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VNS-REHAB 1-Year Outcomes

Long-Term Outcomes of Vagus Nerve Stimulation Paired With Upper Extremity Rehabilitation After Stroke

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Year of Publication: 2025

Authors: Teresa J. Kimberley, PhD; Steven C. Cramer, MD; Steven L. Wolf, ..., MD; VNS-REHAB Trial Group

Journal: Stroke

Citation: Stroke. 2025;56:00-00. DOI: 10.1161/STROKEAHA.124.050479

Link: https://www.ahajournals.org/doi/10.1161/STROKEAHA.124.050479

PDF: https://www.ahajournals.org/doi/epub/10....EAHA.124.050479

Clinical Question

What are the long-term effects (through 12 months) of vagus nerve stimulation (VNS) paired with rehabilitation on impairment, activity, and participation in people with upper extremity (UE) impairment after chronic ischemic stroke?

Bottom Line

Vagus nerve stimulation (VNS) paired with rehabilitation in individuals with chronic UE deficits after ischemic stroke resulted in maintained improvements in UE impairment, activity, participation, and quality-of-life measures at 1 year. This approach is a beneficial treatment option for long-term recovery.

Major Points

  • This is a post hoc analysis of the VNS-REHAB randomized clinical trial, reporting unblinded, partial crossover, and pooled 1-year outcomes. Initially, 108 participants were enrolled.
  • Participants received 6 weeks of in-clinic intensive task-specific rehabilitation and 3 months of home-based exercise with active or sham VNS. Control participants then crossed over to receive active stimulation.
  • 74 participants (69%) completed 1-year follow-up and provided pooled data.
  • At 1 year, compared with baseline, there were significant improvements in impairment (Fugl-Meyer Assessment UE [FMA-UE], 5.23 points [95% CI, 4.08-6.39]; P<0.001) and activity (Wolf Motor Function Test [WMFT], 0.50 points [95% CI, 0.41-0.59]; P<0.001).
  • Significant improvements were also seen in patient-reported outcomes (Motor Activity Log-Quality of Movement: 0.64 [95% CI, 0.46-0.82], P<0.001; Motor Activity Log-Amount of Use: 0.64 [95% CI, 0.46-0.82], P<0.001; Stroke Impact Scale-Activities of Daily Living: 7.43 [95% CI, 5.09-9.77], P<0.001; Stroke Impact Scale-Hand: 17.89 [95% CI, 14.16-21.63], P<0.001; EQ-5D: 5.76 [95% CI, 2.08-9.45], P<0.05; and Stroke Specific-Quality of Life: 0.29 [95% CI, 0.19-0.39], P<0.001).
  • 66.2% of pooled participants (49 of 74) achieved at least a minimal clinically important difference (MCID) improvement in FMA-UE (≥6 points) or WMFT (≥0.4 points) at 1 year.
  • No serious adverse events related to therapy or stimulation were reported in the long-term phase. No serious adverse events led to device explantation.

Design

Study Type: Post hoc analysis of a pivotal randomized clinical trial (VNS-REHAB)

Randomization: 1

Blinding: Initially blinded (6 weeks in-clinic + 3 months home exercise); unblinded after Day-90 outcome assessment for crossover and long-term phases.

Enrollment Period: Original VNS-REHAB trial: October 2, 2017 to September 12, 2019

Follow-up Duration: 1 year (after completion of in-clinic therapy)

Centers: 19

Countries: United States, United Kingdom

Sample Size: 74

Analysis: Pooled data analysis from both randomized groups (as all received active paired VNS for similar periods). Linear mixed-effects regression model with random-intercept model for FMA-UE, WMFT, and PROMs, controlling for side of paresis, sex, time since stroke, and age. Bonferroni adjustment for long-term PROM P-values. RStudio (version 2023.06.1). Response profiles calculated based on MCID.

Inclusion Criteria

  • Participants aged between 22 and 80 years with a history of unilateral supratentorial ischemic stroke occurring 9 months to 10 years before enrollment.
  • Moderate-to-severe arm impairment, defined as an FMA-UE score between 20 and 50.
  • At least minimal active wrist flexion/extension and active abduction/extension of the thumb and at least 2 additional digits.

Baseline Characteristics

CharacteristicControlActive
Sex, n (%) - Male26 (72%)25 (66%)
Sex, n (%) - Female10 (28%)13 (34%)
Age, y; mean±SD60.6 (8.4)58.8 (9.5)
Race, n (%) - Black6 (17%)8 (21%)
Race, n (%) - Asian, Indian, or other2 (6%)1 (3%)
Race, n (%) - White27 (75%)28 (74%)
Race, n (%) - Not reported1 (3%)1 (3%)
Dominant hand, n (%) - Right32 (89%)33 (87%)
Dominant hand, n (%) - Left4 (11%)4 (11%)
Dominant hand, n (%) - Ambidextrous0 (0%)1 (3%)
Side of stroke, n (%) - Left19 (53%)21 (55%)
Side of stroke, n (%) - Right17 (47%)17 (45%)
Time since stroke, y; mean (SD)3.6 (2.8)3.0 (2.0)
Baseline FMA-UE, mean (SD)35.6 (8.6)34.2 (8.1)
Baseline WMFT-FAS, mean (SD)2.8 (0.7)2.7 (0.7)

Arms

FieldActive VNS Group (Original Randomization)Control
InterventionVNS device implantation followed by 18 sessions of in-clinic intensive task-specific rehabilitation paired with active VNS. Then, 3 months of self-initiated home-based exercise with active VNS (activated via magnet swipe). Followed by 1 year of home-based exercises with self-initiated active VNS.VNS device implantation followed by 18 sessions of in-clinic intensive task-specific rehabilitation paired with sham VNS. Then, 3 months of self-initiated home-based exercise with sham VNS. After unblinding, crossed over to receive another 18 sessions of in-clinic rehabilitation with active VNS, followed by 1 year of home-based exercises with self-initiated active VNS.
Duration6 weeks in-clinic + 3 months home + 1 year long-term6 weeks in-clinic (sham) + 3 months home (sham) + 6 weeks in-clinic (active) + 1 year long-term (active)

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Not specified for this 1-year follow-up analysis, which is a post hoc analysis. The primary outcome of the original VNS-REHAB trial was the change in impairment measured by the Fugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy.Primary
FMA-UE change from original baseline to 1 year (pooled data)Secondary5.23 (95% CI, 4.08-6.39)<0.001
WMFT change from original baseline to 1 year (pooled data)Secondary0.50 (95% CI, 0.41-0.59)<0.001
Motor Activity Log-Quality of Movement change from original baseline to 1 year (pooled data)Secondary0.64 (95% CI, 0.46-0.82)<0.001
Motor Activity Log-Amount of Use change from original baseline to 1 year (pooled data)Secondary0.64 (95% CI, 0.46-0.82)<0.001
Stroke Impact Scale-Activities of Daily Living change from original baseline to 1 year (pooled data)Secondary7.43 (95% CI, 5.09-9.77)<0.001
Stroke Impact Scale-Hand change from original baseline to 1 year (pooled data)Secondary17.89 (95% CI, 1.416-21.63)<0.001
EQ-5D change from original baseline to 1 year (pooled data)Secondary5.76 (95% CI, 2.08-9.45)<0.05
Stroke Specific-Quality of Life change from original baseline to 1 year (pooled data)Secondary0.29 (95% CI, 0.19-0.39)<0.001
FMA-UE change from baseline to Day-1_cross (control group crossover to active VNS)Secondary6.13 (95% CI, 4.78-7.48)<0.001
FMA-UE change from baseline to Day-90_cross (control group crossover to active VNS)Secondary5.64 (95% CI, 4.22-7.06)<0.001
WMFT change from baseline to Day-1_cross (control group crossover to active VNS)Secondary0.42 (95% CI, 0.32-0.53)<0.001
WMFT change from baseline to Day-90_cross (control group crossover to active VNS)Secondary0.41 (95% CI, 0.29-0.52)<0.001

Criticisms

  • This is a post hoc analysis of unblinded, partial crossover, and pooled data, which limits the ability to draw definitive conclusions about between-group differences in the long-term phase due to the lack of a control comparator.
  • The study has missing data, particularly for longer-term follow-up visits, though this was attributed to pandemic-related restrictions and deemed 'missing at random'.
  • The study did not include specific steps to ensure the diversity of the sample or the steering committee, potentially limiting generalizability beyond the enrolled population.
  • The self-initiated home exercise was not explicitly monitored, which precludes definitive conclusions related to the specific rehabilitation components that may have contributed to maintaining participants' gains or including adherence to models to explain variance over time.

Subgroup Analysis

Side of stroke, sex, age, and time since stroke did not significantly impact FMA-UE or WMFT outcomes in the pooled analysis. No formal subgroup analyses were presented in the abstract for long-term outcomes.

Funding

Micro Transponder, Inc.

Based on: VNS-REHAB 1-Year Outcomes (Stroke, 2025)

Authors: Teresa J. Kimberley, PhD; Steven C. Cramer, MD; Steven L. Wolf, ..., MD; VNS-REHAB Trial Group

Citation: Stroke. 2025;56:00-00. DOI: 10.1161/STROKEAHA.124.050479

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