The Lancet is heavy!

*Only for medical professionals to read for reference.
Pay attention to the prognosis of stroke patients.

Ischemic stroke is the main cause of disability and death in the world.
It not only brings a heavy burden to the families of patients, but also brings a heavy economic burden to society and the government.

The current treatment of ischemic stroke includes intravenous thrombolysis and mechanical thrombus removal.
Although both treatment methods have made important progress in recent years, only 10% or less of patients have had it in an appropriate time window.
Conditions can accept these treatments, which limits the clinical application of these two treatments.

Moreover, the burden of disability after stroke is extremely high.
About 80% of acute stroke patients have upper limb dyskinesia, and about 60% of patients still have upper limb dysfunction within 6 months after stroke, which restricts the patients’ daily activities and affects Personal quality of life [1].

Vagus nerve stimulation (VNS) refers to any technique that stimulates the vagus nerve.
Vagus nerve stimulation has recently been explored as a promising treatment method.
It targets many different neuroprotective and neuroplastic pathways and is considered for ischemic stroke.
treatment.

One of the targeted strategies is to use VNS combined with rehabilitation therapy to increase neuroplasticity and promote the recovery of upper limb function after stroke.
The stimulation of the vagus nerve triggers the release of neuromodulators, such as acetylcholine and norepinephrine, in conjunction with exercise Training can improve the functional recovery of the motor cortex [2].

Currently, the U.
S.
Food and Drug Administration (FDA) has approved VNS devices for the treatment of medically refractory, partial-onset epilepsy and refractory depression (TRD); in 2017, transcutaneous cervical vagus nerve stimulation (tcVNS) ) Obtained FDA approval for the treatment of migraine and cluster headache.

In addition, other studies are expanding the potential applications of the vagus nerve stimulation system to a wider range of therapeutic applications, such as traumatic brain injury (TBI), cerebral hemorrhage, chronic tinnitus, Alzheimer’s disease (AD), Parkinson’s disease, and multiple Sexual sclerosis [3] and other diseases.

"Electricity" is expected to restore the limb dysfunction of stroke patients? Previously, a Meta analysis of animals showed that VNS combined with rehabilitation training (VNS+Rehab) can continuously improve the recovery of the motor function of the forelimbs in rats [4,5] (see Figure 1).

Figure 1: Forest diagram of the meta-analysis of the animal model of VNS+Rehab So can Zhongfeng patients recover through this treatment? From preclinical experiments to clinical applications, experts from the United Kingdom and the United States have carried out relevant clinical studies in 19 stroke rehabilitation service organizations, and published the results on Lancet on April 24, 2021 [6].

This study aims to investigate whether VNS combined with rehabilitation training (VNS+Rehab) can be a safe and effective treatment to improve the upper limb function of stroke patients.

The trial is a randomized, triple-blind, sham operation trial.
Patients with moderate to severe upper limb dysfunction caused by stroke (at least 9 months after ischemic stroke) were randomly assigned into two groups, each combined with vagus nerve stimulation The rehabilitation treatment group (VNS group) combined with false stimulation (control group).

The study was enrolled from October 2, 2017 to September 12, 2019.
A total of 108 subjects were enrolled (53 in the VNS group and 55 in the control group).

All participants were implanted with vagus nerve stimulation device, VNS group (0.
8mA, 100μs, 30Hz stimulation pulse, lasting 0.
5s) VS control group (0mA pulse).

Intervention measures: The intervention period is 3 months, the clinical treatment lasts for 6 weeks (3 times a week; a total of 18 treatments), after which family rehabilitation exercises are carried out.

Main outcome indicators: Fugl-Meyer assessment-upper limb (FMA-UE) scores on the first day after completion of clinical treatment and 90 days after treatment.

The results of the study showed: ①The included patients were randomized and grouped by SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), by region (US vs.
UK), age (≤30 years vs.
>30 years) and baseline FMA-UE The scores (20-35 vs 36-50) are stratified (see Figure 2). Figure 2: Basic data of the included patients ② 106 people have finally completed the trial (one patient in each group did not complete the study); 1) On the first day after completing the clinical treatment, the average FMA-UE score of the VNS group increased by 5.
0 points (SD4.
4) ), the average FMA-UE score of the control group increased by 2.
4 points (SD3.
8) [the difference between groups was 2.
6, 95% CI (1.
0-4.
2), p=0.
0014].

2) 90 days after clinical treatment, 23 of the 53 patients in the VNS group (47%) obtained a clinically significant FMA-UE score response, while 13 of the 55 patients in the control group (24%) obtained Clinically significant FMA-UE score response [24% difference between groups, 95% CI (6-41), p=0.
0098] (see Figure 3).

Figure 3: Are there other relevant clinical studies on the VNS group vs.
control group endpoint outcome indicators compared to VNS treatment? Regarding the clinical study of VNS in the treatment of ischemic stroke, in addition to the above study, other researchers have conducted related clinical studies before: (1) Published in Stroke in 2016, Dawson et al.
Patients with chronic ischemic stroke with moderate to severe upper limb weakness conducted a single-blind randomized feasibility study to evaluate the effect of combining vagus nerve stimulation with exercise rehabilitation.

The subjects received VNS and rehabilitation at random, the VNS group (n=9) vs the control group (n=11), the selection of stimulation parameters was based on early preclinical research, and the main outcome indicators were the FMA-UE score and response rate Change (FMA-UE change of 6 points is considered clinically significant).
After 6 weeks of clinical recovery, the VNS group improved by 9.
6 points, while the control group only improved by 3.
0 points (the difference between groups = 6.
5 points, 95% CI: 0.
4 -12.
6, P=0.
038), the effective rates of the VNS group and the control group were 66% vs 36.
4%, and no serious adverse reactions were reported.
The results suggest that VNS combined with rehabilitation therapy is effective and safe for ischemic stroke Sex [7].

(2) The second study was also published in Stroke in 2018, a multicenter, completely blinded randomized study conducted by Kimberley et al.
on 17 patients with chronic ischemic stroke with upper limb dysfunction.
All participants All were implanted with a vagus nerve stimulation device and received cross-paired VNS treatment. After 6 weeks of clinical treatment, the FMA-UE score of the VNS group increased by 7.
6 points, and the control group increased by 5.
3 points.

90 days after the end of clinical treatment, the FMA-UE score of the VNS group increased by 9.
5 points, and the control group increased by 3.
8 points.

The remission rate in the VNS group (FMA-UE change 6 points for clinical significance) was 88% vs.
33% in the control group (p=0.
03).

After the control group received clinical VNS, FMA-UE improved by 9.
8 points from baseline (p<0.
001) after 6 weeks.

After 2 months of family VNS treatment, the improvement of FMA-UE remained at 9.
7 points (p=0.
01).

The results show that compared with rehabilitation alone, rehabilitation combined with vagus nerve stimulation has more than doubled the improvement of upper limb injury, which is effective in improving the patient's upper limb dysfunction [8].

Summary: The efficacy of vagus nerve stimulation combined with rehabilitation therapy, whether in animal models or in clinical studies, consistently shows that compared with equivalent rehabilitation therapy without vagus nerve stimulation, vagus nerve stimulation combined with rehabilitation therapy significantly enhances the recovery of nerve function.
This will bring great gospel to the recovery of limb dysfunction of stroke patients. References: [1] Engineer ND, Kimberley TJ, Prudente CN, Dawson J, Tarver WB and Hays SA (2019) Targeted Vagus Nerve Stimulation for Rehabilitation After Stroke.
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Vagus nerve stimulation as a promising adjunctive treatment for ischemic stroke.
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[3]FDA OKs Neuromodulation Device to Improve Gait in MS, Megan Brooks.
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Restoring Central Networks Improves Motor and Sensory Function After Nerve Damage.
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