Epidural Electrical Stimulation for Stroke Rehabilitation: Results of the Prospective, Multicenter, Randomized, Single-Blinded Everest Trial.
BACKGROUND
This prospective, single-blinded, multicenter study assessed the safety and efficacy of electrical epidural motor cortex stimulation (EECS) in improving upper limb motor function of ischemic stroke patients with moderate to moderately severe hemiparesis.


METHODS
Patients ≥ 4 months poststroke were randomized 2:1 to an investigational (n = 104) or control (n = 60) group, respectively. Investigational patients were implanted (n = 94) with an epidural 6-contact lead perpendicular to the primary motor cortex and a pulse generator. Both groups underwent 6 weeks of rehabilitation, but EECS was delivered to investigational patients during rehabilitation. The primary efficacy endpoint (PE) was defined as attaining a minimum improvement of 4.5 points in the upper extremity Fugl-Meyer (UEFM) scale as well as 0.21 points in the Arm Motor Ability Test (AMAT) 4 weeks postrehabilitation. Follow-up assessments were performed 1, 4, 12, and 24 weeks postrehabilitation. Safety was evaluated by monitoring adverse events (AEs) that occurred between enrollment and the end of rehabilitation.


RESULTS
Primary intent-to-treat analysis showed no group differences at 4 weeks, with PE being met by 32% and 29% of investigational and control patients, respectively (P = .36). Repeated-measures secondary analyses revealed no significant treatment group differences in mean UEFM or AMAT scores. However, post hoc comparisons showed that a greater proportion of investigational (39%) than control (15%) patients maintained or achieved PE (P = .003) at 24 weeks postrehabilitation. Investigational group mean AMAT scores also improved significantly (P < .05) when compared to the control group at 24 weeks postrehabilitation. Post hoc analyses also showed that 69% (n = 9/13) of the investigational patients who elicited movement thresholds during stimulation testing met PE at 4 weeks, and mean UEFM and AMAT scores was also significantly higher (P < .05) in this subgroup at the 4-, 12-, and 24-week assessments when compared to the control group. Headache (19%), pain (13%), swelling (7%), and infection (7%) were the most commonly observed implant procedure-related AEs. Overall, there were 11 serious AEs in 9 investigational group patients (7 procedure related, 4 anesthesia related).


CONCLUSIONS
The primary analysis pertaining to efficacy of EECS during upper limb motor rehabilitation in chronic stroke patients was negative at 4 weeks postrehabilitation. A better treatment response was observed in a subset of patients eliciting stimulation induced upper limb movements during motor threshold assessments performed prior to each rehabilitation session. Post hoc comparisons indicated treatment effect differences at 24 weeks, with the control group showing significant decline in the combined primary outcome measure relative to the investigational group. These results have the potential to inform future chronic stroke rehabilitation trial design.
Marcus Neuroscience Institute, Boca Raton, FL, USA.
Robert M
RM
Levy
Northwestern University Feinberg School of Medicine, Chicago, IL, USA The Rehabilitation Institute of Chicago, Chicago, IL, USA rharvey@ric.org.
Richard L
RL
Harvey
University of Cincinnati, Cincinnati, OH, USA.
Brett M
BM
Kissela
University of Southern California, Los Angeles, CA, USA.
Carolee J
CJ
Winstein
Oregon Health & Science University, Portland, OR, USA.
Helmi L
HL
Lutsep
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Todd B
TB
Parrish
University of California, Irvine, CA, USA.
Steven C
SC
Cramer
St. Jude Medical, Plano, TX, USA.
Lalit
L
Venkatesan
D000328:Adult; D000368:Aged; D004599:Electric Stimulation Therapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies; D016037:Single-Blind Method; D000071939:Stroke Rehabilitation
cortical stimulation; hemiparesis; rehabilitation; stroke