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VNS-REHAB 2-Year Follow-up

Two-Year Retention of Benefits After Paired Vagus Nerve Stimulation in Stroke: Follow-Up of the VNS-REHAB Randomized Clinical Trial

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Year of Publication: 2026

Authors: Kimberley TJ, Vora I, Cramer SC, ..., Dawson J; for the VNS-REHAB Trial Group

Journal: Neurology

Citation: Neurology 2026;107:e218298

Link: https://doi.org/10.1212/WNL.0000000000218298

Bottom Line

Paired VNS + rehabilitation produced durable improvements in upper-extremity impairment (FMA-UE +7.51), motor function (WMFT +0.63), and multiple participation/QoL measures that were sustained at 2 years and retained at 3 years in a subset, supporting long-term clinical benefit in chronic ischemic stroke.

Major Points

  • Post-hoc long-term analysis of the pivotal VNS-REHAB triple-blind sham-controlled RCT (Lancet 2021)
  • 49 of the original 108 randomized participants completed the 2-year assessment; 16 had 3-year data
  • Data were pooled across original arms because all participants ultimately received active paired VNS (Control group crossed over)
  • FMA-UE improved 7.51 points (95% CI 5.80–9.22; p<0.001) and WMFT-FAS 0.63 points (95% CI 0.50–0.75; p<0.001) at 2 years
  • Improvements were stable between years 1 and 2 and retained at 3 years (FMA-UE +7.47; WMFT +0.69) in the 16-participant subset
  • 76% (37/49) achieved MCID-level improvement in FMA-UE and/or WMFT at 2 years
  • 5 of 7 PROMs (SIS-ADL, SIS-Hand, MAL-AOU, MAL-QOM, SS-QOL) improved significantly from baseline; EQ-5D and BDI not significant
  • Age, sex, time poststroke, and paretic side were not associated with change in FMA-UE or WMFT
  • Continued self-activated home VNS use may support long-term retention of gains

Design

Study Type: Post-hoc long-term follow-up of a randomized, triple-blind, sham-controlled, multicenter pivotal device trial

Randomization: 1

Blinding: Triple-blind during the original randomized phase; unblinded during the long-term follow-up phase (no sham comparator after Day 90)

Enrollment Period: Original VNS-REHAB pivotal trial; long-term follow-up visits occurred largely 2020–2022

Follow-up Duration: 2 years post–active paired VNS (with 3-year data in a 16-participant subset)

Centers: 19

Countries: United States, United Kingdom

Sample Size: 49

Analysis: Linear mixed-effects regression with random subject-specific intercepts, controlling for age, sex, time poststroke, and paretic side; Bonferroni correction across 7 PROMs; pooled analysis of both original arms

Inclusion Criteria

  • Age 22–80 years
  • Unilateral supratentorial ischemic stroke
  • Chronic stroke with persistent moderate-to-severe upper-extremity motor deficit
  • Baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score between 20 and 50 of 66 (higher = better)
  • Some active wrist and finger movement on the paretic side
  • Completion of the original VNS-REHAB pivotal trial and its cross-over/self-activated phases (for inclusion in this follow-up)
  • Willing and able to attend long-term follow-up visits and perform self-activated home VNS therapy

Exclusion Criteria

  • Hemorrhagic stroke or non-supratentorial (brainstem/cerebellar) infarct
  • Refusal to participate or inability to meet original VNS-REHAB inclusion criteria
  • Explantation of the VNS device or intolerance of stimulation/rehabilitation
  • Recurrent stroke during the trial leading to explantation
  • Inability to complete long-term follow-up assessments (loss to follow-up, largely due to COVID-19 pandemic restrictions)
  • Full trial-level exclusion criteria detailed in the original protocol (Kimberley et al., Eur Stroke J 2019)

Baseline Characteristics

Pooled 2-year cohort (n=49):

  • Note: Detailed baseline demographics and stroke characteristics for the 2-year cohort (eTable 1) and comparison of included vs excluded participants (eTable 2) are reported in the supplementary appendix and were not available in the main text.
  • Original VNS-REHAB randomized n: 108 (53 active VNS, 55 sham/control)
  • Age (eligibility range): 22–80 years
  • Stroke type: Unilateral supratentorial ischemic stroke
  • Baseline FMA-UE range: 20–50/66

Arms

FieldOriginally Active VNSControl
InterventionImplanted paired VNS activated during 6 wk (18 sessions) of in-clinic task-based UE rehab, then 3 mo of daily 30-min self-activated home therapy, then long-term self-activated active VNSImplanted device with sham VNS during blinded phase, then crossover to the same active paired VNS + in-clinic rehab and self-activated home therapy, followed by long-term self-activated active VNS
Duration≥ 2 years of self-activated VNS after initial protocol≥ 2 years of self-activated VNS after crossover

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in Fugl-Meyer Assessment-Upper Extremity (FMA-UE) from baseline to 2 years (pooled)PrimaryN/A — pooled cohort; no concurrent control+7.51 points from baseline<0.001
Wolf Motor Function Test–Functional Ability Scale (WMFT-FAS) change from baseline at 2 yearsSecondaryN/A+0.63 points<0.001 (95% CI 0.50–0.75)
FMA-UE change from baseline at 3 years (subset n=16)SecondaryN/A+7.47 points (95% CI 4.84–10.11)<0.001
WMFT-FAS change from baseline at 3 years (subset n=16)SecondaryN/A+0.69 points (95% CI 0.50–0.89)<0.001
Proportion with MCID-level improvement in FMA-UE and/or WMFT at 2 yearsSecondaryN/A37/49 (76%)N/A
Stroke Impact Scale – Activities of Daily Living (SIS-ADL)SecondaryN/ASignificant improvement from baseline at 2 ySignificant after Bonferroni (see eTable 5)
Stroke Impact Scale – Hand (SIS-Hand)SecondaryN/ASignificant improvement from baseline at 2 ySignificant after Bonferroni
Motor Activity Log – Amount of Use (MAL-AOU)SecondaryN/ASignificant improvement from baseline at 2 ySignificant after Bonferroni
Motor Activity Log – Quality of Movement (MAL-QOM)SecondaryN/ASignificant improvement from baseline at 2 ySignificant after Bonferroni
Stroke-Specific Quality of Life scale (SS-QOL)SecondaryN/ASignificant improvement from baseline at 2 ySignificant after Bonferroni
EQ-5DSecondaryN/ANo significant change from baseline at 2 yNS
Beck Depression Inventory (BDI)SecondaryN/ANo significant change from baseline at 2 yNS
NoteAdverseLong-term adverse event data are not detailed in the main text of this 2-year follow-up note; detailed AE data reside in the supplementary appendix and in the pivotal VNS-REHAB (Lancet 2021) safety report. Attrition during follow-up included 1 explantation, 1 recurrent stroke leading to explantation, 1 exit due to AE and inability to tolerate rehab, and multiple losses to follow-up predominantly related to COVID-19 pandemic restrictions.

Subgroup Analysis

Age, sex, time poststroke, and side of paresis were not significantly associated with change in FMA-UE or WMFT (eTable 3). A subset (n=16) with 3-year data retained improvements; some participants achieved further MCID-level gains between years 1 and 2, and some reached MCID for the first time at 2 years.

Criticisms

  • Post-hoc, open-label long-term extension without a concurrent sham/control comparator during the long-term phase
  • Only 49 of 108 originally randomized participants (~45%) had 2-year data, and only 16 had 3-year data — substantial attrition (largely due to COVID-19 pandemic restrictions) risks selection bias
  • Assessments during the long-term phase were unblinded
  • Minimal data on the actual frequency or intensity of self-activated home VNS use during year 2, limiting interpretation of intersubject variability
  • Detailed baseline characteristics of the 2-year cohort and full adverse event data reside only in the supplementary appendix (not in the main text)
  • Industry-funded (MicroTransponder Inc.); several authors have consulting relationships with the sponsor
  • Findings apply only to the enriched pivotal-trial phenotype (chronic ischemic supratentorial stroke, moderate-to-severe UE deficit, preserved wrist/finger movement); not generalizable to hemorrhagic stroke or more severely impaired patients

Funding

MicroTransponder Inc. (manufacturer of the Vivistim Paired VNS System) funded the VNS-REHAB pivotal trial. Article processing charge funded by the authors.

Based on: VNS-REHAB 2-Year Follow-up (Neurology, 2026)

Authors: Kimberley TJ, Vora I, Cramer SC, ..., Dawson J; for the VNS-REHAB Trial Group

Citation: Neurology 2026;107:e218298

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