Trial Design

We conducted a randomized, controlled trial involving patients with cerebral injury at Huashan Hospital, Shanghai, China. Participants were eligible for inclusion if they had hemiplegia after a stroke, traumatic brain injury, or cerebral palsy, manifesting mainly as spasticity and weakness in the upper extremity contralateral to the cerebral lesion. We recruited patients who were between 12 and 45 years of age and had arm paresis that had ceased to improve after at least 5 years of rehabilitation. The muscle power and tactile sensitivity in the affected hand had to be decreased but not absent (the term “paralyzed” is used to denote this state in the remainder of the description of the trial). Transcranial magnetic stimulation had to have resulted in activation from the contralesional hemisphere to the unaffected arm and exclusive activation of the paralyzed hand by the ipsilesional hemisphere. Patients were excluded if they had systemic diseases such as diabetes mellitus or cardiopulmonary disease, developmental delay or poor cognitive ability, or severe, fixed contracture or joint deformity of the paralyzed arm (the complete list of inclusion and exclusion criteria is provided in the Supplementary Appendix). None of the patients from our previous studies of the nerve-grafting technique were included in this trial.28,29

The trial protocol was approved by the institutional review board of Huashan Hospital. Participants or their parents provided written informed consent. The first and last authors wrote the manuscript, and all the authors vouch for the accuracy and completeness of the results and analysis, the reporting of adverse events, and the adherence of the trial to the protocol, available at NEJM.org.

Patients were assigned in a 1:1 ratio in a blinded fashion by means of simple, nonstratified randomization to undergo contralateral C7 nerve–transfer surgery followed by rehabilitation or rehabilitation only. The randomization sequences were computer-generated by an independent statistician and were not otherwise known to trial personnel until assignment.

Trial Interventions

Figure 1. Figure 1. Contralateral C7 Nerve–Transfer Surgery. A 15-cm transverse incision is made approximately 2 cm superior to the clavicle at the bottom of the neck. The brachial plexus nerves are exposed bilaterally, superior to the clavicle. The C7 nerve on the paralyzed side is severed near the intervertebral foramen, and the C7 nerve on the nonparalyzed side is severed as distally as possible, proximal to the point at which it combines with the fibers of other brachial plexus nerves. The anterolateral aspect of the C7 vertebral body is dissected bluntly, and the esophagus is exposed anterior to the vertebral body, which creates a conduit between the spinal column and the esophagus. The cut end of the C7 nerve on the nonparalyzed side is then drawn through the prespinal route to the paralyzed side and anastomosed directly (without a graft) to the cut end of the C7 nerve on the paralyzed side by means of microsurgical epineurium suturing. After surgery, the paralyzed upper extremity is immobilized with a head–arm brace for 4 weeks, after which the patients have the same rehabilitation therapy as they did before the surgery.

The procedure for C7 nerve transfer to the contralateral side has been described previously28,29 and is shown schematically in Figure 1 and in an , available at NEJM.org, as well as in Figure S1 in the Supplementary Appendix. To limit surgical trauma and to shorten the gap between the distal end of the transplanted nerve and the recipient nerve, the procedure was modified from the original technique. In brief, an incision was made at the superior aspect of the sternum, and the donor C7 nerve on the nonparalyzed side was mobilized, sectioned as distally as possible but proximal to the point at which it combines with other nerves, and routed between the spinal column and esophagus; it was then anastomosed directly with the C7 nerve on the paralyzed side, which had been sectioned and mobilized as proximally as possible. No surgery was performed in the control group. The surgery and control groups received identical rehabilitation therapy four times per week for 12 months at one facility, administered by physiotherapists who were aware of the treatment assignments. Rehabilitation therapy included identical active exercise, passive range of motion, occupational therapy, functional training, physical therapy, acupuncture, massage, and the use of orthoses; the only between-group difference in rehabilitation therapy was the use of a special immobilizing cast during the postoperative period for patients who had undergone surgery (Fig. S2 in the Supplementary Appendix).

Outcomes

The primary outcome was the change in total score on the Fugl–Meyer upper-extremity scale from baseline to the end of month 12. The Fugl–Meyer scale is designed to assess recovery after stroke.30 It measures 33 items, each scored from 0 to 2, with 0 indicating “cannot perform,” 1 indicating “performs partially,” and 2 indicating “performs fully”; the scale contains “shoulder and elbow” and “wrist and fingers” domains (total scores range from 0 to 66, with higher scores reflecting better function). Outcomes were assessed at baseline and at months 2, 4, 6, 8, 10, and 12 after recruitment.

The secondary outcomes included changes from baseline to month 12 in the Modified Ashworth Scale score for the elbow, forearm, wrist, thumb, and digits two through five, as well as active range of motion and functional use of the paralyzed arm. The Modified Ashworth Scale measures spasticity at each joint on a scale from 0 to 5, with higher values indicating more spasticity.31 We considered a positive outcome to be a significant improvement from baseline in the score in at least one of the five joints tested. Evaluation of functional use of the limb included performance of activities such as dressing, tying shoes, wringing out a towel, and operating a mobile phone. The proportion of patients who accomplished at least three of the four tasks was a post hoc outcome.

Other secondary outcomes included neurophysiological and functional magnetic resonance imaging (MRI) assessments. Neurophysiological assessments were performed by means of electrical stimulation over the cervical nerves (Erb’s point) of the unaffected side and recording over the extensor carpi radialis of the paralyzed arm and by means of transcranial magnetic stimulation over each hemisphere of the brain and recording over the extensor carpi radialis of the paralyzed arm (see the Supplementary Appendix). Functional MRI was performed while the patient was at rest and during active extension of the wrist on the paralyzed side (functional MRI methods are described in the Supplementary Appendix). Videos of the patients undergoing Fugl–Meyer scale assessment, Modified Ashworth Scale assessment, range-of-motion testing, and functional-use assessment were evaluated by two rehabilitation experts who were unaware of the treatment assignments, and functional imaging was assessed by investigators who were unaware of the treatment assignments; to mask identities and treatment assignments, the face of each patient and the area in which the incision would have been made in a patient who underwent surgery was obscured in the videos. Safety outcomes included adverse events and changes in muscle strength, tactile sensory threshold, and two-point discrimination of the arm and hand on the side of the severed, donor C7 nerve over a period of 12 months.

Statistical Analysis

On the basis of our preliminary study, we estimated that a sample size of 36 (18 per group), under the assumption of a 20% dropout rate, would provide 90% power to detect a mean (±SD) difference between groups of 6.6±5.2 on the Fugl–Meyer scale at an alpha level of 0.05. Descriptive statistics were used to report the characteristics of the patients at baseline. For continuous variables, Student’s t-tests (or Satterthwaite’s method) or Wilcoxon rank-sum tests were used for between-group comparisons, and paired t-tests or Wilcoxon matched-pairs signed-ranks tests were used for within-group comparisons between each follow-up visit and baseline. Intergroup comparisons of the continuous outcomes of changes from baseline to month 12 were performed by means of analysis of covariance to adjust baseline measures. For discrete variables, chi-square, Cochran–Mantel–Haenszel chi-square, or Fisher’s exact tests were used for between-group comparisons and McNemar’s chi-square tests were used for within-group comparisons. Differences between the groups in the changes from baseline in Modified Ashworth Scale score were compared by means of chi-square tests. Two-tailed P values of 0.05 were considered to indicate statistical significance. Boxcar analysis of functional MRI results was used for all sessions, with a t contrast (a statistical technique used to extract information about changes in functional MRI activity) and a corrected P value threshold of 0.05 for analyses involving a single patient. An analysis was performed for each session across patients with the use of a one-sample t-test, with a corrected P value threshold of 0.05 (family-wise error correction). The P values for changes assessed by means of functional MRI (Tables S8, S9, and S10 in the Supplementary Appendix) refer to comparisons between active movements and rest (detailed methods are provided in the Supplementary Appendix).32