Application of electrophysiological measures in spinal cord injury clinical trials: a narrative review

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

To investigate the adaptational changes in excitability of spinal neuronal circuits below the level of lesion from spinal shock to spasticity in patients with spinal cord injury (SCI). More than 6 months after an acute SCI, clinical follow-up examinations were paralleled by electrophysiologic recordings with tibial nerve stimulation (M-wave, F-wave, H-reflex, and flexor reflex). During spinal shock, the loss of tendon tap reflexes and flaccid muscle tone were associated with low persistence of F-waves and loss of flexor reflexes, whereas H-reflexes were already elicitable. During the transition to spasticity, the reappearance of tendon tap reflexes and muscle tone and the occurrence of spasms was associated with the recovery of F-waves and flexor reflex excitability, whereas the H-to-M ratio remained about stable over months. At later stages (2 to 6 months after SCI) when clinical signs of spasticity became established, the electrophysiologic measures showed little change. In paraplegic patients, in contrast to tetraplegic patients, M-wave and flexor reflex amplitudes even decreased. The late decrease in M-wave and flexor reflex amplitude in paraplegic patients suggests a secondary impairment/degeneration of premotoneuronal circuits and of motoneurons. The divergent course of clinical signs of spasticity and their probable neuronal correlates indicates the occurrence of non-neuronal changes contributing to spasticity.