Vagal Nerve Stimulation Improves Arm Function After Stroke

February 27, 2017

HOUSTON, Texas — An implanted device that stimulates the vagus nerve has shown promising improvement of arm function in stroke patients in a second small clinical study.

While the primary endpoint — change in functional score after 6 weeks of therapy — was not significantly different between treatment groups, the improvement did appear to become significant after a further 60 days of treatment, as did responder rates.

Lead investigator, Jesse Dawson, MD, University of Glasgow, United Kingdom, reported that the group receiving active stimulation with the device showed a 9-point improvement in upper-limb Fugl-Meyer (UEFM) score at this time point.

Dr Jesse Dawson

"All in all, we feel this is quite promising," Dr Dawson said. "A 9-point change in this scale is highly likely to be clinically significant."

This magnitude of change would mean different things for different patients, depending on where they start, he said. "If they start at 20 — which is not much function at all — they might regain some grasp ability so they might be able to carry a plate, for example. If they were in the 30s to start with, they would probably already have the grasp function but they would be able to get back to do more specific tasks."

The results were presented here at the International Stroke Conference (ISC) 2017.

"Spectacular" Results

Commenting on the study, American Heart Association/American Stroke Association spokesperson, Philip Gorelick, MD, MPH, medical director, Hauenstein Neuroscience Center, Grand Rapids, Michigan, described the results as "pretty spectacular."

Dr Philip Gorelick

"It is always difficult to know what you are getting with these scales, but when you see jumps like this I think it's safe to conclude that there is clinical significance. There is probably something real going on," Dr Gorelick said.

"You must remember that these are chronic patients with moderate to severe arm weakness at 18 months down the line from their stroke," he added. "We think these patients are finished — they are not going to be doing much with that arm. Obviously this study is exploratory, but this raises a lot of hope."

A larger trial in 120 patients is now planned.

Dr Dawson noted that arm weakness is a major problem and is associated with a poor quality of life in patients who have had a stroke. He estimated that it affects about 75% of all patients in the early months and remains a permanent issue for about half of patients.

The device used in this study, manufactured by MicroTransponder Inc, is surgically implanted just below the collar bone and delivers electrical stimulation to the vagus nerve. The stimulation, which is given in conjunction with rehabilitation physiotherapy, is believed to cause the brain to be more receptive to the recovery training exercises.

"Experimental data shows that stimulation of the vagus nerve activates structures within the brain stem, which cause release of neurotransmitters such as norepinephrine or acetylcholine onto the surface of the brain," Dr Dawson explained. "This temporary spike of these neurotransmitters at the time of physiotherapy is thought to help the brain adapt to the physical therapy exercises."

He reported that vagal nerve stimulation had shown improvement in forelimb function in rodent models of stroke. A preliminary clinical study in 20 patients (9 active, 11 controls) suggested this approach is safe and feasible and indicated some efficacy in patients with arm weakness up to 5 years after stroke.

The current double-blind study with control sham stimulation was the next step.

For this analysis — which included 17 patients — the device was implanted in all patients; 8 received active stimulation while 9 received sham stimulation (controls). Patients had a mean age of 60 years, and the mean time from stroke was 1.5 years.

Serious adverse events related to the surgical implantation included a wound infection (resolved with antibiotics), dysphagia (resolved within a week after implant surgery), and two vocal cord paralyses (one recovered, one ongoing).

For the first part of the study, the treatment was delivered during physical therapy sessions in the clinic for 6 weeks. These consisted of 3 sessions per week of 2 hours' duration, in which the vagal nerve stimulation was given in 0.5-second bursts, with 0.8-mA stimulation given per movement and approximately 400 stimulations per session. Control patients had the same therapy, but no electrical stimulation was delivered.

Patients then had 30 days without therapy, after which they resumed treatment for a further 60 days at home, with patients delivering the stimulation themselves while performing their exercise program. Again, the devices were programmed so that the active group received the full amount of electrical stimulation while the control group would fire the device but no current would be delivered.

Dr Dawson said he believed the blinding worked well because after the study, only 33% of patients were able to correctly identify which group they were in. "Just by the laws of chance you would expect half of them to guess right, so this seems encouraging," he added.

Results showed that the primary endpoint — change in UEFM score after at the end of the first 6-week treatment period (day 1 of follow up) — was not significantly different between the two groups.

However, the secondary endpoint at 90 days of follow-up showed significant benefits. Also, there was a large improvement in responder rate (the number of patients who crossed what the researchers believed to be a clinically meaningful threshold), which became significant at the 90-day follow-up.

Results were similar for a second functional score, the Wolf Motor Function Test (WMFT) scale.

Table. Vagal Nerve Stimulation: Main Results

Endpoint Active Treatment (n = 8) Control (n = 9) P Value
Change in UEFM score at day 1 of follow-up (primary endpoint) 7.6 5.3 .26
Responder rate at day 1 of follow-up (%) 75 33 .15
Change in UEFM score at day 90 of follow-up 9.5 3.8 .05
Responder rate at day 90 of follow-up (%) 88 33 .05
Change in WMFT score at day 1 of follow-up 0.25 0.13 .26
Change in WMFT score at day 90 of follow-up 0.36 0.04 .07

 

Dr Dawson reported that at the end of the study, the control patients crossed over to receive 6 weeks of active therapy, after which their UEFM scores also improved by a further 9 points.

All patients are now continuing on active treatment for 2 years.

Dr Gorelick said he would like to see quality-of-life data. "It's all very well saying we have improvement in function, but we want to know whether that is meaningful — ie, what exact improvement we get." He added that finger agility is particularly important for quality-of-life benefit. Dr Dawson said quality-of-life data were being finalized.

It would be useful to have functional MRI data to see whether the device is causing changes in the brain, Dr Gorelick noted. "From our experience with functional MRI, you can see the brain reorganizing with other parts taking over. It would be good to see this to know the treatment is working."

Dr Dawson said the current device is not compatible with MRI, but it is hoped that subsequent models will be. He added that much data from experimental models showed functional changes in the brain with this approach.

Finally, Dr Gorelick pointed out that it was crucial to select the right patients for trials of this type of therapy. "There are some preliminary predictors of who may respond: for example, the cortical spinal tract needs to be intact. If patients can still move their arm to some extent, you know that pathway is still working."

Asked why this approach may work when other electrical stimulation strategies have failed, Dr Dawson said this system was simpler to use and enabled a much higher level of stimulation to be applied.

However, he doesn't see it being used earlier after stroke occurrence because of the need for surgery. "Many patients can recover spontaneously in the early months, and it isn't appropriate to put patients through surgery in these cases.

The study was funded by MicroTransponder. Dr Dawson has received reimbursement for travel costs from the company.

International Stroke Conference (ISC) 2017. Abstract LB18. Presented February 24, 2017.

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