PDF: VNS-REHAB 2-Year
(2026)Objective
In adults with moderate-to-severe upper-extremity deficits from chronic ischemic stroke, does implanted paired vagus nerve stimulation (VNS) combined with task-based UE rehabilitation produce durable functional improvement ≥2 years after therapy?
Study Summary
• WMFT-FAS improved 0.63 points from baseline at 2 years (95% CI 0.50–0.75; p<0.001); 37/49 (76%) met MCID on FMA-UE and/or WMFT.
• Gains retained at 3 years in the subset with data (n=16): FMA-UE +7.47 (4.84–10.11) and WMFT-FAS +0.69 (0.50–0.89), both p<0.001.
Intervention
Implanted paired VNS (Vivistim, MicroTransponder) delivered concurrent with 6 weeks (18 sessions) of in-clinic task-based UE rehab, followed by 3 months of daily 30-min self-activated home therapy, then long-term self-activated active VNS. Original sham-control arm crossed over to active VNS after Day-90; long-term data pooled.
Inclusion Criteria
Age 22–80; unilateral supratentorial ischemic stroke; baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score 20–50/66; some active wrist and finger movement (full criteria in original VNS-REHAB protocol/eMethods).
Study Design
Arms: Long-term phase is single-group (all participants on active paired VNS after original active arm continued and original sham arm crossed over). Original pivotal randomization was Active VNS+rehab (n=53) vs Sham VNS+rehab (n=55); 49 of 108 attended the 2-year visit.
Patients per Arm: n=49 pooled at 2 years (of 108 originally randomized ITT); n=16 subset at 3 years
Outcome
• WMFT-FAS change at 2 years = +0.63 (0.50–0.75; p<0.001).
• 5 of 7 PROMs improved significantly from baseline at 2 years after Bonferroni correction: SIS-ADL, SIS-Hand, MAL-AOU, MAL-QOM, SS-QOL (EQ-5D and BDI not significant).
• 37/49 (76%) achieved MCID-level improvement on FMA-UE and/or WMFT at 2 years.
• 3-year subset (n=16): FMA-UE +7.47 (4.84–10.11; p<0.001); WMFT-FAS +0.69 (0.50–0.89; p<0.001).
• Age, sex, time poststroke, and paretic side were not associated with change in FMA-UE or WMFT.
• Safety: no new serious adverse events reported during long-term follow-up.
Bottom Line
Two years after completing paired VNS + task-based rehabilitation, chronic ischemic stroke survivors retained large, clinically meaningful upper-extremity gains (FMA-UE +7.51 points; WMFT-FAS +0.63; both p<0.001; pooled n=49), with 76% meeting MCID on ≥1 measure. Improvements persisted at 3 years in the 16-patient subset with data, supporting paired VNS as a durable rehabilitation option for a defined subset of chronic ischemic stroke patients — although the long-term phase lacked a sham comparator and blinded assessment.
Major Points
- Post hoc long-term follow-up of the pivotal VNS-REHAB triple-blind, sham-controlled, randomized trial (Dawson 2021); after the blinded phase (and cross-over from sham to active for the original control group), all participants continued self-activated active paired VNS in an open-label long-term phase.
- Analysis population: 49 of 108 originally randomized participants attended the 2-year visit; 16 of 24 possible participants had 3-year data. Missing data driven largely by SARS-CoV-2 pandemic restrictions on 2020–2022 visits.
- Primary UE-impairment outcome (FMA-UE, 0–66) improved 7.51 points from baseline at 2 years (95% CI 5.80–9.22; p<0.001) — well above published MCID and stable between year 1 and year 2.
- Activity outcome (WMFT-FAS) improved 0.63 points from baseline at 2 years (95% CI 0.50–0.75; p<0.001).
- Clinical meaningfulness: 37/49 (76%) demonstrated MCID-level improvement on FMA-UE and/or WMFT at 2 years; some participants first achieved MCID between years 1 and 2, suggesting ongoing recovery in some individuals.
- 5 of 7 participation / quality-of-life PROMs improved significantly from baseline at 2 years after Bonferroni correction: SIS-ADL, SIS-Hand, MAL-AOU, MAL-QOM, and SS-QOL. EQ-5D and BDI changes were not significant.
- 3-year subset (n=16): FMA-UE +7.47 (95% CI 4.84–10.11; p<0.001) and WMFT-FAS +0.69 (0.50–0.89; p<0.001) from baseline — gains preserved.
- Baseline covariates (age, sex, time poststroke, side of paresis) were not significantly associated with change in FMA-UE or WMFT; per eTable 2 there were no baseline differences between participants included vs excluded from this 2-year analysis.
- No new safety issues were reported during the long-term self-activated VNS phase.
- Key limitation: no control comparator in the long-term phase (open-label after cross-over), unblinded assessments, and minimal data on the dose or frequency of self-activated therapy in year 2.
Study Design
- Study Type
- Post hoc long-term follow-up (Clinical/Scientific Note) of a phase 3, triple-blind, sham-controlled, randomized, multicenter pivotal device trial; long-term phase is single-arm open-label with pooled data
- Randomization
- Yes
- Blinding
- Original VNS-REHAB pivotal phase was triple-blind (participants, therapists, and outcome assessors). The long-term follow-up phase was unblinded and had no sham comparator (all participants were on active paired VNS).
- Sample Size
- 49
- Follow-up
- 2 years after completion of active paired VNS (primary analysis of this report); 3-year outcomes in a subset (n=16).
- Centers
- 19
- Countries
- USA, United Kingdom
Primary Outcome
Definition: Change from baseline in Fugl-Meyer Assessment–Upper Extremity (FMA-UE, 0–66; higher better) at the 2-year assessment after completion of active paired VNS
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| No concurrent sham control in the long-term phase (all pooled to active VNS) | +7.51 points from baseline (pooled n=49) | - (5.80–9.22) | <0.001 |
Limitations & Criticisms
- Long-term phase is single-arm and unblinded — no sham/no-VNS comparator beyond Day 90, so spontaneous recovery, ongoing usual therapy, and expectancy cannot be excluded as contributors.
- Substantial attrition: only 49 of 108 (45%) enrolled participants had 2-year data, and only 16 had 3-year data — largely attributed to SARS-CoV-2 pandemic restrictions but still limits generalizability.
- Post hoc analysis of a pivotal RCT that was not powered for 2-year outcomes; no prespecified statistical plan for the long-term timepoints.
- Minimal data on the dose, frequency, or adherence to self-activated VNS during year 2 — the amount of ongoing stimulation and home practice that produced these gains is unknown.
- Detailed baseline characteristics of the 2-year cohort are in a supplement (eTable 1); the main article does not tabulate them, limiting standalone interpretability.
- Findings apply only to a narrow phenotype: moderate-severe (FMA-UE 20–50) chronic ischemic supratentorial stroke with preserved active wrist/finger movement — do not generalize to hemorrhagic stroke, plegic hand, or acute/subacute stroke.
- Industry-sponsored (MicroTransponder), with 4 of 5 authors serving as consultants to the sponsor.
- Assessors during the long-term phase were unblinded to treatment — a source of measurement bias on subjective / performance-based scales.
Citation
Neurology 2026;107(3):e218298. DOI: 10.1212/WNL.0000000000218298