About 80% of patients who had acute stroke suffer from certain kinds of upper limb motor damage. Among them, more than half present with persistent upper limb impairment even after 6 months, leading to a lower quality-of-life and diminished wellbeing.¹ Given the dynamic nature of impairment as recovery proceeds and the presence of multiple simultaneous impairments possibly, treatment planning for upper limb disability remains difficult with limited treatment options available.^1,2 Recently, vagus nerve stimulation (VNS) has emerged as a promising technique to enhance the reorganization potential of the brain following stroke. In light of this, a randomized, triple-blinded, sham-controlled trial was conducted to test the potential of VNS combined with rehabilitation in improving upper limb mobility in stroke patients.¹ Upon review, the United States (US) Food and Drug Administration (FDA) granted one-of-its-kind approval to VNS system as the novel treatment of moderate to severe upper extremity motor deficits associated with chronic ischemic stroke.³

VNS is currently approved and indicated for the treatment of refractory epilepsy and chronic treatment resistant depression.⁴ In terms of technique, a device implanted in the left clavicular area is used to deliver regular and mild electrical pulses through the left vagus nerve to modulate brain activity, mostly to produce a parasympathetic response.⁴ The device can be externally controlled, either by a magnet carried on the wrist by the patient, or by a therapist in the case of active VNS rehabilitation therapy.⁵ Recently, evidence from rodent studies has shown that VNS paired with sensory input or motor training may result in input-specific reorganization of cortical neurons, by inducing cholinergic and monoaminergic modulation of the motor cortex.6 Potentially, this would improve forelimb motor recovery and increase synaptic connectivity in patients who had suffered an ischaemic stroke.¹

To evaluate the safety and efficacy of VNS in improving arm function, the randomized, triple-blind, sham-controlled VNS-REHAB trial, involving 19 stroke rehabilitation services in the United Kingdom and the US, was conducted.¹ 108 patients with moderate-tosevere arm weakness, at least 9 months after ischaemic stroke, were recruited and randomly allocated 1:1 to the treatment group (active VNS with rehabilitation) or the control group (sham stimulation with rehabilitation).¹ Participants, outcomes assessors and treating therapists were triply blinded to group assignment.¹ The primary outcome was the change in impairment measured by the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score on the first day after completion of 6 weeks of in-clinic therapy as compared with baseline measurements, which were taken on day 1 of the treatment.¹ The secondary outcomes were the clinically meaningful responses on the FMA-UE measured 90 days after in-clinic therapy, and the Wolf Motor Function Test (WMFT)- Functional score as compared with baseline.¹

The study results revealed that 90 days after in-clinic therapy, the mean change of FMA-UE score increased more in the VNS group than the control group (5.8 vs. 2.8; between-group difference: 3.0, 95% CI: 0.8-5.1).¹ The geographical region was found to be related to the outcomes, but not age and baseline FMA-UE scores.1 A clinically meaningful response on the FMA-UE score was achieved in 23 of 53 patients (47%) in the VNS group vs. 13 of 55 patients (24%) in the control group; between-group difference (24%, 95% CI: 6-41).¹ The WMFT-Functional score was also significantly higher in the VNS group compared with the control group at 90 days after the end of in-clinic therapy (0.5 vs. 0.2; between-group difference: 0.3, 95% CI: 0.16-0.43).¹

Regarding the safety profile, 81% of patients in the VNS group and 76% of patients in the control group had at least 1 adverse event (AE), with no reported deaths.1 Most AEs related to the device were reported to be postoperative pain.¹ There was 1 serious AE related to surgery (vocal cord paresis) in the control group, though the risk was not higher than that in people without past history of ischaemic stroke.¹

To summarize, the data of the VNS-REHAB trial has affirmed a promising picture, in terms of safety and efficacy, for the indication of VNS system in the upper limb motor rehabilitation.

Editor: Nicole Lee