Clinical and mechanistic progress of vagus nerve stimulation in the treatment of comorbidities of epilepsy_Journal of Epilepsy

Authors：

LUO Yingting ^1,2,3 , NI Guanzhong ^1,2,3 , ZHANG Heyu ^1,2,3 , LONG Dingju ^1,2,3 ,  CHEN Ziyi ^1,2,3

1. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China;
2. Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou 510080, China;
3. National Key Clinical Department and Key Discipline of Neurology, Guangzhou 510080, China;

Corresponding author：

CHEN Ziyi, Email: chenziyi@mail.sysu.edu.cn

Keywords：

Epilepsy; Comorbidity; Vagus nerve stimulation

DOI：

10.7507/2096-0247.202410008

Video：

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People with epilepsy often have other comorbidities (such as depression, stroke, obesity, migraine, autism spectrum disorder, anxiety, bipolar disorder, attention deficit hyperactivity disorder, etc.). Approximately 50% of adults with active epilepsy have at least one Comorbidities of epilepsy. Epilepsy comorbidities are often associated with worse quality of life and prognosis. Vagus nerve stimulation (VNS) is a neuromodulation technique that relies on electrical stimulation and was approved by the Food and Drug Administration (FDA) in 1997 for the treatment of epilepsy. In the process of exploring the efficacy and mechanism of VNS in the treatment of epilepsy, an additional benefit was unexpectedly found, that is, VNS can meliorate symptoms of a variety of comorbidities. Since the FDA approved VNS for the treatment of depression in 2005, VNS has shown increasingly bright prospects in the treatment of comorbidities. In addition to the approved indications, including depression, stroke, obesity and migraine, VNS in other neuropsychiatric comorbidities have shown great potential. From invasive implantable VNS (iVNS) to non-invasive transcutaneous VNS (tVNS), studies on the benefits of VNS in the treatment of epilepsy and its Comorbidities are also evolving. This article reviews the progress of clinical treatment and mechanism of VNS in the treatment of epilepsy comorbidities in recent years, with the aim to provide the best treatment strategy for epilepsy patients and research basis for scientific researchers. At the same time, the parameter Settings of previous and latest clinical trials of VNS for the treatment of epilepsy comorbidity were summarized and analyzed to provide more references for the clinical application of VNS.

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1. 中国抗癫痫协会. 临床诊疗指南: 癫痫病分册(2023修订版). 北京: 人民卫生出版社, 2023: 119.
2. Keezer MR, Sisodiya SM, Sander JW. Comorbidities of epilepsy: current concepts and future perspectives. Lancet Neurol, 2016, 15(1): 106-115.
3. Schachter SC, Saper CB. Vagus nerve stimulation. Epilepsia, 1998, 39(7): 677-686.
4. Kamel LY, Xiong W, Gott BM, et al. Vagus nerve stimulation: an update on a novel treatment for treatment-resistant depression. J Neurol Sci, 2022, 434: 120171.
5. Dawson J, Liu CY, Francisco GE, et al. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet, 2021, 397(10284): 1545-1553.
6. Hampton T. Efforts seek to develop systematic ways to objectively assess surgeons' skills. JAMA, 2015, 313(8): 782-784.
7. Goadsby PJ, Grosberg BM, Mauskop A, et al. Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia, 2014, 34(12): 986-993.
8. Morris GL, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 2013, 81(16): 1453-1459.
9. Stefan H, Kreiselmeyer G, Kerling F, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia, 2012, 53(7): e115-118.
10. Fahoum F, Boffini M, Kann L, et al. VNS parameters for clinical response in Epilepsy. Brain Stimul, 2022, 15(3): 814-821.
11. Mylavarapu RV, Kanumuri VV, de Rivero Vaccari JP, et al. Importance of timing optimization for closed-loop applications of vagus nerve stimulation. Bioelectron Med, 2023, 9(1): 8.
12. Voges BR. Bi-level VNS therapy with different therapy modes at night and daytime improves seizures and quality of life in a patient with drug-resistant epilepsy. Epilepsy Behav Rep, 2023, 24: 100633.
13. Lambert MV, Robertson MM. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia, 1999, 40 Suppl 10: S21-47.
14. Ettinger AB, Weisbrot DM, Nolan EE, et al. Symptoms of depression and anxiety in pediatric epilepsy patients. Epilepsia, 1998, 39(6): 595-599.
15. Parker AP, Polkey CE, Binnie CD, et al. Vagal nerve stimulation in epileptic encephalopathies. Pediatrics, 1999, 103(4 Pt 1): 778-782.
16. Assenza G, Tombini M, Lanzone J, et al. Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review. Neurol Sci, 2020, 41(11): 3075-3084.
17. Demyttenaere K, Costa T, Kavakbasi E, et al. Baseline characteristics of a European patient population with difficult-to-treat depression (RESTORE-LIFE) treated with adjunctive vagus nerve stimulation. J Affect Disord, 2024, 344: 284-291.
18. Kavakbasi E, Bauermeister H, Lemcke L, et al. Impact of adjunctive VNS on drug load, depression severity, and number of neuromodulatory maintenance treatments. Brain Sci, 2024, 14(2).
19. Evensen K, Jorgensen MB, Sabers A, et al. Transcutaneous vagal nerve stimulation in treatment-resistant depression: a feasibility study. Neuromodulation, 2022, 25(3): 443-449.
20. Tan C, Qiao M, Ma Y, et al. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. J Affect Disord, 2023, 337: 37-49.
21. McAllister-Williams RH, Bulmer S, Newton K, et al. Assessment for vagus nerve stimulation in patients with difficult-to-treat depression: a model from the Newcastle Regional Affective Disorders Service (RADS). J Affect Disord, 2021, 280(Pt A): 315-318.
22. Reif-Leonhard C, Reif A, Baune BT, et al. Vagus nerve stimulation for difficult to treat depression. Nervenarzt, 2022, 93(9): 921-930.
23. Aboubakr O, Domenech P, Heurtebise I, et al. Vagus nerve stimulation allows to cease maintenance electroconvulsive therapy in treatment-resistant depression: a retrospective monocentric case series. Front Psychiatry, 2023, 14: 1305603.
24. Thompson SL, O'Leary GH, Austelle CW, et al. a review of parameter settings for invasive and non-invasive vagus nerve stimulation (vns) applied in neurological and psychiatric disorders. Front Neurosci, 2021, 15: 709436.
25. Krahl SE, Clark KB, Smith DC, et al. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia, 1998, 39(7): 709-714.
26. Ben-Menachem E, Hamberger A, Hedner T, et al. Effects of vagus nerve stimulation on amino acids and other metabolites in the CSF of patients with partial seizures. Epilepsy Res, 1995, 20(3): 221-227.
27. Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia, 1999, 40(8): 1051-1057.
28. Anisman H, Merali Z, Hayley S. Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol, 2008, 85(1): 1-74.
29. Lesperance P, Desbeaumes Jodoin V, Drouin D, et al. Vagus nerve stimulation modulates inflammation in treatment-resistant depression patients: a pilot study. Int J Mol Sci, 2024, 25(5).
30. Sun L, Ma S, Yu Y, et al. Transcutaneous auricular vagus nerve stimulation ameliorates adolescent depressive- and anxiety-like behaviors via hippocampus glycolysis and inflammation response. CNS Neurosci Ther, 2024, 30(2): e14614.
31. Liu C, Tang H, Liu C, et al. Transcutaneous auricular vagus nerve stimulation for post-stroke depression: A double-blind, randomized, placebo-controlled trial. J Affect Disord, 2024, 354: 82-88.
32. Wang Y, Zhan G, Cai Z, et al. Vagus nerve stimulation in brain diseases: therapeutic applications and biological mechanisms. Neurosci Biobehav Rev, 2021, 127: 37-53.
33. de Jonge WJ, van der Zanden EP, The FO, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the JAK2-STAT3 signaling pathway. Nat Immunol, 2005, 6(8): 844-851.
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