Transferring the C7 nerve from the nonparalyzed to the paralyzed side in patients with a stroke or other cerebral injury resulted in improved function and reduced spasticity in the affected arm, new research has shown.
The study, led by Mou-Xiong Zheng, MD, PhD, Department of Hand Surgery, Huashan Hospital, and National Clinical Research Center for Aging and Medicine, Shanghai, China, was published online December 21 in the New England Journal of Medicine.
“In this single-center trial involving patients who had had unilateral arm paralysis due to chronic cerebral injury for more than 5 years, transfer of the C7 nerve from the nonparalyzed side to the side of the arm that was paralyzed was associated with a greater improvement in function and reduction of spasticity than rehabilitation alone over a period of 12 months,” they conclude. “Physiological connectivity developed between the ipsilateral cerebral hemisphere and the paralyzed hand.”
Spastic limb paralysis due to a stroke or other injury to the cerebral hemisphere causes long-term disability. An estimated 30% to 60% of stroke survivors are unable to use their paralyzed hand.
There’s evidence for involvement of the contralateral hemisphere in the recovery of hand function after a stroke, said the authors. Their previous work suggested that by transferring a cervical spinal nerve from the unaffected side to the paralyzed side, a paralyzed hand could be functionally connected to the unimpaired cerebral hemisphere.
Activation of the paralyzed arm requires both physiologic connections of the anastomosed nerve to contralateral nerves and connectivity of the cerebral hemisphere ipsilateral to the injury to the grafted nerve.
Spinal Nerve
The C7 spinal nerve, one of five that give rise to the brachial plexus, contains thousands of nerve fibers. The motor function of the C7 nerve largely overlaps with that of the other four nerves, so severing this nerve usually results in only transient weakness and numbness in the ipsilateral upper extremity.
The study included 36 patients, all male, mean age about 26 years, at the Huashan Hospital in Shanghai. The patients had hemiplegia due to a stroke, traumatic brain injury, cerebral palsy, or encephalitis, manifesting mainly as spasticity and weakness in the upper extremity contralateral to the cerebral lesion.
At baseline, all patients were unable to reach and grasp with their paralyzed hand and were unable to dress, tie shoes, wring out a towel, or operate a mobile phone with the affected hand.
Patients had to have 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.
Transcranial magnetic stimulation must have resulted in activation from the contra-lesional hemisphere to the unaffected arm and exclusive activation of the paralyzed hand by the ipsi-lesional hemisphere.
MRI showed isolated injury to the brain hemisphere contralateral to the paralyzed hand.
The patients were randomly assigned to undergo contralateral C7 nerve-transfer surgery followed by rehabilitation (n = 18) or to rehabilitation alone (n = 18). The mean interval from the neurologic injury to trial entry was about 15 years in both groups, and the duration of previous rehabilitation was about 10 years in both groups.
The surgical technique used in the study involves making an incision at the superior aspect of the sternum, mobilizing the donor C7 nerve on the nonparalyzed side, sectioning it as distally as possible but proximal to the point at which it combines with other nerves, and routing it between the spinal column and esophagus.
The donor nerve is then anastomosed directly with the C7 nerve on the paralyzed side, which has been sectioned and mobilized as proximally as possible.
The rehabilitation took place four times a week for 12 months and was administered by physiotherapists who were aware of the treatment assignments. The sessions included active exercise, passive range-of-motion exercises, occupational therapy, functional training, physical therapy, acupuncture, massage, and the use of orthoses.
The only between-group difference in rehabilitation was that the surgery group wore an immobilizing cast during the postoperative period.
Performance Assessment
The primary outcome was change in total score on the Fugl-Meyer upper-extremity scale, which measures motor impairment. The scale assesses 33 items, each scored from 0 to 2, with higher scores indicating better function.
Secondary outcomes included changes in the Modified Ashworth Scale score for the elbow, forearm, wrist, thumb, and digits 2 to 5. This scale measures spasticity from 0 to 5, with higher values indicating more spasticity. The researchers considered a positive outcome to be a significant improvement in at least one of the five joints tested.
Other outcomes included active range of motion and functional use of the paralyzed arm in terms of being able to perform four tasks: dressing, tying shoes, wringing out a towel, and operating a mobile phone. The proportion of patients who could do at least three of these tasks was a post hoc outcome.
The study found that mean changes in the Fugl-Meyer score at 12 months were 17.7 in the surgery group and 2.6 in the control group, for a difference of 15.1 (95% confidence interval, 12.2 – 17.9; P < .001).
Scores increased significantly at months 10 and 12 in the surgery group.
Changes in spasticity significantly favored the surgery group at all joints. The authors noted that in some patients, release of spasticity started as early as the first postoperative day.
The mean changes in the active range of motion in the surgery group were 24 degrees at the elbow, 36 degrees in forearm rotation, and 49 degrees at the wrist. The corresponding changes in the control group were 0, 1, and 1 degree, respectively (P < .001 for all comparisons).
In the surgical group, 16 patients were able to use the paralyzed hand to perform at least three of the tasks compared with none in the control group.
Electrophysiologic testing, transcranial magnetic stimulation of the cortex, and functional MRI showed physiologic connectivity between the ipsilateral cerebral hemisphere and the paralyzed hand in the surgery group.
Most of the clinical improvements “coincided with physiological evidence of connectivity between the hemisphere on the side of the donor nerve and the paralyzed arm,” the authors write.
Surgery-related adverse events on the side of the donor nerve included numbness in the hand and decreased elbow or wrist extension, most of which resolved over time. There were no significant differences in sensorimotor function in the nonparalyzed limb between baseline and 12 months, with the exception of a decrease in sensory function in the index finger.
Major Question
In an accompanying editorial, Robert J. Spinner, MD, chair, Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, and colleagues say the trial results “are exciting but need clarification and confirmation.”
The time frame for improvement “is the major question,” they write. “An improvement in function at 10 months cannot be readily explained as being predominantly a result of the contralateral nerve transfer, because nerves do not regenerate that quickly, fully, or consistently.”
That distal muscles are functionally re-innervated in such a short period seems unlikely, Dr Spinner added in an interview with Medscape Medical News.
“The distance from the neck region to the forearm is long,” said Dr Spinner. “While initial axons may reach the forearm in 1 year in adults based on distance, meaningful recovery would take longer.”
He noted that patients treated with contralateral C7 transfer for brachial plexus injuries at the same institution as those in the study (Huashan Hospital) gain recovery only after several years.
Dr Spinner elaborated on an alternative hypothesis offered in the editorial that might explain the functional improvement: C7 neurotomy on the paralyzed side that reduced spasticity.
“The contralateral C7 procedure also involves performing a C7 neurotomy on the affected side,” explained Dr Spinner.
Neurotomy is a procedure used to treat spasticity but has not been performed in the brachial plexus in stroke patients, he noted.
“This part of the procedure could improve spasticity and function. It would also explain evidence of recovery seen immediately following the surgery.”
Retraining with rehabilitation could then have improved results over the year, he said.
Dr Spinner said he would like to see a study comparing patients undergoing contralateral C7 transfer and rehabilitation with a group getting C7 neurotomy alone — without the nerve transfer — along with rehabilitation.
The “creative use” of a strategy involving the peripheral nervous system, whether a nerve transfer or a neurotomy, for problems with the central nervous system “represents a fresh approach and provides opportunities for insights into basic neuroanatomy and neurophysiology,” the editorial concluded.
“Future research will need to address other ways to optimize physiological change — to enhance or speed up nerve regeneration, improve plasticity, and maximize rehabilitation.”
For an additional comment on how this surgery might affect stroke patients, Medscape Medical News reached Ralph L. Sacco, MD, professor and Olemberg Chair of Neurology, chief of neurology, Miller School of Medicine, University of Miami, Florida, and president, American Academy of Neurology.
Although the study was small, it did show significant evidence of improved motor function on the side that was treated with the nerve transfer, said Dr Sacco.
However, he pointed out that because only about a third of the patients in the study had a stroke, “it’s difficult to generalize to a wider array of patients with stroke.”
He stressed the need for “more innovative ways to enhance recovery” after stroke and that “with more studies, this could be a promising possibility for certain stroke patients.”
The study was supported by grants from the National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, Health and Family Planning Commission of Shanghai and Shanghai Shen-Kang Hospital Development Center. The study authors, Dr Spinner, and r Sacco have disclosed no relevant financial relationships.
N Engl J Med. Published online December 20, 2017. Abstract, Editorial
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