Stem cell transplantation in traumatic spinal cord injury: a systematic review and meta-analysis of animal studies.

Spinal cord injury (SCI) is a devastating condition that causes substantial morbidity and mortality and for which no treatments are available. Stem cells offer some promise in the restoration of neurological function. We used systematic review, meta-analysis, and meta-regression to study the impact of stem cell biology and experimental design on motor and sensory outcomes following stem cell treatments in animal models of SCI. One hundred and fifty-six publications using 45 different stem cell preparations met our prespecified inclusion criteria. Only one publication used autologous stem cells. Overall, allogeneic stem cell treatment appears to improve both motor (effect size, 27.2%; 95% Confidence Interval [CI], 25.0%-29.4%; 312 comparisons in 5,628 animals) and sensory (effect size, 26.3%; 95% CI, 7.9%-44.7%; 23 comparisons in 473 animals) outcome. For sensory outcome, most heterogeneity between experiments was accounted for by facets of stem cell biology. Differentiation before implantation and intravenous route of delivery favoured better outcome. Stem cell implantation did not appear to improve sensory outcome in female animals and appeared to be enhanced by isoflurane anaesthesia. Biological plausibility was supported by the presence of a dose-response relationship. For motor outcome, facets of stem cell biology had little detectable effect. Instead most heterogeneity could be explained by the experimental modelling and the outcome measure used. The location of injury, method of injury induction, and presence of immunosuppression all had an impact. Reporting of measures to reduce bias was higher than has been seen in other neuroscience domains but were still suboptimal. Motor outcomes studies that did not report the blinded assessment of outcome gave inflated estimates of efficacy. Extensive recent preclinical literature suggests that stem-cell-based therapies may offer promise, however the impact of compromised internal validity and publication bias mean that efficacy is likely to be somewhat lower than reported here.

Prehospital Cardiovascular Autoregulatory Disturbances Correlate With the Functional Neuroanatomy of Acute Spinal Cord Injury.

STUDY DESIGN: Retrospective study. OBJECTIVE: The importance of attenuating the cardiovascular autoregulatory disturbances accompanying acute spinal cord injury (SCI) has long been recognized. This report assembles SCI emergency service data and correlates cardiovascular parameters to preserved functional neuroanatomy. SUMMARY OF BACKGROUND DATA: The nascent nature of evidence-based reporting of prehospital cardiovascular autoregulatory disturbances in SCI indicates the need to assemble more information. MATERIALS AND METHODS: SCI data for <24 hours were extracted from ambulance and hospital records. The mean arterial pressure (MAP) was calculated. The International Standard for Neurological Classification of SCI (ISNCSCI) evaluates the primary outcome of motor incomplete injury (grades C/D) at acute presentation. Logistic regression was adjusted for multiple confounders that were expected to influence the odds of grade C/D. RESULTS: A cohort of 99 acute SCI cases was retained; mean (SD) age 40.7±20.5 years, 88 male, 84 tetraplegic, 65 grades A/B (motor complete injury), triage time 2±1.6 hours. The lowest recorded prehospital MAP [mean (SD): 77.9±19, range: 45-145 mm Hg] approached the nadir for adequate organ perfusion. Thirty-four (52%) grade A/B and 10 (30%) C/D cases had MAP readings <85 mm Hg. In data adjusted for age, injury level, and triage time a 5 mm Hg increase in the lowest MAP value was associated with a 34% increase in the odds of having motor incomplete injury at acute presentation (adjusted odds ratio=1.34; 95% CI: 1.11-1.61; P =0.002). CONCLUSION: An important observation with implications for timely and selective cardiovascular resuscitation during SCI prehospital care involves significant negative associations between the depth of systemic hypotension and preserved functional neuroanatomy. Regardless of the mechanism, our confounder-adjusted logistic regression model extends in-hospital evidence and provides a conceptual bedside-bench framework for future investigations.

Immediate Cooling and Early Decompression for the Treatment of Cervical Spinal Cord Injury: A Safety and Feasibility Study.

Cervical spinal cord injury (SCI) usually results in severe, long-term disability. Early therapeutic hypothermia (33-34°C) has been used to improve outcomes in preclinical studies, but previous clinical studies have commenced cooling after arrival at hospital. The objective of the study is to determine the feasibility and safety of early therapeutic hypothermia initiated by paramedics and maintained for up to 24 hours in hospital in patients with SCI. This is a pilot clinical study. The study was undertaken at Ambulance Victoria and The Alfred Hospital, Victoria, Australia. A total of 17 consecutive patients with suspected acute traumatic cervical SCI were enrolled. Patients with suspected cervical SCI were administered a bolus (up to 20 mL/kg) intravenous (IV) cold (4°C) normal saline in the prehospital phase of care. After hospital admission and spinal imaging, further cooling used IV catheter temperature control or surface cooling. Major complications and long-term outcomes were compared with historical controls admitted to the same center before the study. A decrease in core temperature of 1.1°C was achieved during prehospital care and the target temperature was achieved in 6 hours with mechanical temperature management devices in the hospital. There were no major safety concerns. Patients with motor complete SCI who underwent early decompressive surgery had a favorable rate of partial spinal cord recovery compared with historical controls. Therapeutic hypothermia induced using bolus, large-volume, ice-cold saline prehospital and maintained for 24 hours using mechanical devices appears to be feasible and safe in patients with SCI. Larger trials need to be undertaken to determine whether prehospital cooling combined with early decompressive surgery improves outcomes in patients with complete cervical SCI. Australian and New Zealand Clinical Trials Registry (ACTRN12616001086459).

Acute Thoracolumbar Spinal Cord Injury: Relationship of Cord Compression to Neurological Outcome.

BACKGROUND: Spinal cord injury in the cervical spine is commonly accompanied by cord compression and urgent surgical decompression may improve neurological recovery. However, the extent of spinal cord compression and its relationship to neurological recovery following traumatic thoracolumbar spinal cord injury is unclear. The purpose of this study was to quantify maximum cord compression following thoracolumbar spinal cord injury and to assess the relationship among cord compression, cord swelling, and eventual clinical outcome. METHODS: The medical records of patients who were 15 to 70 years of age, were admitted with a traumatic thoracolumbar spinal cord injury (T1 to L1), and underwent a spinal surgical procedure were examined. Patients with penetrating injuries and multitrauma were excluded. Maximal osseous canal compromise and maximal spinal cord compression were measured on preoperative mid-sagittal computed tomography (CT) scans and T2-weighted magnetic resonance imaging (MRI) by observers blinded to patient outcome. The American Spinal Injury Association (ASIA) Impairment Scale (AIS) grades from acute hospital admission (≤24 hours of injury) and rehabilitation discharge were used to measure clinical outcome. Relationships among spinal cord compression, canal compromise, and initial and final AIS grades were assessed via univariate and multivariate analyses. RESULTS: Fifty-three patients with thoracolumbar spinal cord injury were included in this study. The overall mean maximal spinal cord compression (and standard deviation) was 40% ± 21%. There was a significant relationship between median spinal cord compression and final AIS grade, with grade-A patients (complete injury) exhibiting greater compression than grade-C and D patients (incomplete injury) (p < 0.05). Multivariate logistic regression identified mean spinal cord compression as independently influencing the likelihood of complete spinal cord injury (p < 0.01). CONCLUSIONS: Traumatic thoracolumbar spinal cord injury is commonly accompanied by substantial cord compression. Greater cord compression is associated with an increased likelihood of severe neurological deficits (complete injury) following thoracolumbar spinal cord injury. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Early Spinal Surgery Following Thoracolumbar Spinal Cord Injury: Process of Care From Trauma to Theater.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aims of this study were to (1) determine the timing of surgery for traumatic thoracolumbar spinal cord injury (TLSCI) between 2010 and 2014 and (2) identify major delays in the process of care from accident scene to surgery. SUMMARY OF BACKGROUND DATA: Early spinal surgery may promote neurological recovery and reduce acute complications after TLSCI; however, it is difficult to achieve due to logistical issues and the frequent presence of other nonlife-threatening injuries. METHODS: Data were extracted from the medical records of 46 cases of acute traumatic TLSCI (AIS level T1-L1) aged between 15 and 70 years. Patients with life-threatening injuries, not requiring spinal surgery or with poor general health, were excluded. RESULTS: The median time to surgery was 27 hours [interquartile range (IQR): 20-43 hours] and improved from 27 hours in 2010 to 22 hours in 2014. Cases admitted via a pre-surgical hospital had a longer median time to surgery than direct surgical hospital admissions (28 vs. 24 hours, respectively). The median time from completion of radiological investigations to surgery was 18 hours, suggesting that theater access and organization of a surgical team were the major factors contributing to surgical delay. Number of vertebral levels fractured (≥5) and upper thoracic level of injury (T1-8) were also found to be associated with surgical delay. CONCLUSION: Earlier spinal surgery in TLSCI would be facilitated by direct surgical hospital admission and improved access to the operating theater and surgical teams. LEVEL OF EVIDENCE: 3.

Reduced bone formation markers, and altered trabecular and cortical bone mineral densities of non-paretic femurs observed in rats with ischemic stroke: A randomized controlled pilot study.

BACKGROUND: Immobility and neural damage likely contribute to accelerated bone loss after stroke, and subsequent heightened fracture risk in humans. OBJECTIVE: To investigate the skeletal effect of middle cerebral artery occlusion (MCAo) stroke in rats and examine its utility as a model of human post-stroke bone loss. METHODS: Twenty 15-week old spontaneously hypertensive male rats were randomized to MCAo or sham surgery controls. Primary outcome: group differences in trabecular bone volume fraction (BV/TV) measured by Micro-CT (10.5 micron istropic voxel size) at the ultra-distal femur of stroke affected left legs at day 28. Neurological impairments (stroke behavior and foot-faults) and physical activity (cage monitoring) were assessed at baseline, and days 1 and 27. Serum bone turnover markers (formation: N-terminal propeptide of type 1 procollagen, PINP; resorption: C-terminal telopeptide of type 1 collagen, CTX) were assessed at baseline, and days 7 and 27. RESULTS: No effect of stroke was observed on BV/TV or physical activity, but PINP decreased by -24.5% (IQR -34.1, -10.5, p = 0.046) at day 27. In controls, cortical bone volume (5.2%, IQR 3.2, 6.9) and total volume (6.4%, IQR 1.2, 7.6) were higher in right legs compared to left legs, but these side-to-side differences were not evident in stroke animals. CONCLUSION: MCAo may negatively affect bone formation. Further investigation of limb use and physical activity patterns after MCAo is required to determine the utility of this current model as a representation of human post-stroke bone loss.

Early Rapid Neurological Assessment for Acute Spinal Cord Injury Trials.

Clinical trials evaluating early therapies after spinal cord injury (SCI) are challenging because of the absence of a rapid assessment. The aim of this study was to determine whether the severity and level of SCI could be established from a brief neurological assessment capable of being used in an emergency setting. A brief assessment called the SPinal Emergency Evaluation of Deficits (SPEED) was developed and retrospectively evaluated in a cohort of 118 patients with SCI. Foot motor and sensory function was used to indicate injury severity. C3 dermatome sensation, handgrip strength and location of spinal pain were used to indicate the level of injury. With regard to injury severity, a high proportion of patients (94%) with no foot movement at the time of injury were initially diagnosed as motor complete (American Spinal Injury Association Impairment Scale [AIS] grade A-B), whereas all patients with foot movement were identified as motor incomplete (AIS grade C-D). This was reflected by a good correlation (rs = 0.79) and agreement (κ = 0.85) between the SPEED motor score and the acute hospital assessment. With respect to injury level, the majority of cases with cervical SCI (92%) had no or weak handgrip at the time of paramedic assessment, whereas all cases with thoracolumbar SCI had a strong handgrip. The location of spinal pain was also in accordance with the level of spinal injury. The SPEED assessment appears capable of accurately determining the severity and level of cervical SCI in the first hours post-injury. A neurological assessment that can be performed rapidly after injury is important for clinical trials of early therapy and to identify patients most likely to benefit from intervention.

Early Decompression following Cervical Spinal Cord Injury: Examining the Process of Care from Accident Scene to Surgery.

Early decompression may improve neurological outcome after spinal cord injury (SCI), but is often difficult to achieve because of logistical issues. The aims of this study were to 1) determine the time to decompression in cases of isolated cervical SCI in Australia and New Zealand and 2) determine where substantial delays occur as patients move from the accident scene to surgery. Data were extracted from medical records of patients aged 15-70 years with C3-T1 traumatic SCI between 2010 and 2013. A total of 192 patients were included. The median time from accident scene to decompression was 21 h, with the fastest times associated with closed reduction (6 h). A significant decrease in the time to decompression occurred from 2010 (31 h) to 2013 (19 h, p = 0.008). Patients undergoing direct surgical hospital admission had a significantly lower time to decompression, compared with patients undergoing pre-surgical hospital admission (12 h vs. 26 h, p < 0.0001). Medical stabilization and radiological investigation appeared not to influence the timing of surgery. The time taken to organize the operating theater following surgical hospital admission was a further factor delaying decompression (12.5 h). There was a relationship between the timing of decompression and the proportion of patients demonstrating substantial recovery (2-3 American Spinal Injury Association Impairment Scale grades). In conclusion, the time of cervical spine decompression markedly improved over the study period. Neurological recovery appeared to be promoted by rapid decompression. Direct surgical hospital admission, rapid organization of theater, and where possible, use of closed reduction, are likely to be effective strategies to reduce the time to decompression.

Meta-analysis of pre-clinical studies of early decompression in acute spinal cord injury: a battle of time and pressure.

BACKGROUND: The use of early decompression in the management of acute spinal cord injury (SCI) remains contentious despite many pre-clinical studies demonstrating benefits and a small number of supportive clinical studies. Although the pre-clinical literature favours the concept of early decompression, translation is hindered by uncertainties regarding overall treatment efficacy and timing of decompression. METHODS: We performed meta-analysis to examine the pre-clinical literature on acute decompression of the injured spinal cord. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of (i) the reporting of efficacy of decompression at various time intervals (ii) number of animals and (iii) the mean outcome and variance in each group. Random effects meta-analysis was used and the impact of study design characteristics assessed with meta-regression. RESULTS: Overall, decompression improved behavioural outcome by 35.1% (95%CI 27.4-42.8; I(2)=94%, p<0.001). Measures to minimise bias were not routinely reported with blinding associated with a smaller but still significant benefit. Publication bias likely also contributed to an overestimation of efficacy. Meta-regression demonstrated a number of factors affecting outcome, notably compressive pressure and duration (adjusted r(2)=0.204, p<0.002), with increased pressure and longer durations of compression associated with smaller treatment effects. Plotting the compressive pressure against the duration of compression resulting in paraplegia in individual studies revealed a power law relationship; high compressive forces quickly resulted in paraplegia, while low compressive forces accompanying canal narrowing resulted in paresis over many hours. CONCLUSION: These data suggest early decompression improves neurobehavioural deficits in animal models of SCI. Although much of the literature had limited internal validity, benefit was maintained across high quality studies. The close relationship of compressive pressure to the rate of development of severe neurological injury suggests that pressure local to the site of injury might be a useful parameter determining the urgency of decompression.

Systematic review and meta-analysis of therapeutic hypothermia in animal models of spinal cord injury.

BACKGROUND: Therapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously. METHODS: In this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group. RESULTS: Systemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI -3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature. CONCLUSION: Systemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies.