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-to-severe 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.