Vagus nerve stimulation

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Vagus nerve stimulation (VNS) is an adjunctive treatment for certain types of intractable epilepsy and treatment-resistant depression.

Mechanism of action[edit]

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 system activation.[1]

Randomized control trials indicated that thirty-percent of patients would have a greater than fifty-percent reduction of seizures.[2] On average, about fifty-percent of patients experience a forty percent or greater reduction in seizure frequency and severity. About 75% of patients choose to have the battery replaced (continue with the therapy).

Approval and endorsement[edit]

In 1997, the United States Food and Drug Administration (FDA) approved the use of VNS as an adjunctive therapy for partial-onset epilepsy. In 2005, the FDA approved the use of VNS for treatment-resistant depression.[3]

Although the use of VNS for refractory depression has been endorsed by the American Psychiatric Association, the FDA's approval of VNS for refractory depression 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[edit]

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]

Other uses[edit]

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,[3] fibromyalgia,[8] obesity,[9] and tinnitus.[10]

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.[11] Trigeminal Nerve Stimulation (TNS) is being researched at UCLA as a treatment for epilepsy.[12]

Adverse effects[edit]

Sleep apnea[edit]

Intermittent decrease in respiratory flow during sleep has consistently been demonstrated in patients with VNS implants.[13] This seems to be due to an increase in vagal tone,[14] a measure of the control the vagus nerve has over the heartbeat.[15] Clinically significant sleep disordered breathing associated with VNS has been described in pediatric[16] and adult[17] patient populations. Most patients undergoing VNS treatment experience an increase of apnoea hypopnoea index (AHI) post treatment,[17] up to approximately one third develop mild obstructive sleep apnoea post treatment,[17] and a minority of patients develop severe obstructive sleep aponea related to VNS therapy.[16] These obstructive events can be alleviated by decreasing the frequency or intensity of VNS stimulation,[13] by having the patient sleep in non-supine position or by applying positive airway pressure.[17]

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.[18]

Patients undergoing vagal nerve stimulator placement are at risk for developing OSA related to the VNS and should therefore be screened clinically for the presence of OSA after the procedure. Continuous Positive Airway Pressure (CPAP) is a viable therapeutic option for patients who develop OSA related to the VNS. Other options include increasing the cycle length or stimulation frequency of the device. With increasing number of indications and the number of patients undergoing the procedure, awareness of this causation is important for appropriate diagnosis and treatment of OSA related to vagal nerve stimulators.[citation needed]

Symptoms such as loud snoring or intermittent cessation of breathing during the night or daytime symptoms as behavioral changes, fatigue and sleepiness may alert the patient or parent to the presence of obstructive sleep apnoea, but these symptoms are generally insensitive and a sleep study (diagnostic polysomnography) is generally required to diagnose the presence of obstructive sleep apnoea. The fact that many of these patients are children and may have associated cognitive deficits makes diagnosing the problem even more difficult without a sleep study.[citation needed]

Other[edit]

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%)[16] and hoarseness (very common) to frank laryngeal muscle spasm and upper airway obstruction (rare).[19] "Increased muscle tension," presumably in the upper body, may be experienced during the stimulation period.[20] 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.[21] Other nonspecific symptoms such as headache, nausea, vomiting, dyspepsia,[21] dyspnea and paresthesia.[11]

Anti-inflammatory activities of vagus nerve stimulation[edit]

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.[22] 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.[23] This efferent arc is also known as the Cholinergic anti-inflammatory pathway[24] 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. SetPoint Medical, Inc. is an early-stage medical device company developing an implantable neurostimulation platform for the treatment of inflammatory diseases.[25]

A recent study published in Science (Sept 15, 2011 DOI : 10.1126/science.1209985) 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[edit]

Direct vagus nerve stimulation[edit]

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]."[26]

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.[27] 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.[11]

The device is currently only made by Cyberonics, Inc. However, other "wearable" devices are being tested and developed by other companies that involve transcutaneous stimulation and do not require surgery. These devices are similar to TENS (Transcutaneous Electrical Nerve Stimulation) devices that are often used for pain management.[citation needed]

Transcutaneous vagus nerve stimulation (t-VNS)[edit]

This method allows for the stimulation of the vagus nerve without surgical procedure. 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.[citation needed]

One such t-VNS device is cerbomed's NEMOS.[28] It is available on the market since 2012, and costs roughly 4000 euros. To date, there have been conducted several pilot studies on the effectiveness of t-VNS in different indications:[29][30]

  1. Epilepsy: A case series with seven patients who suffer from drug-resistant epilepsy has been conducted. The patients have been treated with t-VNS for nine months. The results indicate the potential for seizure reduction of t-VNS in drug-resistant epilepsies.[31]
  2. Pain: Results of a randomized, controlled study investigating somatosensory pain processing with 48 healthy volunteers showed a statistically significant and thus potentially clinically relevant lowering of the mechanical pain perception and a rise in the pressure pain threshold in subjects receiving t-VNS.[32] However, these studies have all been carried out by Cerbomed's staff or associates, and there are currently no independent studies demonstrating the effectiveness of t-VNS.

See also[edit]

References[edit]

  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. ^ http://www.youtube.com/watch?v=PdlqfdlSoT4
  3. ^ a b 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. doi:10.1016/j.neubiorev.2005.01.004. 
  4. ^ Doctor's Guide: Vagus Nerve Stimulation Successful For Depression
  5. ^ Neurology Channel: Vagus Nerve Stimulation[dead link]
  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. [non-primary source needed]
  8. ^ ClinicalTrials.gov NCT00294281 Vagus Nerve Stimulation for Treating Adults With Severe Fibromyalgia
  9. ^ Karason, K., Molgaard, H., Wikstrand, J., & Sjostrom, L. (1999). Heart rate variability in obesity and the effect of weight loss. The American Journal of Cardiology, 83, 1242-1247.
  10. ^ http://www.utdallas.edu/news/2010/8/9-4791_NIH-Grant-Supports-Profs-Search-for-Tinnitus-Cure_article.html
  11. ^ a b c George, M; Sackeim, HA; Rush, AJ; Marangell, LB; Nahas, Z; Husain, MM; Lisanby, S; Burt, T et al. (2000). "Vagus nerve stimulation: A new tool for brain research and therapy*". Biological Psychiatry 47 (4): 287–95. doi:10.1016/S0006-3223(99)00308-X. PMID 10686263. 
  12. ^ "UCLA Develops Unique Nerve-stimulation Epilepsy Treatment; "Brain Pacemaker" Designed as External or Implant Device" (Press release). 2006-07-25. Retrieved 2006-07-26. 
  13. ^ a b Malow, BA; Edwards, J; Marzec, M; Sagher, O; Fromes, G (2000). "Effects of vagus nerve stimulation on respiration during sleep: A pilot study". Neurology 55 (10): 1450–4. PMID 11094096. 
  14. ^ Marzec, Mary; Edwards, Jonathan; Sagher, Oren; Fromes, Gail; Malow, Beth A. (2003). "Effects of Vagus Nerve Stimulation on Sleep-related Breathing in Epilepsy Patients". Epilepsia 44 (7): 930–5. doi:10.1046/j.1528-1157.2003.56202.x. PMID 12823576. 
  15. ^ http://www.iworx.com/support/manuals/pieces/214_bp1L.pdf[full citation needed]
  16. ^ a b c Hsieh, T; Chen, M; McAfee, A; Kifle, Y (2008). "Sleep-Related Breathing Disorder in Children with Vagal Nerve Stimulators". Pediatric Neurology 38 (2): 99–103. doi:10.1016/j.pediatrneurol.2007.09.014. PMID 18206790. 
  17. ^ a b c d Marzec, Mary; Edwards, Jonathan; Sagher, Oren; Fromes, Gail; Malow, Beth A. (2003). "Effects of Vagus Nerve Stimulation on Sleep-related Breathing in Epilepsy Patients". Epilepsia 44 (7): 930–5. doi:10.1046/j.1528-1157.2003.56202.x. PMID 12823576. 
  18. ^ Vaughn, B; Dcruz, O; Beach, R; Messenheimer, J (1996). "Improvement of epileptic seizure control with treatment of obstructive sleep apneoa". Seizure 5 (1): 73–8. doi:10.1016/S1059-1311(96)80066-5. PMID 8777557. 
  19. ^ Bernards, Christopher M. (2004). "An Unusual Cause of Airway Obstruction during General Anesthesia with a Laryngeal Mask Airway". Anesthesiology 100 (4): 1017–8. doi:10.1097/00000542-200404000-00037. PMID 15087642. 
  20. ^ "Vagus Nerve Stimulation". University of Michigan Depression Center. Retrieved 28 August 2013. 
  21. ^ a b Hatton, Kevin W.; McLarney, J Thomas; Pittman, Thomas; Fahy, Brenda G. (2006). "Vagal Nerve Stimulation: Overview and Implications for Anesthesiologists". Anesthesia & Analgesia 103 (5): 1241–9. doi:10.1213/01.ane.0000244532.71743.c6. 
  22. ^ Tracey, Kevin J. (2007). "Physiology and immunology of the cholinergic antiinflammatory pathway". Journal of Clinical Investigation 117 (2): 289–96. doi:10.1172/JCI30555. PMC 1783813. PMID 17273548. 
  23. ^ Rosas-Ballina, M.; Ochani, M.; Parrish, W. R.; Ochani, K.; Harris, Y. T.; Huston, J. M.; Chavan, S.; Tracey, K. J. (2008). "Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia". Proceedings of the National Academy of Sciences 105 (31): 11008–13. doi:10.1073/pnas.0803237105. PMC 2504833. PMID 18669662. 
  24. ^ Tracey, Kevin J. (2009). "Reflex control of immunity". Nature Reviews Immunology 9 (6): 418–28. doi:10.1038/nri2566. PMID 19461672. 
  25. ^ http://www.setpointmedical.com/[full citation needed]
  26. ^ Cyberonics, Inc. (2007.) VNS Therapy Patient Essentials: Depression.
  27. ^ Panescu, Dorin (2005). Emerging Technologies: Vagus Nerve Stimulation for the Treatment of Depression. IEEE Engineering in Medicine and Biology Magazine.[page needed]
  28. ^ http://www.cerbomed.com/product.html[full citation needed]
  29. ^ ClinicalTrials.gov NCT01178437 Transcutaneous Non-invasive Stimulation of the Vagus Nerve for the Treatment of Difficult-to-treat Epilepsy
  30. ^ ClinicalTrials.gov NCT01174498 Pilot Study of the Effect of Transcutaneous Stimulation of the Vagus Nerve on Pain Perception and Parameters of the Autonomic Nervous System
  31. ^ http://www.cerbomed.com/index.php?lang=en#faq[full citation needed]
  32. ^ Ellrich J, Busch V, Eichhammer P, "Inhibition of Pain Processing by Transcutaneous Vagus Nerve Stimulation" p.383 in "Abstracts". Neuromodulation 14 (4): 357–88. 2011. doi:10.1111/j.1525-1403.2011.00363.x. [unreliable medical source?]

Further reading[edit]

External links[edit]