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A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.

Abstract Individuals with SCI are severely affected by immune system changes, resulting in increased risk of infections and persistent systemic inflammation. While recent data support that immunological changes after SCI differ in the acute and chronic phases of living with SCI, only limited immunological phenotyping in humans is available. To characterize dynamic molecular and cellular immune phenotypes over the first year, we assess RNA (bulk-RNA sequencing), protein, and flow cytometry (FACS) profiles of blood samples from 12 individuals with SCI at 0-3 days and at 3, 6, and 12 months post injury (MPI) compared to 23 uninjured individuals (controls). We identified 967 differentially expressed (DE) genes in individuals with SCI (FDR <0.001) compared to controls. Within the first 6 MPI we detected a reduced expression of NK cell genes, consistent with reduced frequencies of CD56 bright , CD56 dim NK cells present at 12 MPI. Over 6MPI, we observed increased and prolonged expression of genes associated with inflammation (e.g. HMGB1, Toll-like receptor signaling) and expanded frequencies of monocytes acutely. Canonical T-cell related DE genes (e.g. FOXP3, TCF7, CD4) were upregulated during the first 6 MPI and increased frequencies of activated T cells at 3-12 MPI. Neurological injury severity was reflected in distinct whole blood gene expression profiles at any time after SCI, verifying a persistent 'neurogenic' imprint. Overall, 2876 DE genes emerge when comparing motor complete to motor incomplete SCI (ANOVA, FDR <0.05), including those related to neutrophils, inflammation, and infection. In summary, we identify a dynamic immunological phenotype in humans, including molecular and cellular changes which may provide potential targets to reduce inflammation, improve immunity, or serve as candidate biomarkers of injury severity.

Given the complexity of care necessitated after an acute traumatic spinal cord injury (SCI), it seems intuitively beneficial for such care to be delivered at hospitals with specialized SCI expertise. Demonstrating these benefits is not straightforward, however. We sought to determine whether specialized acute hospital care influenced the most fundamental outcomes after SCI: mortality within the first year of injury. We compared survival among patients with incomplete tSCI admitted to a single quaternary-level trauma hospital with a specialized acute SCI program versus those admitted to trauma hospitals without specialized acute SCI care. We performed a population-based retrospective observational cohort study using administrative and clinical data linked from multiple sources in British Columbia (BC) from 2001 to 2017. Among a cohort of 1920 patients, there were 193 deaths within one year. We failed to identify a significant overall benefit for survival after adjusting for potential confounders, and the confidence intervals (CIs) were compatible with both benefit and harm (odds ratio [OR] 1.01, 95% CI 0.17 to 6.11, p  = 0.99). Significant associations were observed with age greater than 65 (OR 4.92, 95% CI 1.66 to 14.57, p  < 0.01), Charlson Comorbidity Index (OR 1.61, 95% CI 1.42 to 1.83, p  < 0.01), Injury Severity Score (OR 1.08, 95% CI 1.06 to 1.11, p  < 0.01), and traumatic brain injury (OR 2.12, 95% CI 1.32 to 3.41, p < 0.01). Among patients with acute tSCI, admission to a hospital with specialized acute SCI care was not associated with improved overall one-year survival. Subgroup analyses, however, suggested heterogeneity of effects, with little benefit for older patients with less polytrauma and substantial benefit for younger patients with greater polytrauma.

Multiple types and classes of medications are administered in the acute management of traumatic spinal cord injury. Prior clinical studies and evidence from animal models suggest that several of these medications could modify (i.e., enhance or impede) neurological recovery. We aimed to systematically determine the types of medications commonly administered, alone or in combination, in the transition from acute to subacute spinal cord injury. For that purpose, type, class, dosage, timing, and reason for administration were extracted from two large spinal cord injury datasets. Descriptive statistics were used to describe the medications administered within the first 60 days after spinal cord injury. Across 2040 individuals with spinal cord injury, 775 unique medications were administered within the two months after injury. On average, patients enrolled in a clinical trial were administered 9.9 ± 4.9 (range 0-34), 14.3 ± 6.3 (range 1-40), 18.6 ± 8.2 (range 0-58), and 21.5 ± 9.7 (range 0-59) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Those enrolled in an observational study were administered on average 1.7 ± 1.7 (range 0-11), 3.7 ± 3.7 (range 0-24), 8.5 ± 6.3 (range 0-42), and 13.5 ± 8.3 (range 0-52) medications within the first 7, 14, 30, and 60 days post-injury, respectively. Polypharmacy was commonplace (up to 43 medications per day per patient). Approximately 10% of medications were administered acutely as prophylaxis (e.g., against the development of pain or infections). To our knowledge, this was the first time acute pharmacological practices have been comprehensively examined after spinal cord injury. Our study revealed a high degree of polypharmacy in the acute stages of spinal cord injury, raising the potential to impact neurological recovery. All results can be interactively explored on the R X SCI web site ( https://jutzelec.shinyapps.io/RxSCI/ ) and GitHub repository ( https://github.com/jutzca/Acute-Pharmacological-Treatment-in-SCI/ )., (© 2023. The Author(s).)

Background and Objectives: Traumatic spinal cord injury (SCI) is highly heterogeneous, and tools to better delineate pathophysiology and recovery are needed. Our objective was to profile the response of 2 biomarkers, neurofilament light (NF-L) and glial fibrillary acidic protein (GFAP), in the serum and CSF of patients with acute SCI to evaluate their ability to objectively characterize injury severity and predict neurologic recovery., Methods: Blood and CSF samples were obtained from prospectively enrolled patients with acute SCI through days 1-4 postinjury, and the concentration of NF-L and GFAP was quantified using Simoa technology. Neurologic assessments defined the ASIA Impairment Scale (AIS) grade and motor score (MS) at presentation and 6 months postinjury., Results: One hundred eighteen patients with acute SCI (78 AIS A, 20 AIS B, and 20 AIS C) were enrolled, with 113 (96%) completing 6-month follow-up. NF-L and GFAP levels were strongly associated between paired serum and CSF specimens, were both increased with injury severity, and distinguished among baseline AIS grades. Serum NF-L and GFAP were significantly ( p = 0.02 to <0.0001) higher in AIS A patients who did not improve at 6 months, predicting AIS grade conversion with a sensitivity and specificity (95% CI) of 76% (61, 87) and 77% (55, 92) using NF-L and 72% (57, 84) and 77% (55, 92) using GFAP at 72 hours, respectively. Independent of clinical baseline assessment, a serum NF-L threshold of 170 pg/mL at 72 hours predicted those patients who would be classified as motor complete (AIS A/B) compared with motor incomplete (AIS C/D) at 6 months with a sensitivity of 87% (76, 94) and specificity of 84% (69, 94); a serum GFAP threshold of 13,180 pg/mL at 72 hours yielded a sensitivity of 90% (80, 96) and specificity of 84% (69, 94)., Discussion: The potential for NF-L and GFAP to classify injury severity and predict outcome after acute SCI will be useful for patient stratification and prognostication in clinical trials and inform communication of prognosis., Classification of Evidence: This study provides Class I evidence that higher serum NF-L and GFAP are associated with worse neurological outcome after acute SCI., Trial Registration Information: Registered on ClinicalTrials.gov: NCT00135278 (March 2006) and NCT01279811 (January 2012)., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Intraparenchymal hemorrhage (IPH) after a traumatic injury has been associated with poor neurological outcomes. Although IPH may result from the initial mechanical trauma, the blood and its breakdown products have potentially deleterious effects. Further, the degree of IPH has been correlated with injury severity and the extent of subsequent recovery. Therefore, accurate evaluation and quantification of IPH following traumatic spinal cord injury (SCI) is important to define treatments' effects on IPH progression and secondary neuronal injury. Imaging modalities, such as magnetic resonance imaging (MRI) and ultrasound (US), have been explored by researchers for the detection and quantification of IPH following SCI. Both quantitative and semiquantitative MRI and US measurements have been applied to objectively assess IPH following SCI, but the optimal methods for doing so are not well established. Studies in animal SCI models (rodent and porcine) have explored US and histological techniques in evaluating SCI and have demonstrated the potential to detect and quantify IPH. Newer techniques using machine learning algorithms (such as convolutional neural networks [CNN]) have also been studied to calculate IPH volume and have yielded promising results. Despite long-standing recognition of the potential pathological significance of IPH within the spinal cord, quantifying IPH with MRI or US is a relatively new area of research. Further studies are warranted to investigate their potential use. Here, we review the different and emerging quantitative MRI, US, and histological approaches used to detect and quantify IPH following SCI.

Over the past few decades, tremendous advances have been made in our understanding of the biological changes underpinning the devastating impairment of traumatic spinal cord injury (SCI). Much of this scientific research has focused on animal models of SCI, and comparatively little has been done in human SCI, largely because biospecimens from human SCI patients are not readily available. This paucity of scientific enquiry in human SCI represents an important void in the spectrum of translational research, as biological differences between animal models and the human condition need to be considered in the pre-clinical development of therapeutic approaches. The International Spinal Cord Injury Biobank (ISCIB) is a multi-user biorepository with the mission of accelerating therapeutic development in traumatic SCI through improved biological understanding of human injury, and the vision of serving as a global research resource where human SCI biospecimens are shared with researchers around the world. Aligned with internationally recognized best practices, ISCIB's formal governance structure and standard operating procedures have earned it official biobank certification through the Canadian Tissue Repository Network. Herein, we describe the translational research gap that ISCIB is helping to fill; its structure, governance and certification; how data and samples are accrued, processed and stored; and finally, the process through which samples and data are shared with global researchers. The purpose of this paper describing ISCIB is to serve as an introductory guidance document for the wider community of SCI researchers. By helping researchers understand the contents of ISCIB and the process of accessing biospecimens, we seek to further ISCIB's vision as being a resource for human and translational research in SCI, with the ultimate goal of finding disease-modifying therapies for this disabling condition.

Background: Traumatic spinal cord injury (tSCI) is a debilitating neurological condition often associated with lifelong disability. Despite this, there are limited data on pediatric tSCI epidemiology in the United States., Objectives: Our primary objective was to estimate tSCI hospitalization rates among children, including by age, sex, and race. Secondary objectives were to characterize tSCI hospitalizations and examine associations between sociodemographic characteristics and tSCI etiology., Methods: We used the 2016 Kids' Inpatient Database to examine tSCI hospitalizations among children (<21 years). Descriptive statistics were used to report individual and care setting characteristics for initial tSCI hospitalizations. We used Census Bureau data to estimate tSCI hospitalization rates (number of pediatric tSCI hospitalizations / number of US children) and logistic regression modeling to assess associations between documented sociodemographic characteristics and injury etiology., Results: There were 1.48 tSCI admissions per 100,000 children; highest rates of hospitalization involved older (15-20 years), male, and Black children. Hospitalization involving male (adjusted odds ratio [AOR] 0.43; 95% CI, 0.33-0.58) or Black (AOR 0.37; 95% CI, 0.25-0.55) children were less likely to involve a motor traffic accident. Hospitalizations of Black children were significantly more likely to have a diagnosis of tSCI resulting from a firearm incident (AOR 18.97; 95% CI, 11.50-31.28) or assault (AOR 11.76; 95% CI, 6.75-20.50) compared with hospitalizations of White children., Conclusion: Older, male, and Black children are disproportionately burdened by tSCI. Implementation of broad health policies over time may be most effective in reducing pediatric tSCI hospitalizations and preventable injuries., Competing Interests: Conflicts of Interest The authors report no conflicts of interest., (© 2022 American Spinal Injury Association.)

Background: Proper utilization of high-quality clinical practice guidelines (CPGs) eliminates the dependence of patients' outcomes on the ability and knowledge of "individual" health care providers and reduces unwarranted variation in care. The aim of this study was to adapt/adopt two CPGs for pharmacologic management of acute spinal cord injury (SCI) using guideline adaptation methods., Methods: This study was conducted based on the ADAPTE process. Following establishment of an organizing committee and choosing the health topics, we appraised the quality of the CPGs using the Appraisal of Clinical Guidelines for Research & Evaluation II (AGREE II). Then, the authors extracted and categorized suggestions according to Population, Intervention, Professions, Outcomes and Health care setting (PIPOH). The decision-making process was based on systemic evaluation of each suggestion, utilizing a combination of AGREE II scores, the quality of supporting evidence for or against each suggestion and the triad of feasibility, acceptance and adoptability for the Iranian health-care context., Results: Two guidelines were included in the adaptation process. Based on high-quality of these guidelines and the feasibility and adoptability evaluation of the organizing committee, we decided to adopt the suggestion of both guidelines. Overall, seven suggestions were extracted from the source guidelines., Conclusion: This work provides a framework to apply guidelines for acute SCI to the developing regions of the world. Attempts should be made to implement these suggestions in order to improve the health outcomes of Iranian SCI patients., (© 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons. org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Study Design: Observational study., Objectives: To examine the feasibility of meeting the current clinical guidelines for the hemodynamic management of acute spinal cord injury (SCI) which recommend maintaining mean arterial pressure (MAP) at 85-90 mmHg in the days following injury., Methods: This study examined data collected minute-by-minute to describe the pressure profile in the first 5 days following SCI in 16 patients admitted to the Intensive Care Unit at Vancouver General Hospital (40 ± 19 years, 13 M/3 F, C4-T11). MAP and intrathecal pressure (ITP) were monitored at 100 Hz by arterial and lumbar intrathecal catheters, respectively, and reported as the average of each minute. Spinal cord perfusion pressure was calculated as the difference between MAP and ITP. The minute-to-minute difference (MMdiff) of each pressure variable was calculated as the absolute difference between consecutive minutes., Results: Only 24 ± 7% of MAP recordings were between 85 and 90 mmHg. Average MAP MMdiff was ~3 mmHg. The percentage of MAP recordings within target range was negatively correlated with the degree of variability (i.e. MMdiff; r = -0.64, p < 0.008) whereas higher mean MAP was correlated with greater variability (r = 0.57, p = 0.021)., Conclusions: Our findings point to the 'real life' challenges in maintaining MAP in acute SCI patients. Given MAP fluctuated ~3 mmHg minute-to-minute, maintaining MAP within a 5 mmHg range with conventional volume replacement and vasopressors presents an almost impossible task for clinicians and warrants reconsideration of current management guidelines., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background Context: Current prognostic tools such as the Injury Severity Score (ISS) that predict mortality following trauma do not adequately consider the unique characteristics of traumatic spinal cord injury (tSCI)., Purpose: Our aim was to develop and validate a prognostic tool that can predict mortality following tSCI., Study Design: Retrospective review of a prospective cohort study., Patient Sample: Data was collected from 1245 persons with acute tSCI who were enrolled in the Rick Hansen Spinal Cord Injury Registry between 2004 and 2016., Outcome Measures: In-hospital and 1-year mortality following tSCI., Methods: Machine learning techniques were used on patient-level data (n=849) to develop the Spinal Cord Injury Risk Score (SCIRS) that can predict mortality based on age, neurological level and completeness of injury, AOSpine classification of spinal column injury morphology, and Abbreviated Injury Scale scores. Validation of the SCIRS was performed by testing its accuracy in an independent validation cohort (n=396) and comparing its performance to the ISS, a measure which is used to predict mortality following general trauma., Results: For 1-year mortality prediction, the values for the Area Under the Receiver Operating Characteristic Curve (AUC) for the development cohort were 0.84 (standard deviation=0.029) for the SCIRS and 0.55 (0.041) for the ISS. For the validation cohort, AUC values were 0.86 (0.051) for the SCIRS and 0.71 (0.074) for the ISS. For in-hospital mortality, AUC values for the development cohort were 0.87 (0.028) and 0.60 (0.050) for the SCIRS and ISS, respectively. For the validation cohort, AUC values were 0.85 (0.054) for the SCIRS and 0.70 (0.079) for the ISS., Conclusions: The SCIRS can predict in-hospital and 1-year mortality following tSCI more accurately than the ISS. The SCIRS can be used in research to reduce bias in estimating parameters and can help adjust for coefficients during model development. Further validation using larger sample sizes and independent datasets is needed to assess its reliability and to evaluate using it as an assessment tool to guide clinical decision-making and discussions with patients and families., Competing Interests: Declarations of Competing Interests Vanessa Noonan, Nader Fallah, Nancy Thorogood and Zeina Waheed are employees of the Praxis Spinal Cord Institute. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

There is currently a lack of information regarding neuropathic pain in the very early stages of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) for the patient's worst pain within the first 5 days of injury (i.e., hyperacute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time frame (i.e., 5 days), at- and below-level neuropathic pain were reported as the worst pain in 23% (n = 18) and 5% (n = 4) of individuals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late presenting neuropathic pain was characterized by more intense painful electrical and cold sensations, but less itching sensations. Phenotypic differences between acute and late neuropathic pain support the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuropathic pains, with the former potentially masking the latter. This may lead to an underestimation of the incidence of neuropathic pain during the very early, hyperacute time points post-injury. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01279811) PERSPECTIVE: This article presents distinct pain phenotypes of hyperacute and late presenting neuropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute phase after injury. This information may be relevant to clinical trial design and broaden our understanding of neuropathic pain mechanisms after spinal cord injury., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO 2 ), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO 2 values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.

Background: The gut microbiome is a diverse network of bacteria which inhabit our digestive tract and is crucial for efficient cellular metabolism, nutrient absorption, and immune system development. Spinal cord injury (SCI) disrupts autonomic function below the level of injury and can alter the composition of the gut microbiome. Studies in rodent models have shown that SCI-induced bacterial imbalances in the gut can exacerbate the spinal cord damage and impair recovery. In this study we, for the first time, characterized the composition of the gut microbiome in a Yucatan minipig SCI model. We compared the relative abundance of the most dominant bacterial phyla in control samples to those collected from animals who underwent a contusion-compression SCI at the 2nd or 10th Thoracic level., Results: We identify specific bacterial fluctuations that are unique to SCI animals, which were not found in uninjured animals given the same dietary regimen or antibiotic administration. Further, we identified a specific time-frame, "SCI-acute stage", during which many of these bacterial fluctuations occur before returning to "baseline" levels., Conclusion: This work presents a dynamic view of the microbiome changes that accompany SCI, establishes a resource for future studies and to understand the changes that occur to gut microbiota after spinal cord injury and may point to a potential therapeutic target for future treatment., (© 2021. The Author(s).)

Study Design: Qualitative study., Objectives: The purpose of this study is to understand the patient perspective after diagnosis of an acute traumatic spinal cord injury (tSCI). Discussing the diagnosis and prognosis of a tSCI with a patient can be a challenging experience for both the patient and the physician. As such, this paper attempts to better understand the patient experience to improve communication when discussing this life-altering injury., Setting: Vancouver General Hospital, Vancouver, British Columbia, Canada., Methods: This study is a qualitative study utilizing grounded theory and semi-structured interviews. The interview transcripts were manually coded using manifest and latent content analysis. Major and minor codes were identified and discussed., Results: In total, 17 interviews were conducted, fifteen individuals with tSCI who received acute care at Vancouver General Hospital (VGH) and eleven family members were interviewed. Patient participants were interviewed individually or in a paired interview with a participating family member. Patient participants had varying spinal cord injuries from AIS A-D. Two major themes were identified from the interviews. The first major theme was physician demeanor (general approach and attitude towards patients) and the second major theme was delivery of information (content, timing, and source)., Conclusions: This study summarizes the preferences of patients who sustained a tSCI discussions regarding their diagnosis and prognosis in the acute care setting. The goal of this study is to help guide physician interactions at this difficult and vulnerable time for patients with hopes to improve patient care through effective communication., (© 2021. The Author(s), under exclusive licence to International Spinal Cord Society.)

Accurate safety information in published clinical trials guides the assessment of risk-benefit, as well as the design of future clinical trials. Comprehensive reporting of adverse events, toxicity, and discontinuations from acute spinal cord injury clinical trials is an essential step in this process. Here, we sought to assess the degree of "satisfactoriness" of reporting in past clinical trials in spinal cord injury. A review of citations from MEDLINE and EMBASE identified eligible clinical trials in acute (within 30 days) spinal cord injury. English language studies, published between 1980 and 2020, with sensory, motor, or autonomic neurological assessments as the primary outcome measure were eligible for inclusion. Criteria were then established to qualify the safety reporting as satisfactory (i.e., distinguished severe/life-threatening events), partially satisfactory, or unsatisfactory (i.e., only mentioned in general statements, or reported but without distinguishing severe events). A total of 40 trials were included. Satisfactory reporting for clinical adverse events was observed in 30% of trials; partially satisfactory was achieved by 10% of the trials, and the remaining 60% were unsatisfactory. The majority of trials were determined to be unsatisfactory for the reporting of laboratory-defined toxicity (82.5%); only 17.5% were satisfactory. Discontinuations were satisfactorily reported for the majority of trials (80%), with the remaining partially satisfactory (5%) or unsatisfactory (15%). Reporting of safety in clinical trials for acute spinal cord injury is suboptimal. Due to the complexities of acute spinal cord injury (e.g., polytrauma, multiple systems affected), tailored and specific standards for tracking adverse events and safety reporting should be established.

Acute traumatic spinal cord injury (SCI) can result in severe, lifelong neurological deficits. After SCI, Rho activation contributes to collapse of axonal growth cones, failure of axonal regeneration, and neuronal loss. This randomized, double-blind, placebo-controlled phase 2b/3 study evaluated the efficacy and safety of Rho inhibitor VX-210 (9 mg) in patients after acute traumatic cervical SCI. The study enrolled patients 14-75 years of age with acute traumatic cervical SCIs, C4-C7 (motor level) on each side, and American Spinal Injury Association Impairment Scale (AIS) Grade A or B who had spinal decompression/stabilization surgery commencing within 72 h after injury. Patients were randomized 1:1 with stratification by age (<30 vs. ≥30 years) and AIS grade (A vs. B with sacral pinprick preservation vs. B without sacral pinprick preservation). A single dose of VX-210 or placebo in fibrin sealant was administered topically onto the dura over the site of injury during decompression/stabilization surgery. Patients were evaluated for medical, neurological, and functional changes, and serum was collected for pharmacokinetics and immunological analyses. Patients were followed up for up to 12 months after treatment. A planned interim efficacy-based futility analysis was conducted after ∼33% of patients were enrolled. The pre-defined futility stopping rule was met, and the study was therefore ended prematurely. In the final analysis, the primary efficacy end-point was not met, with no statistically significant difference in change from baseline in upper-extremity motor score at 6 months after treatment between the VX-210 (9-mg) and placebo groups. This work opens the door to further improvements in the design and conduct of clinical trials in acute SCI.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain >8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.

High-level spinal cord injury (SCI) can disrupt cardiovascular autonomic function. However, the evolution of cardiovascular autonomic function in the acute phase following injury is unknown. We evaluated the timing, severity, progression, and implications of cardiovascular autonomic injury following acute SCI. We tested 63 individuals with acute traumatic SCI (aged 48 ± 2 years) at five time-points: <2 weeks, and 1, 3, 6-12, and >12 months post-injury. Supine beat-to-beat systolic arterial pressure (SAP) and R-R interval (RRI) were recorded and low-frequency variability (LF SAP and LF RRI) determined. Cross-spectral analyses were used to determine baroreflex function (low frequency) and cardiorespiratory interactions (high frequency). Known electrocardiographic (ECG) markers for arrhythmia and self-reported symptoms of cardiovascular dysfunction were determined. Comparisons were made with historical data from individuals with chronic SCI and able-bodied controls. Most individuals had high-level (74%) motor/sensory incomplete (63%) lesions. All participants had decreased LF SAP at <2 weeks (2.22 ± 0.65 mm Hg 2 ). Autonomic injury was defined as high-level SCI with LF SAP <2 mm Hg 2 . Two distinct groups emerged by 1 month: autonomically complete SCI with sustained low LF SAP (0.76 ± 0.17 mm Hg 2 ) and autonomically incomplete SCI with increased LF SAP (5.46 ± 1.0 mm Hg 2 , p  < 0.05). Autonomically complete injuries did not recover over time. Cardiovascular symptoms were prevalent and worsened with time, especially in those with autonomically complete lesions, and chronic SCI. Baroreflex function and cardiorespiratory interactions were impaired after SCI. Risk of arrhythmia increased immediately after SCI, and remained elevated throughout the acute phase. Acute SCI is associated with severe cardiovascular dysfunction. LF SAP provides a simple, non-invasive, translatable, quantitative assessment of autonomic function, and is most informative 1 month after injury.

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

As the incidence of traumatic spinal cord injury (tSCI) in the elderly rises, clinicians are increasingly faced with difficult discussions regarding aggressiveness of management, likelihood of recovery, and survival. Our objective was to outline risk factors associated with in-hospital mortality in elderly surgical and non-surgical patients following tSCI and to determine those unlikely to have a favorable outcome. Data from elderly patients (≥ 65 years of age) in the Canadian Rick Hansen SCI Registry from 2004 to 2017 were analyzed using descriptive analysis. Survival and mortality groups in each of the surgical and non-surgical group were compared to explore factors associated with in-hospital mortality and their impact, using logistical regression. Of 1340 elderly patients, 1018 had surgical data with 826 having had surgery. In the surgical group, the median time to death post-injury was 30 days with 75% dying within 50 days compared with 7 days and 20 days, respectively, in the non-surgical group. Significant predictors for in-hospital mortality following surgery are age, comorbidities, neurological injury severity (American Spinal Injury Association [ASIA] Impairment Scale [AIS]), and ventilation status. The odds of dying 50 days post-surgery are six times higher for patients ≥77 years of age versus those 65-76 years of age, five times higher for those with AIS A versus those with AIS B/C/D, and seven times higher for those who are ventilator dependent. An expected probability of dying within 50 days post-surgery was determined using these results. In-hospital mortality in the elderly after tSCI is high. The trend with age and time to death and the significant predictors of mortality identified in this study can be used to inform clinical decision making and discussions with patients and their families.

One of the only currently available treatment options to potentially improve neurological recovery after acute spinal cord injury (SCI) is augmentation of mean arterial blood pressure (MAP) to promote blood flow and oxygen delivery to the injured cord. However, to optimize such hemodynamic management, clinicians require a method to monitor the physiological effects of these MAP alterations within the injured cord. Therefore, we investigated the feasibility and effectiveness of using a novel optical sensor, based on near-infrared spectroscopy (NIRS), to monitor real-time spinal cord oxygenation and hemodynamics during the first 7 days post-injury in a porcine model of acute SCI. Six Yucatan miniature pigs underwent a T10 vertebral level contusion-compression injury. Spinal cord oxygenation and hemodynamics were continuously monitored by a minimally invasive custom-made NIRS sensor, and by invasive intraparenchymal (IP) probes to validate the NIRS measures. Episodes of MAP alteration and hypoxia were performed acutely after injury, and at 2 and 7 days post-injury to simulate the types of hemodynamic changes SCI patients experience after injury. The NIRS sensor demonstrated the ability to provide oxygenation and hemodynamic measurements over the 7-day post-SCI period. NIRS measures showed statistically significant correlations with each of the invasive IP measures and MAP changes during episodes of MAP alteration and hypoxia throughout the first week post-injury ( p  < 0.05). These results indicate that this novel NIRS system can monitor real-time changes in spinal cord oxygenation and hemodynamics over the first 7 days post-injury, and has the ability to detect local tissue changes that are reflective of systemic hemodynamic changes.

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO 2 ), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO 2 and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO 2 and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the β-agonist dobutamine increases SCO 2 and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.

Current practice guidelines for acute spinal cord injury (SCI) recommend augmenting mean arterial blood pressure (MAP) for the first 7 days post-injury. After SCI, the cord may be compressed by the bone/ligaments of the spinal column, limiting regional spinal cord blood flow. Following surgical decompression, blood flow may be restored, and can potentially promote a "reperfusion" injury. The effects of MAP augmentation on the injured cord during the compressed and decompressed conditions have not been previously characterized. Here, we used our porcine model of SCI to examine the impact of MAP augmentation on blood flow, oxygenation, hydrostatic pressure, metabolism, and intraparenchymal (IP) hemorrhage within the compressed and then subsequently decompressed spinal cord. Yucatan mini-pigs underwent a T10 contusion injury followed by 2 h of sustained compression. MAP augmentation of ∼20 mm Hg was achieved with norepinephrine (NE). Animals received MAP augmentation either during the period of cord compression (CP), after decompression (DCP), or during both periods (CP-DCP). Probes to monitor spinal cord blood flow (SCBF), oxygenation, pressure, and metabolic responses were inserted into the cord parenchyma adjacent to the injury site to measure these responses. The cord was harvested for histological evaluation. MAP augmentation increased SCBF and oxygenation in all groups. In the CP-DCP group, spinal cord pressure steadily increased and histological analysis showed significantly increased hemorrhage in the spinal cord at and near the injury site. MAP augmentation with vasopressors may improve blood flow and reduce ischemia in the injured cord but may also induce undesirable increases in IP pressure and hemorrhage.

Patients with acute traumatic cervical spinal cord injury (ATCSCI) have an increased risk of catheter-associated urinary tract infection (CAUTI). The effectiveness of silver alloy-coated silicone urinary catheters (SACC) in preventing CAUTI in ATCSCI is unknown and was the objective of this study. We performed a quality improvement initiative in an attempt to reduce CAUTI in patients undergoing spine surgery at a single quaternary center. Prior to July 2015, all patients received a latex indwelling catheter (LIC). All patients with ATCSCI with limited hand function (AIS A,B, or C) received a SACC. Incidence of CAUTI, microbiology, duration of infection, antibiotic susceptibility, and catheter-associated adverse events were recorded prospectively. We studied 3081 consecutive patients over the three years, of whom 302 (9.8%) had ATCSCI; 63% of ATCSCI patients were ASIA Impairment Scale (AIS) A or B. The overall rate of CAUTI was 19% (585/3081), and was 38% (116/302) in patients with ATCSCI. Of 178 ATCSCI patients with LIC, 100 (56%) developed a CAUTI compared with 28 of 124 (23%) patients with SACC (p < 0.05). Poly-microbial and gram-positive infection was more common in LIC than in SACC (p < 0.05). Median duration of infection was 9 days in SACC group and 12 days in LIC group (p = 0.08). Resistance to trimethoprim (p < 0.001) and ciprofloxacin (p < 0.05) were more common in LIC group. There was no difference in catheter-associated adverse events or length of stay between the groups. This quality improvement initiative illustrates the effectiveness of antiseptic silver alloy-coated silicone urinary catheters in patients with ATCSCI. In our population, the use of SACC reduces the incidence and the complexity of CAUTI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although experience suggests a shift in the epidemiology of spinal cord injury (SCI) toward an older demographic, population studies are lacking. We aimed to evaluate (1) how the epidemiology and age profile of SCI have changed over time, and (2) how increased age impacts health outcomes up to 15 years post-injury. A population-based cohort study was performed in Ontario including adults diagnosed with traumatic SCI between 2002 and 2017. Older and younger SCI cohorts were created based on an age cutoff of 65 years. An older cohort of uninjured persons was matched to the older SCI cohort based on age, gender, and comorbidity status. Changes in crude incidence were reported as average annual percentage change (AAPC). Survival, readmissions, and costs were compared between the older and younger SCI cohorts as well as the between the older SCI and older matched uninjured cohorts. The incidence of SCI increased among females (AAPC 2.2; 95% confidence interval [CI] 0.1, 4.3), driven by a marked rise (4%/year) among elderly females (AAPC 4.3; 95% CI 0.1, 4.3). Although no change in incidence was detected for males, there was a trend toward increased incidence among older males (AAPC 1.2; 95% CI -1.3, 3.8). There were a higher proportion of cervical, incomplete, and fall-related injuries in the older than in younger SCI cohorts. Being over 65 years of age was associated with a sixfold increased risk of death (hazard ratio [HR] 5.75; 95% CI 4.72, 7.00). In comparison with the older uninjured cohort, the older SCI cohort had double the risk of death (HR 2.23; 95% CI 2.00, 2.50). Older persons with SCI had higher odds of readmission and higher costs. The incidence of SCI among the elderly is increasing, particularly among women. Prevention through fall reduction and education to improve outcomes are needed.

Non-human primate (NHP) spinal cord injury (SCI) models can be informative in the evaluation of treatments that show promise in rodent models prior to translation to humans. In the present study, we aimed to establish a cervical spinal hemi-contusion model with controlled displacement and evaluate the abnormalities in behavior, electrophysiology, histology, and magnetic resonance imaging. Twelve adult NHPs were divided into an SCI group ( n  = 8, 24 and 48 weeks) and a control group ( n  = 4). An impactor (Φ = 4 mm) was driven to compress the left C5 cord at 800 mm/sec. The contusion displacement and peak force was 4.08 ± 0.17 mm and 19.8 ± 4.6 N. The behavioral assessment showed a consistent dysfunction below the wrist and spontaneous recovery of limb function after injury. Lesion length and lesion area at the epicenter based on T2 hyperintensity were 5.68 ± 0.47 mm and 5.99 ± 0.24 mm 2 at 24 weeks post-injury (wpi), and 5.29 ± 0.17 mm and 5.95 ± 0.24 mm 2 at 48 wpi. The spared spinal cord area immuno-positive for glial fibrillary acidic protein was significantly reduced, while the staining intensity increased at 24 wpi and 48 wpi, compared with the sham group. Ipsilateral somatosensory and motor evoked potentials were dynamic, increasing in latency and decreasing in amplitude compared with pre-operative values or the contralateral values, and correlated to varying degrees with behavioral outcomes. A shift in size-frequency distribution of sensory neurons of the dorsal root ganglia (DRG) was consistent with a loss of large-diameter cells. The present study demonstrated that the NHP SCI model resulted in consistent unilateral limb dysfunction and potential plasticity in the face of loss of spinal cord and DRG tissue.

Cell transplantation for spinal cord injury (SCI) has largely been studied in sub-acute settings within 1-2 weeks of injury. In contrast, here we transplanted skin-derived precursors differentiated into Schwann cells (SKP-SCs) into the contused rat spinal cord 8 weeks post-injury (wpi). Twenty-one weeks later (29 wpi), SKP-SCs were found to have survived transplantation, integrated with host tissue, and mitigated the formation of a dense glial scar. Furthermore, transplanted SKP-SCs filled much of the lesion sites and greatly enhanced the presence of endogenous SCs, which myelinated thousands of sprouting/spared host axons in and around the injury site. In addition, SKP-SC transplantation improved locomotor outcomes and decreased pathological thickening of bladder wall. To date, functional improvements have very rarely been observed with cell transplantation beyond the sub-acute stage of injury. Hence, these findings indicate that skin-derived SCs are a promising candidate cell type for the treatment of chronic SCI., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To identify early predictors and develop reliable, validated prediction models for development of problematic spasticity after traumatic spinal cord injury (SCI). Design: Prospective cohort study of the Rick Hansen Spinal Cord Injury Registry (RHSCIR), retrospective review of inpatient medical charts. Setting: Quaternary trauma center, rehabilitation center, community settings. Participants: Individuals with traumatic SCI between March 1, 2005, and March 31, 2014, prospectively enrolled in the Vancouver site RHSCIR. Interventions: None. Main Outcome Measure: Spasticity limiting function or requiring treatment (problematic spasticity) on the Spinal Cord Injury Health Questionnaire. Results: In 350 patients, variables documented during hospitalization that predicted the development of problematic spasticity up to 5 years post-injury included: initial Glasgow Coma Scale; age at time of injury; admission to rehabilitation center; community discharge anti-spasticity medication prescription, neurological status, Penn Spasm Frequency Scale, and pain interference with quality of life, sleep, activities; greater change in AIS motor scores between admission and discharge. The predictive models had area under the receiver operating characteristic curve of 0.80 (95% CI 0.75, 0.85) in the development set ( N  = 244) and 0.84 (95% CI 0.74, 0.92) in the validation set ( N  = 106) for spasticity limiting function and 0.81 (95% CI 0.76, 0.85) in the development set and 0.85 (95% CI 0.77, 0.92) in the validation set for spasticity requiring treatment. Conclusions: Our prediction models provide an early prognosis of risk of developing problematic spasticity after traumatic SCI, which can be used to improve clinical spasticity management and assist research (e.g. risk stratification in interventional trials).

Interventions to optimize spinal cord perfusion via support of mean arterial pressure (MAP) or spinal cord perfusion pressure (SCPP) are thought to play a critical role in the management of patients with acute traumatic spinal cord injuries, but there is ongoing controversy about efficacy and safety. We aimed to determine the effects of optimizing spinal cord perfusion on neurological recovery and risks for adverse events. We searched multiple databases for published and unpublished reports. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. We synthesized data and evaluated confidence in anticipated treatment effects according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. We identified 20 eligible observational studies and 1 eligible randomized controlled trial. According to low or very low quality evidence, the effect of MAP support on neurological recovery after acute traumatic spinal cord injury is uncertain, and the use of vasopressors to support MAP may be associated with increased rates of predominantly cardiac adverse events. Increased SCPP appears likely to be associated with improved neurological recovery, but SCPP monitoring via intradural catheters at the anatomical site of injury may involve increased risks of cerebrospinal fluid leakage requiring revision surgery or pseudomeningocele. No study directly compared the effects of specific MAP goal ranges, SCPP ranges, SCPP monitoring techniques, or durations of treatment. Very low quality evidence suggests that norepinephrine may have less risk of adverse events than dopamine. The current literature is insufficient to make strong recommendations about interventions to support spinal cord perfusion via MAP or SCPP goals in patients with acute traumatic spinal cord injuries. Data are compatible with a variety of treatment decisions, and individualized approaches may be optimal. Further investigation to clarify the risks, benefits, and alternatives to MAP or SCPP support in this population is warranted.

Early decompression of the traumatically injured and persistently compressed spinal cord is intuitively beneficial for neurological outcome. Despite considerable pre-clinical evidence of a neurological benefit to early decompression, the effect of early surgical decompression in clinical spinal cord injury (SCI) remains less clear. The discrepancy between pre-clinical and clinical results may be due to differences between the biomechanical variables used in pre-clinical animal models and the biomechanical conditions occurring in clinical injuries. These pre-clinical variables include region of spinal cord, velocity of impact, and injury mechanism. In this study, the effect of velocity and duration of residual compression on injury severity were evaluated using a novel, rodent model of cervical dislocation SCI. Fifty-two male Sprague-Dawley rats were included in five groups: two timings of decompression (24 min, 240 min), two velocities (10 mm/sec, 500 mm/sec), and a sham group. All injuries involved a 1.45-mm dorsal dislocation of the C6 vertebra relative to C5 with subsequent residual compression of 0.8 mm. Animals were evaluated for motor function using the Martinez open field, grip strength, and grooming tests for 6 weeks post-injury. Immunohistochemistry and histology following sacrifice were conducted with counts for NeuN- and choline acetyltransferase (ChAT)-positive neurons, and length of cavitation. Behavioral testing and histological analysis revealed that injuries induced by the high velocity were consistently more severe than those induced by the low velocity, with behavioral correlations ranging between 0.46 and 0.58 ( p  < 0.05). Longer duration of residual compression did not produce significantly more severe injuries as measured by functional tests and histology. These findings demonstrate that the velocity of the initial traumatic impact may be a more important factor than duration of residual compression in determining SCI severity in a dislocation model of SCI.

Frailty negatively affects outcome in elective spine surgery populations. This study sought to determine the effect of frailty on patient outcome after traumatic spinal cord injury (tSCI). Patients with tSCI were identified from our prospectively collected database from 2004 to 2016. We examined effect of patient age, admission Total Motor Score (TMS), and Modified Frailty Index (mFI) on adverse events (AEs), acute length of stay (LOS), in-hospital mortality, and discharge destination (home vs. other). Subgroup analysis (for three age groups: <60, 61-75, and 76+ years), and multi-variable analysis was performed to investigate the impact of age, TMS, and mFI on outcome. For the 634 patients, the mean age was 50.3 years, 77% were male, and falls were the main cause of injury (46.5%). On bivariate analysis, mFI, age at injury, and TMS were predictors of AEs, acute LOS, and in-hospital mortality. After statistical adjustment, mFI was a predictor of LOS ( p  = 0.0375), but not of AEs ( p  = 0.1428) or in-hospital mortality ( p  = 0.1245). In patients <60 years of age, mFI predicted number of AEs, acute LOS, and in-hospital mortality. In those aged 61-75, TMS predicted AEs, LOS, and mortality. In those 76+ years of age, mFI no longer predicted outcome. Age, mFI, and TMS on admission are important determinants of outcome in patients with tSCI. mFI predicts outcomes in those <75 years of age only. The inter-relationship of advanced age and decreased physiological reserve is complex in acute tSCI, warranting further study. Identifying frailty in younger patients with tSCI may be useful for peri-operative optimization, risk stratification, and patient counseling.

Key Points: We have developed a novel porcine model of high-thoracic midline contusion spinal cord injury (SCI) at the T2 spinal level. We describe this model and the ensuing cardiovascular and neurohormonal responses, and demonstrate the model is efficacious for studying clinically relevant cardiovascular dysfunction post-SCI. We demonstrate that the high-thoracic SCI model, but not a low-thoracic SCI model, induces persistent hypotension along with a gradual reduction in plasma noradrenaline and increases in plasma aldosterone and angiotensin II. We additionally conducted a proof-of-concept long-term (12 weeks) survival study in animals with T2 contusion SCI demonstrating the potential utility of this model for not only acute experimentation but also long-term drug studies prior to translation to the clinic., Abstract: Cardiovascular disease is a leading cause of morbidity and mortality in the spinal cord injury (SCI) population, especially in those with high-thoracic or cervical SCI. With this in mind, we aimed to develop a large animal (porcine) model of high-thoracic (T2 level) contusion SCI and compare the haemodynamic and neurohormonal responses of this injury against a low-thoracic (T10 level) model. Ten Yorkshire pigs were randomly subjected to 20 cm weight drop contusion SCI at either the T2 or the T10 spinal level. Systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were continuously monitored until 4 h post-SCI. Plasma noradrenaline (NA), aldosterone and angiotensin II (ANGII) were measured pre-SCI and at 30, 60, 120 and 240 min post-SCI. Additionally, two Yucatan pigs were subjected to T2-SCI and survived up to 12 weeks post-injury to demonstrate the efficacy of this model for long-term survival studies. Immediately after T2-SCI, SBP, MAP and HR increased (P < 0.0001). Between decompression (5 min post-SCI) and 30 min post-decompression in T2-SCI, SBP and MAP were lower than pre-SCI (P < 0.038). At 3 and 4 h after T2-SCI, SBP remained lower than pre-SCI (P = 0.048). After T10-SCI, haemodynamic indices remained largely unaffected. Plasma NA was lower in T2- vs. T10-SCI post-SCI, whilst aldosterone and ANGII were higher. Both chronically injured pigs demonstrated a vast reduction in SBP at 12 weeks post-SCI. Our model of T2-SCI causes a rapid and sustained alteration in neurohormonal control and cardiovascular function, which does not occur in the T10 model., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Study Design: Cohort study., Objectives: It is widely accepted that the prediction of long-term neurologic outcome after traumatic spinal cord injury (SCI) can be done more accurately with neurological examinations conducted days to weeks post injury. However, modern clinical trials of neuroprotective interventions often require patients be examined and enrolled within hours. Our objective was to determine whether variability in timing of neurological examinations within 48 h after SCI is associated with differences in observations of follow-up neurologic recovery., Setting: Level I trauma hospital., Methods: An observational analysis testing for differences in AIS conversion rates and changes in total motor scores by neurological examination timing, controlling for potential confounders with multivariate stepwise regression., Results: We included 85 patients, whose mean times from injury to baseline and follow-up examinations were 11.8 h (SD 9.8) and 208.2 days (SD 75.2), respectively. AIS conversion by 1+ grade was significantly more likely in patients examined at ≤4 h in comparison with later examination (78% versus 47%, RR = 1.66, p = 0.04), even after controlling for timing of surgery, age, and sex (OR 5.0, 95% CI 1.1-10, p = 0.04). We failed to identify any statistically significant associations for total motor score recovery in unadjusted or adjusted analyses., Conclusions: AIS grade conversion was significantly more likely in those examined ≤4 h of injury; the effect of timing on motor scores remains uncertain. Variability in neurological examination timing within hours after acute traumatic SCI may influence observations of long-term neurological recovery, which could introduce bias or lead to errors in interpretation of studies of therapeutic interventions.

Background: To optimize traumatic spinal cord injury (tSCI) care, administrative and clinical linked data are required to describe the patient's journey., Objectives: To describe the methods and progress to deterministically link SCI data from multiple databases across the SCI continuum in British Columbia (BC) and Ontario (ON) to answer epidemiological and health service research questions., Methods: Patients with tSCI will be identified from the administrative Hospital Discharge Abstract Database using International Classification of Diseases (ICD) codes from Population Data BC and ICES data repositories in BC and ON, respectively. Admissions for tSCI will range between 1995-2017 for BC and 2009-2017 for ON. Linkage will occur with multiple administrative data holdings from Population Data BC and ICES to create the "Admin SCI Cohorts." Clinical data from the Rick Hansen SCI Registry (and VerteBase in BC) will be transferred to Population Data BC and ICES. Linkage of the clinical data with the incident cases and administrative data at Population Data BC and ICES will create subsets of patients referred to as the "Clinical SCI Cohorts" for BC and ON. Deidentified patient-level linked data sets will be uploaded to a secure research environment for analysis. Data validation will include several steps, and data analysis plans will be created for each research question., Discussion: The creation of provincially linked tSCI data sets is unique; both clinical and administrative data are included to inform the optimization of care across the SCI continuum. Methods and lessons learned will inform future data-linking projects and care initiatives., Competing Interests: Conflicts of Interest Dr. Noonan is an employee of the Praxis Spinal Cord Institute and is paid from a grant administered by the University of British Columbia. The other authors report no conflicts of interest., (© 2020 American Spinal Injury Association.)

The aim of this study was to determine the current trends in magnetic resonance imaging (MRI)/computed tomography (CT) utilization for spine trauma in various clinical scenarios. We conducted a survey across six AO regions and preformed pair-wise comparisons between responses obtained from different AO regions. The survey was sent to 5813 surgeons and had a 9.6% response rate with the majority being orthopedic followed by neurosurgeons. In a neurologically intact patient, the predominant imaging modality for all AO regions was CT. For patients with spinal cord injury (SCI), the predominant choice for all AO regions was CT + MRI + x-ray except North America, which was CT + MRI; pair-wise comparisons revealed significant differences involving LATAM (Latin America) versus (Asia-Pacific [APAC], Europe [EU], and Middle East [MEA]) and APAC versus (LATAM and North America [NA]). In a patient with incomplete SCI (ISCI) who presented within 4 h and had CT, the predominant choice for all AO regions was "forgo MRI and proceed to operating room (OR)." Similar to ISCI, in a patient with complete SCI, the predominant option for all AO regions was the same as ISCI, but the range was lower. Pair-wise comparisons noted significant differences between MEA and APAC, with both exhibiting differences compare to NA, LATAM, and EU for complete and ISCI. Most AO regions obtained post-operative MRI only if there was a new deficit. In summary, decisions about the use of a particular imaging modality across AO regions appears to be influenced by the neurological status of the patient upon admission and the presence of neurological deficits post-surgery. Type of residency training and fellowship training did not have an influence on choosing the appropriate imaging modality for both intact and impaired patients. Further study is needed to determine whether accessibility to MRI would change surgeons' attitude toward obtaining MRI in patients with SCI.

Despite advances in the treatment of acute spinal cord injury (SCI), measures to mitigate permanent neurological deficits in affected patients are limited. Immediate post-trauma hemodynamic management of patients, to maintain blood supply and improve oxygenation to the injured spinal cord, is currently one aspect of critical care which clinicians can utilize to improve neurological outcomes. However, without a way to monitor the response of spinal cord hemodynamics and oxygenation in real time, optimizing hemodynamic management is challenging and limited in scope. This study aims to investigate the feasibility and validity of using a miniaturized multi-wavelength near-infrared spectroscopy (NIRS) sensor for direct transdural monitoring of spinal cord oxygenation in an animal model of acute SCI. Nine Yorkshire pigs underwent a weight-drop T10 contusion-compression injury and received episodes of ventilatory hypoxia and alterations in mean arterial pressure (MAP). Spinal cord hemodynamics and oxygenation were monitored throughout by a non-invasive transdural NIRS sensor, as well as an invasive intraparenchymal sensor as a comparison. NIRS parameters of tissue oxygenation were highly correlated with intraparenchymal measures of tissue oxygenation. In particular, during periods of hypoxia and MAP alterations, changes of NIRS-derived spinal cord oxygenated hemoglobin and tissue oxygenation percentage corresponded well with the changes in spinal cord oxygen partial pressures measured by the intraparenchymal sensor. Our data confirm that during hypoxic episodes and as changes occur in the MAP, non-invasive NIRS can detect and measure real-time changes in spinal cord oxygenation with a high degree of sensitivity and specificity.

One of the challenges associated with conducting experiments in animal models of traumatic spinal cord injury (SCI) is inducing a consistent injury with minimal variability in the degree of tissue damage and resultant behavioral and biochemical outcomes. We evaluated how the variability in morphometry of the spinal cord and surrounding cerebrospinal fluid (CSF) contributes to the variability in behavioral and histological outcomes in our porcine model of SCI. Using intraoperative ultrasound imaging, spinal cord morphometry was assessed in seven Yucatan minipigs undergoing a weight-drop T10 contusion-compression injury. Bivariate and multi-variate analysis and modeling were used to identify native morphometrical determinants of interanimal variability in histological and behavioral outcomes. The measured biomechanical impact parameters did not correlate with the histological measures or hindlimb locomotor behavior (Porcine Thoracic Injury Behavior Scale). In contrast, clear associations were revealed between CSF layer morphometry and the amount of white matter and tissue sparing. Specifically, the dorsoventral diameter of the dural sac and ventral CSF space were strong predictors of behavioral and histological outcome and together explained ≥95.0% of the variance in these parameters. In addition, a dorsoventral diameter of the spinal cord less than 5.331 mm was a strong contributing factor to poor behavioral recovery over 12 weeks. These results indicate that interanimal variability in cord morphometry provides a potential biological explanation for the observed heterogeneity in histological and behavioral outcomes. Such knowledge is helpful for appropriately balancing experimental groups, and/or varying impact parameters to match cord and CSF layer dimensions for future studies.

Acute traumatic spinal cord injury is a devastating condition affecting 17,700 new patients per year in the United States alone. Typically, orthopaedic surgeons focus on managing the acute surgical aspects of care (eg, surgical spinal decompression and stabilization). However, in the care of these patients, being familiar with how to prognosticate neurologic recovery and manage secondary complications is extremely important. In addition, as an integral part of the multidisciplinary care team, the surgeon should have an awareness of contemporary rehabilitation approaches to maximize function and facilitate reintegration into the community. The purpose of this review article is to provide a surgeon's perspective on these aspects of spinal cord injury care.

Study Design: This is a narrative review of the literature on neurochemical biomarkers in spinal cord injury (SCI)., Objectives: The objective was to summarize the literature on neurochemical biomarkers in SCI and describe their use in facilitating clinical trials for SCI. Clinical trials in spinal cord injury (SCI) have been notoriously difficult to conduct, as exemplified by the paucity of definitive prospective randomized trials that have been completed, to date. This is related to the relatively low incidence and the complexity and heterogeneity of the human SCI condition. Given the increasing number of promising approaches that are emerging from the laboratory which are vying for clinical evaluation, novel strategies to help facilitate clinical trials are needed., Methods: A literature review was conducted, with a focus on neurochemical biomarkers that have been described in human neurotrauma., Results: We describe advances in our understanding of neurochemical biomarkers as they pertain to human SCI. The application of biomarkers from serum and cerebrospinal fluid (CSF) has been led by efforts in the human traumatic brain injury (TBI) literature. A number of promising biomarkers have been described in human SCI whereby they may assist in stratifying injury severity and predicting outcome., Conclusions: Several time-specific biomarkers have been described for acute SCI and for chronic SCI. These appear promising for stratifying injury severity and potentially predicting outcome. The subsequent application within a clinical trial will help to demonstrate their utility in facilitating the study of novel approaches for SCI.

Objective: To determine the hemodynamic conditions associated with optimal neurologic improvement in individuals with acute traumatic spinal cord injury (SCI) who had lumbar intrathecal catheters placed to measure CSF pressure (CSFP)., Methods: Ninety-two individuals with acute SCI were enrolled in this multicenter prospective observational clinical trial. We monitored mean arterial pressure (MAP) and CSFP during the first week after injury and assessed neurologic function at baseline and 6 months after injury. We used relative risk iterations to determine transition points at which the likelihood of either improving neurologically or remaining unchanged neurologically was equivalent. These transition points guided our analyses in which we examined the linear relationships between time spent within target hemodynamic ranges (i.e., clinical adherence) and neurologic recovery., Results: Relative risk transition points for CSFP, MAP, and spinal cord perfusion pressure (SCPP) were linearly associated with neurologic improvement and directed the identification of key hemodynamic target ranges. Clinical adherence to the target ranges was positively and linearly related to improved neurologic outcomes. Adherence to SCPP targets, not MAP targets, was the best indicator of improved neurologic recovery, which occurred with SCPP targets of 60 to 65 mm Hg. Failing to maintain the SCPP within the target ranges was an important detrimental factor in neurologic recovery, particularly if the target range is set lower., Conclusion: We provide an empirical, data-driven approach to aid institutions in setting hemodynamic management targets that accept the real-life challenges of adherence to specific targets. Our results provide a framework to guide the development of widespread institutional management guidelines for acute traumatic SCI., (© 2019 American Academy of Neurology.)

Clinical trials of novel therapies for acute spinal cord injury (SCI) are challenging because variability in spontaneous neurologic recovery can make discerning actual treatment effects difficult. Unbiased Recursive Partitioning regression with Conditional Inference Trees (URP-CTREE) is a novel approach developed through analyses of a large European SCI database (European Multicenter Study about Spinal Cord Injury). URP-CTREE uses early neurologic impairment to predict achieved motor recovery, with potential to optimize clinical trial design by optimizing patient stratification and decreasing sample sizes. We performed external validation to determine how well a previously reported URP-CTREE model stratified patients into distinct homogeneous subgroups and predicted subsequent neurologic recovery in an independent cohort. We included patients with acute cervical SCI level C4-C6 from a prospective registry at a quaternary care center from 2004-2018 ( n  = 101) and applied the URP-CTREE model and evaluated Upper Extremity Motor Score (UEMS) recovery, considered correctly predicted when final UEMS scores were within a pre-specified threshold of 9 points from median; sensitivity analyses evaluated the effect of timing of baseline neurological examination. We included 101 patients, whose mean times from injury baseline and follow-up examinations were 6.1 days (standard deviation [SD] 17) and 235.0 days (SD 71), respectively. Median UEMS recovery was 7 points (interquartile range 2-12). One of the predictor variables was not statistically significant in our sample; one group did not fit progressively improving UEMS scores, and three of five groups had medians that were not significantly different from adjacent groups. Overall accuracy was 75%, but varied from 82% among participants whose examinations occurred at <12 h, to 64% at 12-24 h, and 58% at >24 h. A previous URP-CTREE model had limited ability to stratify an independent into homogeneous subgroups. Overall accuracy was promising, but may be sensitive to timing of baseline neurological examinations. Further evaluation of external validity in incomplete injuries, influence of timing of baseline examinations, and investigation of additional stratification strategies is warranted.

Spinal cord injury (SCI) is a devastating condition with variability in injury mechanisms and neurologic recovery. Spinal cord impairment after SCI is measured and classified by a widely accepted standard neurological examination. In the very acute stages post-injury, however, this examination is extremely challenging (and often impossible) to conduct and has modest prognostic value in terms of neurological recovery. The lack of objective tools to classify injury severity and predict outcome is a barrier for clinical trials and thwarts development of therapies for those with SCI. Biological markers (biomarkers) represent a promising, complementary approach to these challenges because they represent an unbiased approach to classify injury severity and predict neurological outcome. Identification of a suitable panel of molecular biomarkers would comprise a fundamental shift in how patients with acute SCI are evaluated, stratified, and treated in clinical trials. MicroRNA are attractive biomarker candidates in neurological disorders for several reasons, including their stability in biological fluids, their conservation between humans and model mammals, and their tissue specificity. In this study, we used next-generation sequencing to identify microRNA associated with injury severity within the cerebrospinal fluid (CSF) and serum of human patients with acute SCI. The CSF and serum samples were obtained 1-5 days post-injury from 39 patients with acute SCI (24 American Spinal Injury Association Impairment Scale [AIS] A, 8 AIS B, 7 AIS C) and from five non-SCI controls. We identified a severity-dependent pattern of change in microRNA expression in CSF and identified a set of microRNA that are diagnostic of baseline AIS classification and prognostic of neurological outcome six months post-injury. The data presented here provide a comprehensive description of the CSF and serum microRNA expression changes that occur after acute human SCI. This data set reveals microRNA candidates that warrant further evaluation as biomarkers of injury severity after SCI and as key regulators in other neurological disorders.

Study Design: Review., Objectives: Clinical studies have shown that the hemodynamic management of patients following acute spinal cord injury (SCI) is an important aspect of their treatment for maintaining spinal cord (SC) perfusion and minimizing ischemic secondary injury to the SC. While this highlights the importance of ensuring adequate perfusion and oxygenation to the injured cord, a method for the real-time monitoring of these hemodynamic measures within the SC is lacking. The purpose of this review is to discuss current and potential methods for SC hemodynamic monitoring with special focus on applications using near-infrared spectroscopy (NIRS)., Methods: A literature search using the PubMed database. All peer-reviewed articles on NIRS monitoring of SC published from inception to May 2019 were reviewed., Results: Among 125 papers related to SC hemodynamics monitoring, 26 focused on direct/indirect NIRS monitoring of the SC., Discussion: Current options for continuous, non-invasive, and real-time monitoring of SC hemodynamics are challenging and limited in scope. As a relatively new technique, NIRS has been successfully used for monitoring human cerebral hemodynamics, and has shown promising results in intraoperative assessment of SC hemodynamics in both human and animal models. Although utilizing NIRS to monitor the SC has been validated, applying NIRS clinically following SCI requires further development and investigation., Conclusions: NIRS is a promising non-invasive technique with the potential to provide real-time monitoring of relevant parameters in the SC. Currently, in its first developmental stages, further clinical and experimental studies are mandatory to ensure the validity and safety of NIRS techniques.

Background: Preclinical spinal cord injury models do not represent the wide range of biomechanical factors seen in human injuries, such as spinal level, injury mechanism, velocity of spinal cord impact, and residual compression. These factors may be responsible for differences observed between experimental and clinical study results, especially related to the controversial issue of timing of surgical decompression., New Method: Somatosensory Evoked Potentials were used to: a) characterize residual compression depths in a dislocation model, and b) evaluate the physiological effect of whether or not the spinal cord was decompressed following the initial injury, prior to the application of residual compression. Modifications to vertebral clamps and the development of a novel surgical frame allowed us to conduct surgical and injury procedures in a controlled manner without the risk of additional damage to the spinal cord. Behavioural outcomes were evaluated following varying dislocation displacements, in addition to the survivability of 4 h of residual compression following a traumatic injury., Results: Residual compression immediately following the initial dislocation demonstrated significantly different electrophysiological response compared to when the residual compression was delayed., Comparison With Existing Method: There are currently no other residual compression models that utilize a dislocation injury mechanism. Many residual compression studies have demonstrated the effectiveness of early decompression, however the compression of the spinal cord is often not representative of clinical traumatic injuries. Preclinical studies typically model residual compression using a sustained force through quasi-static application, when human injuries often occur at high velocities, followed by a sustained displacement occlusion of the spinal canal., Conclusions: This study has validated several novel procedural approaches and injury parameters, and provided critical details to implement in the development of a traumatic cervical dislocation SCI model with residual compression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In spinal cord injury (SCI), timely therapeutic intervention is critical to inhibit the post-injury rapidly progressing degeneration of spinal cord. Towards that objective, we determined the accessibility of intravenously administered biodegradable nanoparticles (NPs) as a drug delivery system to the lesion site in rat and pig contusion models of SCI. Poly (d,l-lactide co-glycolide, PLGA)-based NPs loaded with a near-infrared dye as a marker for NPs were used. To analyze and quantify localization of NPs to the lesion site, we mapped the entire spinal cord, segment-by-segment, for the signal count. Our objectives were to determine the NP dose effect and duration of retention of NPs at the lesion site, and the time window post-SCI within which NPs localize at the lesion site. We hypothesized that breakdown of the blood-spinal cord barrier following contusion injury could lead to more specific localization of NPs at the lesion site. The mapping data showed a dose-dependent increase and significantly greater localization of NPs at the lesion site than in the remaining uninjured segment of the spinal cord. Further, NPs were seen to be retained at the lesion site for more than a week. With delayed post-SCI administration, localization of NPs at the lesion site was reduced but still localize even at four weeks post-injury administration. Interestingly, in uninjured animals (sham control), greater accumulation of NPs was seen in the thoracic and lumbar enlargement regions of the spinal cord, which in animals with SCI changed to the lesion site, indicating drastic post-injury hemodynamic changes in the spinal cord. Similar to the rat results, pig contusion model of SCI showed greater NP localization at the lesion site. In conclusion, NPs could potentially be explored as a carrier for delivery of therapeutics to the lesion site to minimize the impact of post-SCI response., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Study Design: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI)., Objectives: To identify key problems of recruitment and explore potential approaches to overcoming them., Methods: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors., Results: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies., Conclusions: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.

The wide variability, or heterogeneity, in human spinal cord injury is due partially to biomechanical factors. This review summarizes our current knowledge surrounding the patterns of human spinal column injury and the biomechanical factors affecting injury. The biomechanics of human spinal injury is studied most frequently with human cadaveric models and the features of the two most common injury patterns, burst fracture and fracture dislocation, are outlined. The biology of spinal cord injury is typically studied with animal models and the effects of the most relevant biomechanical factors - injury mechanism, injury velocity, and residual compression, are described. Tissue damage patterns and behavioural outcomes following dislocation or distraction injury mechanisms differ from the more commonly used contusion mechanism. The velocity of injury affects spinal cord damage, principally in the white matter. Ongoing, or residual compression after the initial impact does affect spinal cord damage, but few models exist that replicate the clinical scenario. Future research should focus on the effects of these biomechanical factors in different preclinical animal models as recent data suggests that treatment outcomes may vary between models., (Copyright © 2018 Elsevier Ltd. All rights reserved.)