Danny R. Rose, Jr., MD

Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, et al. Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke. Stroke. 2016

Arm weakness is common after stroke and can result in significant disability for affected patients. Current rehabilitative strategies centered on intensive, repetitive, and task-specific activities have shown only modest benefit–only 40% of stroke survivors with non-functional arms at one week are able to recover function by 6 months. These therapies have been shown to facilitate neuronal plasticity, but currently there are no proven methods to augment this plasticity to enhance recovery. Developing more efficacious ways of recovering motor function could lead to significant quality of life improvements for stroke survivors and reduction in healthcare costs and medical co-morbidities associated with loss of
independence.

Vagus nerve stimulation (VNS) has been proposed as a potential adjunctive therapy, as it activates neurons in the basal forebrain and locus coeruleus that facilitate reorganization of cortical networks. Preliminary animal studies have shown that pairing forelimb rehabilitation with VNS significantly increases recovery of speed and strength compared to rehabilitation alone. Dawson et al. sought to begin investigating the potential for VNS therapy to improve upper limb rehabilitation in patients with chronic stroke by conducting a small safety and feasibility study with a randomized open active comparator design.

Patients considered for inclusion were 18-80 years of age with a history of unilateral supra-tentorial ischemic stroke occurring at least 6 months prior. The Action Research Arm Test (ARAT) score was used to determine eligibility with respect to arm impairment, using a score of 15-50 indicating moderate to severe impairment. Twenty participants were randomized. Eleven were randomized to receive rehabilitation alone, consisting of a six week course of two-hour therapy sessions three times per week that focused on repetition of seven standardized tasks, and nine were randomized to receive the same therapy after VNS implantation, with the therapist delivering 500 millisecond bursts of VNS manually when the patient performed the rehabilitative tasks. One patient in the VNS group received medications that may interfere with VNS and was excluded from the per-protocol analysis. Outcome assessments were performed on days one, seven, and 30 after the conclusion of therapy in both groups and included the aforementioned ARAT score as well as upper extremity Fugl-Meyer assessment, Stroke Impact Scale (SIS), grip and pinch strength as assessed by a handheld dynamometer, Box and Block test, 9-hole peg test, and robotic assessment using an InMotion Technologies robot.

A total of 22 adverse events (AEs) were reported in the eight participants in the VNS group compared to ten AEs in three participants in the rehabilitation only group. Two participants suffered a serious adverse event in the VNS group and one participant suffered four SAEs in the rehabilitation group, with none of them being related to device effects or the rehabilitative therapy. Adverse device effects were minor and all resolved, although one participant suffered temporary left vocal cord palsy and dysphagia and had their VNS stopped in case it would hinder recovery.

The mean change in FMA-UE scores in the VNS group was +8.7 (5.8) vs. +3.0 (6.1) in the rehab only group (p=0.064), with the per-protocol analysis showing a statistically significant improvement in the VNS group (+9.6[5.3] vs +3.0[6.1], p=0.038). There were no significant differences in the other secondary efficacy endpoints. Although baseline imaging characteristics between the two groups were similar, VNS responders had significantly higher infarct volumes as compared to rehabilitation only responders (p<0.05).

This study represents an exciting novel therapy with dramatic implications for motor recovery following stroke. The statistically significant improvement in the per-protocol analysis suggests the potential of a more appreciable effect in a study with a larger sample size. The significantly higher infarct volume in VNS responders suggests that VNS may enhance recovery in patients with larger strokes that tend to benefit less from rehabilitative therapy alone. As VNS is already widely used in refractory epilepsy with a proven safety record, the lack of concerning adverse effects is not surprising. As this is an entirely new application for VNS therapy, further protocol refinement to establish VNS parameters for further study is needed.