear), at points where branches of the vagus nerve have cutaneous representation. Specifically the concha has been target for t-VNS.[77]

See also

References

  1. ↑ Ghanem, T; Early, S (2006). "Vagal nerve stimulator implantation: An otolaryngologist's perspective". Otolaryngology - Head and Neck Surgery 135 (1): 46–51. doi:10.1016/j.otohns.2006.02.037. PMID 16815181.
  2. ↑ Lenzer J, Brownlee S (2010). "Why the FDA can't protect the public". BMJ 341: c4753. doi:10.1136/bmj.c4753.
  3. ↑ http://www.sciencedaily.com/releases/2010/11/101102191841.htm
  4. ↑ Doctor's Guide: Vagus Nerve Stimulation Successful For Depression
  5. ↑ Neurology Channel: Vagus Nerve Stimulation Archived October 27, 2005, at the Wayback Machine.
  6. ↑ FDA Summary of VNS Data
  7. ↑ Donovan, Charles E. (2006). Out of the Black Hole: A Patient's Guide to Vagus Nerve Stimulation and Depression. Wellness Publishers. ISBN 978-0-9748484-3-3.
  8. ↑ http://center4research.org/nrc-in-the-news/news-analysis-interviews-op-eds-editorials/medical-devices-that-can-kill/
  9. ↑ Groves, Duncan A.; Brown, Verity J. (2005). "Vagal nerve stimulation: A review of its applications and potential mechanisms that mediate its clinical effects". Neuroscience & Biobehavioral Reviews 29 (3): 493–500. doi:10.1016/j.neubiorev.2005.01.004.
  10. ↑ Clinical trial number NCT00294281 for "Vagus Nerve Stimulation for Treating Adults With Severe Fibromyalgia" at ClinicalTrials.gov
  11. ↑ Karason K, Mølgaard H, Wikstrand J, Sjöström L (April 1999). "Heart rate variability in obesity and the effect of weight loss". The American Journal of Cardiology 83 (8): 1242–7. doi:10.1016/S0002-9149(99)00066-1. PMID 10215292.
  12. ↑ http://www.utdallas.edu/news/2010/8/9-4791_NIH-Grant-Supports-Profs-Search-for-Tinnitus-Cure_article.html[]
  13. ↑ Herremans SC, Baeken C (September 2012). "The current perspective of neuromodulation techniques in the treatment of alcohol addiction: a systematic review" (PDF). Psychiatria Danubina 24 (Suppl 1): S14–20. PMID 22945180.
  14. ↑ Shen MJ, Shinohara T, Park HW, et al. (May 2011). "Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines". Circulation 123 (20): 2204–12. doi:10.1161/CIRCULATIONAHA.111.018028. PMC 3101282. PMID 21555706.
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