Minimizing Errors in Acute Traumatic Spinal Cord Injury Trials by Acknowledging the Heterogeneity of Spinal Cord Anatomy and Injury Severity: An Observational Canadian Cohort Analysis

Abstract

Clinical trials of therapies for acute traumatic spinal cord injury (tSCI) have failed to convincingly demonstrate efficacy in improving neurologic function. Failing to acknowledge the heterogeneity of these injuries and under-appreciating the impact of the most important baseline prognostic variables likely contributes to this translational failure. Our hypothesis was that neurological level and severity of initial injury (measured by the American Spinal Injury Association Impairment Scale [AIS]) act jointly and are the major determinants of motor recovery. Our objective was to quantify the influence of these variables when considered together on early motor score recovery following acute tSCI. Eight hundred thirty-six participants from the Rick Hansen Spinal Cord Injury Registry were analyzed for motor score improvement from baseline to follow-up. In AIS A, B, and C patients, cervical and thoracic injuries displayed significantly different motor score recovery. AIS A patients with thoracic (T2-T10) and thoracolumbar (T11-L2) injuries had significantly different motor improvement. High (C1-C4) and low (C5-T1) cervical injuries demonstrated differences in upper extremity motor recovery in AIS B, C, and D.A hypothetical clinical trial example demonstrated the benefits of stratifying on neurological level and severity of injury. Clinically meaningful motor score recovery is predictably related to the neurological level of injury and the severity of the baseline neurological impairment. Stratifying clinical trial cohorts using a joint distribution of these two variables will enhance a study's chance of identifying a true treatment effect and minimize the risk of misattributed treatment effects. Clinical studies should stratify participants based on these factors and record the number of participants and their mean baseline motor scores for each category of this joint distribution as part of the reporting of participant characteristics. Improved clinical trial design is a high priority as new therapies and interventions for tSCI emerge.

IVIg attenuates complement and improves spinal cord injury outcomes in mice

“…With an increasing number of promising therapeutic interventions under development and/or already being tested in human SCI, there is an urgent need for noninvasive and transferable methods to assess treatment efficacy between animal and human studies and/or to also better account for patient heterogeneity in lesion severity at the outset . Based on a growing body of evidence in support of DTI being one such technique, we explored whether longitudinal in vivo DTI could detect the beneficial effects of IVIg therapy in live subjects.…”

“…Aside from the need for new and effective immunomodulatory treatments in SCI, there is an additional unmet demand for transferable approaches that can assess treatment efficacy in both preclinical studies and human SCI patients. Proving the efficacy of promising new therapeutic interventions in clinical trials remains one of the biggest challenges in translational SCI research due to the heterogeneity in the patient population (i.e., differences in the initiating cause, lesion level, and severity) . Furthermore, although rodent SCI models replicate much of the etiology of human SCI, including the inflammatory response, there are important intrinsic anatomical differences between species.…”

The Influence of Time from Injury to Surgery on Motor Recovery and Length of Hospital Stay in Acute Traumatic Spinal Cord Injury: An Observational Canadian Cohort Study

“…By analyzing the motor recovery based on the Canadian classification table for motor recovery, 52 it became clear that the AIS A patients demonstrated a significantly different pattern of neurological recovery than did the AIS B, C, and D patients. We therefore chose to analyze the AIS A and the AIS B, C, and D subgroups separately.…”

“…Authors have demonstrated that the severity of the initial neurological injury and the anatomic region of the injury are strong predictors of neurological recovery. 45,52,62,[64][65][66] Others have identified patients' age and sex as a predictor of recovery. 51 Our current study has provided evidence that the time from injury to operation influences motor recovery in neurologically incomplete (B, C, and D) patients but not in all complete (AIS A) patients.…”

Characterization of the Antibody Response after Cervical Spinal Cord Injury

“…1 Despite advances in medical, surgical, and rehabilitation approaches, there is a major need for effective neuroprotective or neuroregenerative treatment options to enhance functional recovery following SCI. In the U.S. alone, more than 1 million individuals are estimated to suffer from the effects of SCI, the majority of whom are affected at the cervical level.…”