Top

Published in:

Open Access 01-12-2020 | Magnetic Resonance Imaging | Study protocol

NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial

Authors: Anne van der Meij, Marianne A. A. van Walderveen, Nyika D. Kruyt, Erik W. van Zwet, Eric J. Liebler, Michel D. Ferrari, Marieke J. H. Wermer

Published in: Trials | Issue 1/2020

Abstract

Background

Secondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models, vagus nerve stimulation (VNS) inhibits these detrimental changes and thereby reduces tissue injury. The aim of this study is to investigate whether non-invasive cervical VNS (nVNS) in addition to the current standard treatment can improve penumbral recovery and limit final infarct volume.

Methods

NOVIS is a single-center prospective randomized clinical trial with blinded outcome assessment. One hundred fifty patients will be randomly allocated (1:1) within 12 h from clinical stroke onset to nVNS for 5 days in addition to standard treatment versus standard treatment alone. The primary endpoint is the final infarct volume on day 5 assessed with MRI.

Discussion

We hypothesize that nVNS will result in smaller final infarct volumes as compared to standard treatment due to improved penumbral recovery. The results of this study will be used to assess the viability and approach to power a larger trial to more definitively assess the clinical efficacy of nVNS after stroke.

Trial registration

ClinicalTrials.govNCT04050501. Registered on 8 August 2019

Wardlaw JM, Murray V, Berge E, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2014:Cd000213. https://doi.org/10.1002/14651858.CD000213.pub3.

Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723–31. https://doi.org/10.1016/s0140-6736(16)00163-x.CrossRefPubMed

Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38–360. https://doi.org/10.1161/cir.0000000000000350.CrossRefPubMed

Rai AT, Seldon AE, Boo S, et al. A population-based incidence of acute large vessel occlusions and thrombectomy eligible patients indicates significant potential for growth of endovascular stroke therapy in the USA. J Neurointerv Surg. 2017;9:722–6. https://doi.org/10.1136/neurintsurg-2016-012515.CrossRefPubMed

Hankey GJ. Stroke. Lancet. 2017;389:641–54. https://doi.org/10.1016/s0140-6736(16)30962-x.CrossRefPubMed

Heiss WD. The ischemic penumbra: how does tissue injury evolve? Ann N Y Acad Sci. 2012;1268, 26:–34. https://doi.org/10.1111/j.1749-6632.2012.06668.x.

Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med. 2011;17:439–47. https://doi.org/10.1038/nm.2333.CrossRefPubMed

Nakamura H, Strong AJ, Dohmen C, et al. Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain. 2010;133:1994–2006. https://doi.org/10.1093/brain/awq117.CrossRefPubMedPubMedCentral

Hartings JA, Shuttleworth CW, Kirov SA, et al. The continuum of spreading depolarizations in acute cortical lesion development: examining Leao’s legacy. J Cerebral Blood Flow Metab. 2017;37:1571–94. https://doi.org/10.1177/0271678x16654495.CrossRef

10.

Cai PY, Bodhit A, Derequito R, et al. Vagus nerve stimulation in ischemic stroke: old wine in a new bottle. Front Neurol. 2014;5:107. https://doi.org/10.3389/fneur.2014.00107.CrossRefPubMedPubMedCentral

11.

Yang Y, Yang LY, Orban L, et al. Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke. Brain Stimul. 2018. https://doi.org/10.1016/j.brs.2018.01.034.

12.

Chen SP, Ay I, de Morais AL, et al. Vagus nerve stimulation inhibits cortical spreading depression. Pain. 2016;157:797–805. https://doi.org/10.1097/j.pain.0000000000000437.CrossRefPubMedPubMedCentral

13.

Ay I, Nasser R, Simon B, et al. Transcutaneous cervical vagus nerve stimulation ameliorates acute ischemic injury in rats. Brain Stimul. 2016;9:166–73. https://doi.org/10.1016/j.brs.2015.11.008.CrossRefPubMed

14.

Sun Z, Baker W, Hiraki T, et al. The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat. Brain Stimul. 2012;5:1–10. https://doi.org/10.1016/j.brs.2011.01.009.CrossRefPubMed

15.

Hiraki T, Baker W, Greenberg JH. Effect of vagus nerve stimulation during transient focal cerebral ischemia on chronic outcome in rats. J Neurosci Res. 2012;90:887–94. https://doi.org/10.1002/jnr.22812.CrossRefPubMedPubMedCentral

16.

Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38:1091–6. https://doi.org/10.1161/01.STR.0000258355.23810.c6.CrossRefPubMed

17.

van Os HJ, Mulder IA, van der Schaaf IC, et al. Role of atherosclerosis, clot extent, and penumbra volume in headache during ischemic stroke. Neurology. 2016;87:1124–30. https://doi.org/10.1212/wnl.0000000000003092.CrossRefPubMed

18.

Bjelland I, Dahl AA, Haug TT, et al. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res. 2002;52:69–77.CrossRef

19.

Barber M, Stott DJ. Validity of the Telephone Interview for Cognitive Status (TICS) in post-stroke subjects. Int J Geriatric Psychiatry. 2004;19:75–9. https://doi.org/10.1002/gps.1041.CrossRef

20.

Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–36. https://doi.org/10.1007/s11136-011-9903-x.CrossRefPubMedPubMedCentral

21.

Sarraj A, Hassan AE, Savitz S, et al. Outcomes of endovascular thrombectomy vs medical management alone in patients with large ischemic cores: a secondary analysis of the Optimizing Patient’s Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT) study. JAMA Neurol. 2019. https://doi.org/10.1001/jamaneurol.2019.2109.

22.

Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20. https://doi.org/10.1056/NEJMoa1411587.CrossRefPubMed

23.

DeGiorgio CM, Schachter SC, Handforth A, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia. 2000;41:1195–200.CrossRef

24.

Morris GL 3rd, 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;81:1453–9. https://doi.org/10.1212/WNL.0b013e3182a393d1.CrossRefPubMedPubMedCentral

25.

Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014;1:64–73. https://doi.org/10.1007/s40473-014-0010-5.CrossRefPubMedPubMedCentral

26.

Gaul C, Diener HC, Silver N, et al. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): a randomised controlled study. Cephalalgia. 2016;36:534–46. https://doi.org/10.1177/0333102415607070.CrossRefPubMed

27.

Goadsby PJ, de Coo IF, Silver N, et al. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. 2018;38:959–69. https://doi.org/10.1177/0333102417744362.CrossRefPubMed

28.

Tassorelli C, Grazzi L, de Tommaso M, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology. 2018;91:e364–73. https://doi.org/10.1212/wnl.0000000000005857.CrossRefPubMedPubMedCentral

29.

Dawson J, Pierce D, Dixit A, et al. Safety, feasibility, and efficacy of vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke. Stroke. 2016;47:143–50. https://doi.org/10.1161/strokeaha.115.010477.CrossRefPubMed

30.

Capone F, Miccinilli S, Pellegrino G, et al. Transcutaneous vagus nerve stimulation combined with robotic rehabilitation improves upper limb function after stroke. Neural Plasticity. 2017;2017:7876507. https://doi.org/10.1155/2017/7876507.CrossRefPubMedPubMedCentral

31.

Redgrave JN, Moore L, Oyekunle T, et al. Transcutaneous auricular vagus nerve stimulation with concurrent upper limb repetitive task practice for poststroke motor recovery: a pilot study. J Stroke Cerebrovasc Dis. 2018;27:1998–2005. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.02.056.CrossRefPubMed

32.

Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378:708–18. https://doi.org/10.1056/NEJMoa1713973.CrossRefPubMedPubMedCentral

33.

Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21. https://doi.org/10.1056/NEJMoa1706442.CrossRefPubMed

34.

Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380:1795–803. https://doi.org/10.1056/NEJMoa1813046.CrossRefPubMed

35.

Albers GW. Use of imaging to select patients for late window endovascular therapy. Stroke. 2018;49:2256–60. https://doi.org/10.1161/strokeaha.118.021011.CrossRefPubMed

36.

Straka M, Albers GW, Bammer R. Real-time diffusion-perfusion mismatch analysis in acute stroke. J Magnet Resonance Imaging. 2010;32:1024–37. https://doi.org/10.1002/jmri.22338.CrossRef

Title: NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial
Authors: Anne van der Meij
Marianne A. A. van Walderveen
Nyika D. Kruyt
Erik W. van Zwet
Eric J. Liebler
Michel D. Ferrari
Marieke J. H. Wermer
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Stroke
Vagus Nerve Stimulation
Published in: Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-020-04794-1

At a glance: The STEP trials

Springer Medicine

NOn-invasive Vagus nerve stimulation in acute Ischemic Stroke (NOVIS): a study protocol for a randomized clinical trial

Abstract

Background

Methods

Discussion

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2020

A double-blind, randomized, crossover trial protocol of whole hemp seed protein and hemp seed protein hydrolysate consumption for hypertension

Effectiveness and tolerability of repetitive transcranial magnetic stimulation for preventive treatment of episodic migraine: a single-centre, randomised, double-blind, sham-controlled phase 2 trial (Magnet-EM)

Neuromuscular exercise and pain neuroscience education compared with pain neuroscience education alone in patients with chronic pain after primary total knee arthroplasty: study protocol for the NEPNEP randomized controlled trial

Quantitative response of healthy muscle following the induction of capsaicin: an exploratory randomized controlled trial

Design and rationale of the Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction: study protocol for a randomized controlled trial

“Early transfusion of convalescent plasma in older patients with COVID-19 to prevent disease progression: A structured summary of a study protocol for a randomised controlled trial”