The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.

Cultured adult rat Schwann cells (SCs) or olfactory ensheathing glia (OEG), or both, were transplanted in the adult Fischer rat thoracic (T9) spinal cord 1 week after a moderate contusion (10 gm, 12.5 mm, NYU impactor). Rats received either a total of 2 x 10(6) cells suspended in culture medium or culture medium only (controls). At 12 weeks after injury, all grafted animals exhibited diminished cavitation. Although in medium-injected rats 33% of spinal tissue within a 5-mm-long segment of cord centered at the injury site was spared, significantly more tissue was spared in SC (51%), OEG (43%), and SC/OEG (44%) grafted animals. All three types of glial grafts were filled with axons, primarily of spinal origin. SC grafts contained more myelinated axons than SC/OEG and OEG grafts. Both types of SC-containing grafts expressed more intense staining for glial fibrillary acidic protein and chondroitin sulfate proteoglycan compared with OEG-only grafts. Retrograde tracing demonstrated that the number of propriospinal and brainstem axons reaching 5-6 mm beyond the grafted area was significantly higher with SC and SC/OEG grafts but not with OEG-only grafts compared with controls. Corticospinal fibers terminated closer to the lesion epicenter in all grafted animals than in controls. With SC-only grafts, a modest but statistically significant improvement in hindlimb locomotor performance was detected at 8-11 weeks after injury. Thus, in addition to this functional improvement, our results show that an SC graft is more effective in promoting axonal sparing/regeneration than an SC/OEG or OEG graft in the moderately contused adult rat thoracic spinal cord.

Schwann cells (SC) have been shown to promote regeneration in both the peripheral and central nervous systems. In this study we tested the ability of SC to enhance axonal regeneration in adult rat spinal cord by grafting SC-seeded guidance channels into transected cords. SC were purified in culture from adult inbred rat sciatic nerves, suspended in Matrigel, and seeded into semipermeable PAN/PVC channels (2.6 mm I.D. x 10 mm long) at a final density of 120 x 10(6) cells/ml. Channels filled with Matrigel alone served as controls. Adult isologous rat spinal cords were transected at the T8 level, and segments T9-T11 were removed. The rostral stump was inserted 1 mm into channels with capped distal ends. One month after grafting, a vascularized tissue cable was present within the channel in all animals. In SC-seeded channels (n = 14), a mean of 501 myelinated axons was found in the cable, and many axons extended 9-10 mm. Electron microscopy revealed typical SC ensheathment and myelination of axons with four times more unmyelinated than myelinated axons. Control channels (n = 8) contained fewer myelinated axons (mean = 71). When SC were prelabeled in culture with a nuclear dye, labeled nuclei were observed at 30 days, confirming SC survival. Astrocytes identified by glial fibrillary acidic protein staining did not migrate far into the cable, and prelabeled SC did not enter the cord. Lack of immunostaining for serotonin and dopamine beta-hydroxylase indicated that supraspinal axons did not regenerate into the cable. Fast Blue injections into the middle of the cable (n = 3) marked spinal cord interneurons (mean = 306) as far as nine segments rostral (25 mm, C7) extending axons into the graft; fewer dorsal root ganglion neurons were retrogradely labeled. In conclusion, purified populations of SC transplanted within channels promote both propriospinal and sensory axonal regeneration in the adult rat thoracic spinal cord.

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