Vagus nerve stimulation (VNS) plus rehabilitation provided greater functional improvements compared with sham stimulation plus rehabilitation for patients with moderate to severe arm impairment after ischemic stroke, results of a phase 3 randomized trial show.
"VNS combined with rehabilitation is an acceptably safe and effective intervention for improving upper-limb impairment and function in people with moderate to severe arm weakness at least 9 months after ischemic stroke," said Jesse Dawson, MD, MBChB, professor of stroke medicine at the University of Glasgow, Glasgow, United Kingdom, during a presentation at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.
Approximately half of people with stroke experience severe arm weakness after the event, which is a predictor of poor quality of life. VNS appears to promote the release of norepinephrine and acetylcholine onto the cerebral cortex. Pairing VNS and rehabilitation increases the recruitment of neurons and has shown promise in increasing the benefits of rehabilitation among patients with stroke.
Dawson and colleagues hypothesized that intense rehabilitation plus VNS would promote increased plasticity for patients with stroke and upper-limb deficits. To test their hypothesis, they conducted a pivotal phase 3 trial that compared VNS and sham stimulation as supplements to rehabilitation.
The investigators enrolled patients who experienced long-term arm weakness after ischemic stroke. Eligible patients were between the ages of 22 and 80 years. They had had an ischemic stroke 9 months to 10 years before enrollment and had undergone a rehabilitation program. The cutoff for the date of stroke onset was "based on our previous studies where time from stroke did not appear to influence effect, and we did not want to include people too early after stroke," Dawson told Medscape Medical News. Patients with severe spasticity and those with a history of hemorrhagic stroke were excluded.
All participants underwent VNS implantation. The investigators randomly assigned patients to VNS plus intense rehabilitation or sham stimulation plus intense rehabilitation. Rehabilitation consisted of 6 weeks of in-clinic sessions (ie, three 2-hour sessions per week), followed by a home-based program for 90 days. Patients were assessed at 1, 30, and 90 days after the completion of in-clinic therapy.
The study's primary outcome measure was change in score on the Fugl-Meyer Assessment–Upper Extremity (FMA-UE) from baseline to day 1 after completion of therapy. Secondary endpoints included the number of responders (defined as those with an improvement of 6 or more points on the FMA-UE) after day 90, the change in score on the Wolf Motor Function Test (WMFT) from baseline to after day 90, and change in FMA-UE score from baseline to after day 90.
Dawson and colleagues implanted a VNS system in 108 patients and randomly assigned them to a study arm. Overall, 107 participants completed the intervention, and 106 underwent assessment of the primary outcome. Participants' responses to a questionnaire indicated that they had remained successfully blinded to their treatment assignment.
The active and control groups were well matched on demographic characteristics. Women represented approximately 35% of each group, and approximately 80% were White patients. The active group was slightly younger (59.1 years) than the control group (61.1 years), however. The baseline FMA-UE score was lower in the active group (34.4) than in the control group (35.7), but these differences likely had no clinical significance, said Dawson.
The analysis of the primary endpoint showed that at day 1 after the completion of 6 weeks of in-clinic therapy, the mean FMA-UE score increased by 5.0 points in the VNS group and by 2.4 points in the sham-stimulation group (P = .001).
In addition, 25 patients (47%) in the VNS group achieved a clinically meaningful response on the FMA-UE score at day 90 after completion of in-clinic therapy, compared with 13 participants (24%) in the control group (P = .01), said Dawson.
After day 90, the WMFT score had increased by 0.46 points in the VNS group and by 0.16 points among control patients (P < .0001). From baseline to after day 90, the FMA-UE score had increased by 5.8 points with VNS and by 2.8 points for control patients (P = .008).
Adverse events occurred at expected rates, according to the researchers. One patient experienced vocal cord palsy, and two leads needed to be replaced. Five serious adverse events occurred in the VNS group; three occurred in the control group. No serious adverse events were related to the VNS device. Forty-three participants in the VNS group and 42 control patients had nonserious adverse events.
Patients with stroke who are appropriate candidates for VNS implantation include those with "moderately severe to severe arm problems, but at least some hand movement, at 9 months or more after stroke who do not have major problems with spasticity or major sensory loss and who are fit enough for general anesthesia," said Dawson. "We hope to begin some implementation research and trials in people with no arm movement at all, who were excluded from this study."
A significant strength of the current study is that the investigators measured not only functional impairment but also functional capacity, Catherine E. Lang, PT, PhD, professor of physical therapy, occupational therapy, and neurology at Washington University School of Medicine, St. Louis, Missouri, told Medscape Medical News. Measures of impairment are useful to clinicians and researchers, but patients are more concerned about measures of capacity, she added.
Although the functional differences between groups reached statistical significance, they appear to be small. The difference between groups in scores on the FMA-UE, for example, "is well within the error of measurement on that tool," said Lang. These differences are not necessarily clinically significant, she added.
An analysis that identifies patients most likely to respond to VNS as an adjunct to rehabilitation would provide clinically relevant information, she added. Future research also could seek to identify the appropriate stimulation parameters, as well as evaluate whether stimulation parameters could be individualized. Another question is how to optimize the stimulation parameters and the training parameters in tandem. "It's a wide-open field for continuing research," said Lang.
The research was funded by MicroTransponder. Dawson and one of his coauthors have received travel reimbursement from MicroTransponder, the company that manufactured the VNS system used in this study. Lang has disclosed no relevant financial relationships.
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Cite this: VNS May Improve Upper-Limb Rehabilitation After Stroke - Medscape - Nov 16, 2020.