Safety and comparative efficacy of initiating low-molecular-weight heparin within 24 hours of injury or surgery for venous thromboembolism prophylaxis in patients with spinal cord injury: a prospective TRACK-SCI registry study.

OBJECTIVE: Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a significant clinical concern. This study sought to determine the incidence of VTE and hemorrhagic complications among patients with SCI who received low-molecular-weight heparin (LMWH) within 24 hours of injury or surgery and identify variables that predict VTE using the prospective Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database. METHODS: The TRACK-SCI database was queried for individuals with traumatic SCI from 2015 to 2022. Primary outcomes of interest included rates of VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and in-hospital hemorrhagic complications that occurred after LWMH administration. Secondary outcomes included intensive care unit and hospital length of stay, discharge location type, and in-hospital mortality. RESULTS: The study cohort consisted of 162 patients with SCI. Fifteen of the 162 patients withdrew from the study, leading to loss of data for certain variables for these patients. One hundred thirty patients (87.8%) underwent decompression and/or fusion surgery for SCI. DVT occurred in 11 (7.4%) of 148 patients, PE in 9 (6.1%) of 148, and any VTE in 18 (12.2%) of 148 patients. The analysis showed that admission lower-extremity motor score (p = 0.0408), injury at the thoracic level (p = 0.0086), admission American Spinal Injury Association grade (p = 0.0070), and younger age (p = 0.0372) were significantly associated with VTE. There were 3 instances of postoperative spine surgery-related bleeding (2.4%) in the 127 patients who had spine surgery with bleeding complication data available, with one requiring return to surgery (0.8%). Thirteen (8.8%) of 147 patients had a bleeding complication not related to spine surgery. There were 2 gastrointestinal bleeds associated with nasogastric tube placement, 3 cases of postoperative non-spine-related surgery bleeding, and 8 cases of other bleeding complications (5.4%) not related to any surgery. CONCLUSIONS: Initiation of LMWH within 24 hours was associated with a low rate of spine surgery-related bleeding. Bleeding complications unrelated to SCI surgery still occur with LMWH administration. Because neurosurgical intervention is typically the limiting factor in initializing chemical DVT prophylaxis, many of these bleeding complications would have likely occurred regardless of the protocol.

Hypotension requiring vasopressor treatment and increased cardiac complications in elderly spinal cord injury patients: a prospective TRACK-SCI registry study.

OBJECTIVE: Increasing life expectancy has led to an older population. In this study, the authors analyzed complications and outcomes in elderly patients following spinal cord injury (SCI) using the established multi-institutional prospective study Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database collected in the Department of Neurosurgical Surgery at the University of California, San Francisco. METHODS: TRACK-SCI was queried for elderly individuals (≥ 65 years of age) with traumatic SCI from 2015 to 2019. Primary outcomes of interest included total hospital length of stay, perioperative complications, postoperative complications, and in-hospital mortality. Secondary outcomes included disposition location, and neurological improvement based on the American Spinal Injury Association Impairment Scale (AIS) grade at discharge. Descriptive analysis, Fisher's exact test, univariate analysis, and multivariable regression analysis were performed. RESULTS: The study cohort consisted of 40 elderly patients. The in-hospital mortality rate was 10%. Every patient in this cohort experienced at least 1 complication, with a mean of 6.6 separate complications (median 6, mode 4). The most common complication categories were cardiovascular, with a mean of 1.6 complications (median 1, mode 1), and pulmonary, with a mean of 1.3 (median 1, mode 0) complications, with 35 patients (87.5%) having at least 1 cardiovascular complication and 25 (62.5%) having at least 1 pulmonary complication. Overall, 32 patients (80%) required vasopressor treatment for mean arterial pressure (MAP) maintenance goals. The use of norepinephrine correlated with increased cardiovascular complications. Only 3 patients (7.5%) of the total cohort had an improved AIS grade compared with their acute level at admission. CONCLUSIONS: Given the increased frequency of cardiovascular complications associated with vasopressor use in elderly SCI patients, caution is warranted when targeting MAP goals in these patients. A downward adjustment of blood pressure maintenance goals and prophylactic cardiology consultation to select the most appropriate vasopressor agent may be advisable for SCI patients ≥ 65 years of age.

Expert-augmented automated machine learning optimizes hemodynamic predictors of spinal cord injury outcome.

Artificial intelligence and machine learning (AI/ML) is becoming increasingly more accessible to biomedical researchers with significant potential to transform biomedicine through optimization of highly-accurate predictive models and enabling better understanding of disease biology. Automated machine learning (AutoML) in particular is positioned to democratize artificial intelligence (AI) by reducing the amount of human input and ML expertise needed. However, successful translation of AI/ML in biomedicine requires moving beyond optimizing only for prediction accuracy and towards establishing reproducible clinical and biological inferences. This is especially challenging for clinical studies on rare disorders where the smaller patient cohorts and corresponding sample size is an obstacle for reproducible modeling results. Here, we present a model-agnostic framework to reinforce AutoML using strategies and tools of explainable and reproducible AI, including novel metrics to assess model reproducibility. The framework enables clinicians to interpret AutoML-generated models for clinical and biological verifiability and consequently integrate domain expertise during model development. We applied the framework towards spinal cord injury prognostication to optimize the intraoperative hemodynamic range during injury-related surgery and additionally identified a strong detrimental relationship between intraoperative hypertension and patient outcome. Furthermore, our analysis captured how evolving clinical practices such as faster time-to-surgery and blood pressure management affect clinical model development. Altogether, we illustrate how expert-augmented AutoML improves inferential reproducibility for biomedical discovery and can ultimately build trust in AI processes towards effective clinical integration.

Decision tree-based machine learning analysis of intraoperative vasopressor use to optimize neurological improvement in acute spinal cord injury.

OBJECTIVE: Previous work has shown that maintaining mean arterial pressures (MAPs) between 76 and 104 mm Hg intraoperatively is associated with improved neurological function at discharge in patients with acute spinal cord injury (SCI). However, whether temporary fluctuations in MAPs outside of this range can be tolerated without impairment of recovery is unknown. This retrospective study builds on previous work by implementing machine learning to derive clinically actionable thresholds for intraoperative MAP management guided by neurological outcomes. METHODS: Seventy-four surgically treated patients were retrospectively analyzed as part of a longitudinal study assessing outcomes following SCI. Each patient underwent intraoperative hemodynamic monitoring with recordings at 5-minute intervals for a cumulative 28,594 minutes, resulting in 5718 unique data points for each parameter. The type of vasopressor used, dose, drug-related complications, average intraoperative MAP, and time spent in an extreme MAP range (< 76 mm Hg or > 104 mm Hg) were collected. Outcomes were evaluated by measuring the change in American Spinal Injury Association Impairment Scale (AIS) grade over the course of acute hospitalization. Features most predictive of an improvement in AIS grade were determined statistically by generating random forests with 10,000 iterations. Recursive partitioning was used to establish clinically intuitive thresholds for the top features. RESULTS: At discharge, a significant improvement in AIS grade was noted by an average of 0.71 levels (p = 0.002). The hemodynamic parameters most important in predicting improvement were the amount of time intraoperative MAPs were in extreme ranges and the average intraoperative MAP. Patients with average intraoperative MAPs between 80 and 96 mm Hg throughout surgery had improved AIS grades at discharge. All patients with average intraoperative MAP > 96.3 mm Hg had no improvement. A threshold of 93 minutes spent in an extreme MAP range was identified after which the chance of neurological improvement significantly declined. Finally, the use of dopamine as compared to norepinephrine was associated with higher rates of significant cardiovascular complications (50% vs 25%, p < 0.001). CONCLUSIONS: An average intraoperative MAP value between 80 and 96 mm Hg was associated with improved outcome, corroborating previous results and supporting the clinical verifiability of the model. Additionally, an accumulated time of 93 minutes or longer outside of the MAP range of 76-104 mm Hg is associated with worse neurological function at discharge among patients undergoing emergency surgical intervention for acute SCI.

Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury.

Background: Predicting neurological recovery after spinal cord injury (SCI) is challenging. Using topological data analysis, we have previously shown that mean arterial pressure (MAP) during SCI surgery predicts long-term functional recovery in rodent models, motivating the present multicenter study in patients. Methods: Intra-operative monitoring records and neurological outcome data were extracted (n = 118 patients). We built a similarity network of patients from a low-dimensional space embedded using a non-linear algorithm, Isomap, and ensured topological extraction using persistent homology metrics. Confirmatory analysis was conducted through regression methods. Results: Network analysis suggested that time outside of an optimum MAP range (hypotension or hypertension) during surgery was associated with lower likelihood of neurological recovery at hospital discharge. Logistic and LASSO (least absolute shrinkage and selection operator) regression confirmed these findings, revealing an optimal MAP range of 76-[104-117] mmHg associated with neurological recovery. Conclusions: We show that deviation from this optimal MAP range during SCI surgery predicts lower probability of neurological recovery and suggest new targets for therapeutic intervention. Funding: NIH/NINDS: R01NS088475 (ARF); R01NS122888 (ARF); UH3NS106899 (ARF); Department of Veterans Affairs: 1I01RX002245 (ARF), I01RX002787 (ARF); Wings for Life Foundation (ATE, ARF); Craig H. Neilsen Foundation (ARF); and DOD: SC150198 (MSB); SC190233 (MSB).

Spinal cord injury is a devastating condition that involves damage to the nerve fibers connecting the brain with the spinal cord, often leading to permanent changes in strength, sensation and body functions, and in severe cases paralysis. Scientists around the world work hard to find ways to treat or even repair spinal cord injuries but few patients with complete immediate paralysis recover fully. Immediate paralysis is caused by direct damage to neurons and their extension in the spinal cord. Previous research has shown that blood pressure regulation may be key in saving these damaged neurons, as spinal cord injuries can break the communication between nerves that is involved in controlling blood pressure. This can lead to a vicious cycle of dysregulation of blood pressure and limit the supply of blood and oxygen to the damaged spinal cord tissue, exacerbating the death of spinal neurons. Management of blood pressure is therefore a key target for spinal cord injury care, but so far, the precise thresholds to enable neurons to recover are poorly understood. To find out more, Torres-Espin, Haefeli et al. used machine learning software to analyze previously recorded blood pressure and heart rate data obtained from 118 patients that underwent spinal cord surgery after acute spinal cord injury. The analyses revealed that patients who suffered from either low or high blood pressure during surgery had poorer prospects of recovery. Statistical models confirming these findings showed that the optimal blood pressure range to ensure recovery lies between 76 to 104-117 mmHg. Any deviation from this narrow window would dramatically worsen the ability to recover. These findings suggests that dysregulated blood pressure during surgery affects to odds of recovery in patients with a spinal cord injury. Torres-Espin, Haefeli et al. provide specific information that could improve current clinical practice in trauma centers. In the future, such machine learning tools and models could help develop real-time models that could predict the likelihood of a patient's recovery following spinal cord injury and related neurological conditions.

Clinical Implementation of Novel Spinal Cord Perfusion Pressure Protocol in Acute Traumatic Spinal Cord Injury at U.S. Level I Trauma Center: TRACK-SCI Study.

OBJECTIVE: We sought to report the safety of implementation of a novel standard of care protocol using spinal cord perfusion pressure (SCPP) maintenance for managing traumatic spinal cord injury (SCI) in lieu of mean arterial pressure goals at a U.S. Level I trauma center. METHODS: Starting in December 2017, blunt SCI patients presenting <24 hours after injury with admission American Spinal Injury Association Impairment Scale (AIS) A-C (or AIS D at neurosurgeon discretion) received lumbar subarachnoid drain (LSAD) placement for SCPP monitoring in the intensive care unit and were included in the TRACK-SCI (Transforming Research and Clinical Knowledge in Spinal Cord Injury) data registry. This SCPP protocol comprises standard care at our institution. SCPPs were monitored for 5 days (goal ≥65 mm Hg) achieved through intravenous fluids and vasopressor support. AISs were assessed at admission and day 7. RESULTS: Fifteen patients enrolled to date were aged 60.5 ± 17 years. Injury levels were 93.3% (cervical) and 6.7% (thoracic). Admission AIS was 20.0%/20.0%/26.7%/33.3% for A/B/C/D. All patients maintained mean SCPP ≥65 mm Hg during monitoring. Fourteen of 15 cases required surgical decompression and stabilization with time to surgery 8.8 ± 7.1 hours (71.4% <12 hours). At day 7, 33.3% overall and 50% of initial AIS A-C had an improved AIS. Length of stay was 14.7 ± 8.3 days. None had LSAD-related complications. There were 7 respiratory complications. One patient expired after transfer to comfort care. CONCLUSIONS: In our initial experience of 15 patients with acute SCI, standardized SCPP goal-directed care based on LSAD monitoring for 5 days was feasible. There were no SCPP-related complications. This is the first report of SCPP implementation as clinical standard of care in acute SCI.

Exploration of surgical blood pressure management and expected motor recovery in individuals with traumatic spinal cord injury.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: To assess the impact of mean arterial blood pressure (MAP) during surgical intervention for spinal cord injury (SCI) on motor recovery. SETTING: Level-one Trauma Hospital and Acute Rehabilitation Hospital in San Jose, CA, USA. METHODS: Twenty-five individuals with traumatic SCI who received surgical and acute rehabilitation care at a level-one trauma center were included in this study. The Surgical Information System captured intraoperative MAPs on a minute-by-minute basis and exposure was quantified at sequential thresholds from 50 to 104 mmHg. Change in International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor score was calculated based on physiatry evaluations at the earliest postoperative time and at discharge from acute rehabilitation. Linear regression models were used to estimate the rate of recovery across the entire MAP range. RESULTS: An exploratory analysis revealed that increased time within an intraoperative MAP range (70-94 mmHg) was associated with ISNCSCI motor score improvement. A significant regression equation was found for the MAP range 70-94 mmHg (F[1, 23] = 5.07, r2 = 0.181, p = 0.034). ISNCSCI motor scores increased 0.039 for each minute of exposure to the MAP range 70-94 mmHg during the operative procedure; this represents a significant correlation between intraoperative time with MAP 70-94 and subsequent motor recovery. Blood pressure exposures above or below this range did not display a positive association with motor recovery. CONCLUSIONS: Hypertension as well as hypotension during surgery may impact the trajectory of recovery in individuals with SCI, and there may be a direct relationship between intraoperative MAP and motor recovery.

Dexmedetomidine modulates neuroinflammation and improves outcome via alpha2-adrenergic receptor signaling after rat spinal cord injury.

BACKGROUND: Spinal cord injury induces inflammatory responses that include the release of cytokines and the recruitment and activation of macrophages and microglia. Neuroinflammation at the lesion site contributes to secondary tissue injury and permanent locomotor dysfunction. Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, is anti-inflammatory and neuroprotective in both preclinical and clinical trials. We investigated the effect of DEX on the microglial response, and histological and neurological outcomes in a rat model of cervical spinal cord injury. METHODS: Anaesthetised rats underwent unilateral (right) C5 spinal cord contusion (75 kdyne) using an impactor device. The locomotor function, injury size, and inflammatory responses were assessed. The effect of DEX was also studied in a microglial cell culture model. RESULTS: DEX significantly improved the ipsilateral upper-limb motor dysfunction (grooming and paw placement; P<0.0001 and P=0.0012), decreased the injury size (P<0.05), spared white matter (P<0.05), and reduced the number of activated macrophages (P<0.05) at the injury site 4 weeks post-SCI. In DEX-treated rats after injury, tissue RNA expression indicated a significant downregulation of pro-inflammatory markers (e.g. interleukin [IL]-1ß, tumour necrosis factor-α, interleukin (IL)-6, and CD11b) and an upregulation of anti-inflammatory and pro-resolving M2 responses (e.g. IL-4, arginase-1, and CD206) (P<0.05). In lipopolysaccharide-stimulated cultured microglia, DEX produced a similar inflammation-modulatory effect as was seen in spinal cord injury. The benefits of DEX on these outcomes were mostly reversed by an α2-adrenergic receptor antagonist. CONCLUSIONS: DEX significantly improves neurological outcomes and decreases tissue damage after spinal cord injury, which is associated with modulation of neuroinflammation and is partially mediated via α2-adrenergic receptor signaling.

Value of aggressive surgical and intensive care unit in elderly patients with traumatic spinal cord injury.

OBJECTIVEThe elderly are a growing subpopulation within traumatic spinal cord injury (SCI) patients. Studies have reported high morbidity and mortality rates in elderly patients who undergo surgery for SCI. In this study, the authors compare the perioperative outcomes of surgically managed elderly SCI patients with those of a younger cohort and those reported in the literature.METHODSData on a consecutive series of adult traumatic SCI patients surgically managed at a single institution in the period from 2007 to 2017 were retrospectively reviewed. The cohort was divided into two groups based on age: younger than 70 years and 70 years or older. Assessed outcomes included complications, in-hospital mortality, intensive care unit (ICU) stay, hospital length of stay (LOS), disposition, and neurological status.RESULTSA total of 106 patients were included in the study: 83 young and 23 elderly. The two groups were similar in terms of imaging features (cord hemorrhage and fracture), operative technique, and American Spinal Injury Association Impairment Scale (AIS) grade. The elderly had a significantly higher proportion of cervical SCIs (95.7% vs 71.1%, p = 0.047). There were no significant differences between the young and the elderly in terms of the ICU stay (13.1 vs 13.3 days, respectively, p = 0.948) and hospital LOS (23.3 vs 21.7 days, p = 0.793). Elderly patients experienced significantly higher complication (73.9% vs 43.4%, p = 0.010) and mortality (13.0% vs 1.2%, p = 0.008) rates; in other words, the elderly patients had 1.7 times and 10.8 times the rate of complications and mortality, respectively, than the younger patients. No elderly patients were discharged home (0.0% vs 18.1%, p = 0.029). Discharge AIS grade and AIS grade change were similar between the groups.CONCLUSIONSElderly patients had higher complication and mortality rates than those in younger patients and were less likely to be discharged home. However, it does seem that mortality rates have improved compared to those in prior historical reports.

Ultra-Early (<12 Hours) Surgery Correlates With Higher Rate of American Spinal Injury Association Impairment Scale Conversion After Cervical Spinal Cord Injury.

BACKGROUND: Cervical spinal cord injury (SCI) is a devastating condition with very few treatment options. It remains unclear if early surgery correlated with conversion of American Spinal Injury Association Impairment Scale (AIS) grade A injuries to higher grades. OBJECTIVE: To determine the optimal time to surgery after cervical SCI through retrospective analysis. METHODS: We collected data from 48 patients with cervical SCI. Based on the time from Emergency Department (ED) presentation to surgical decompression, we grouped patients into ultra-early (decompression within 12 h of presentation), early (within 12-24 h), and late groups (>24 h). We compared the improvement in AIS grade from admission to discharge, controlling for confounding factors such as AIS grade on admission, injury severity, and age. The mean time from injury to ED for this group of patients was 17 min. RESULTS: Patients who received surgery within 12 h after presentation had a relative improvement in AIS grade from admission to discharge: the ultra-early group improved on average 1.3. AIS grades compared to 0.5 in the early group (P = .02). In addition, 88.8% of patients with an AIS grade A converted to a higher grade (AIS B or better) in the ultra-early group, compared to 38.4% in the early and late groups (P = .054). CONCLUSION: These data suggest that surgical decompression after SCI that takes place within 12 h may lead to a relative improved neurological recovery compared to surgery that takes place after 12 h.

Compressive mechanical characterization of non-human primate spinal cord white matter.

The goal of developing computational models of spinal cord injury (SCI) is to better understand the human injury condition. However, finite element models of human SCI have used rodent spinal cord tissue properties due to a lack of experimental data. Central nervous system tissues in non human primates (NHP) closely resemble that of humans and therefore, it is expected that material constitutive models obtained from NHPs will increase the fidelity and the accuracy of human SCI models. Human SCI most often results from compressive loading and spinal cord white matter properties affect FE predicted patterns of injury; therefore, the objectives of this study were to characterize the unconfined compressive response of NHP spinal cord white matter and present an experimentally derived, finite element tractable constitutive model for the tissue. Cervical spinal cords were harvested from nine male adult NHPs (Macaca mulatta). White matter biopsy samples (3 mm in diameter) were taken from both lateral columns of the spinal cord and were divided into four strain rate groups for unconfined dynamic compression and stress relaxation (post-mortem <1-hour). The NHP spinal cord white matter compressive response was sensitive to strain rate and showed substantial stress relaxation confirming the viscoelastic behavior of the material. An Ogden 1st order model best captured the non-linear behavior of NHP white matter in a quasi-linear viscoelastic material model with 4-term Prony series. This study is the first to characterize NHP spinal cord white matter at high (>10/sec) strain rates typical of traumatic injury. The finite element derived material constitutive model of this study will increase the fidelity of SCI computational models and provide important insights for transferring pre-clinical findings to clinical treatments. STATEMENT OF SIGNIFICANCE: Spinal cord injury (SCI) finite element (FE) models provide an important tool to bridge the gap between animal studies and human injury, assess injury prevention technologies (e.g. helmets, seatbelts), and provide insight into the mechanisms of injury. Although, FE model outcomes depend on the assumed material constitutive model, there is limited experimental data for fresh spinal cords and all was obtained from rodent, porcine or bovine tissues. Central nervous system tissues in non human primates (NHP) more closely resemble humans. This study characterizes fresh NHP spinal cord material properties at high strains rates and large deformations typical of SCI for the first time. A constitutive model was defined that can be readily implemented in finite strain FE analysis of SCI.

Motor Evoked Potentials Correlate With Magnetic Resonance Imaging and Early Recovery After Acute Spinal Cord Injury.

BACKGROUND: While the utilization of neurophysiologic intraoperative monitoring with motor evoked potentials (MEPs) has become widespread in surgery for traumatic spine fractures and spinal cord injury (SCI), clinical validation of its diagnostic and therapeutic benefit has been limited. OBJECTIVE: To describe the use of intraoperative MEP at a large level I trauma center and assess the prognostic capability of this technology. METHODS: The SCI REDCap database at our institution, a level I trauma center, was queried for acute cervical SCI patients who underwent surgery with intraoperative monitoring between 2005 and 2011, yielding 32 patients. Of these, 23 patients had severe SCI (association impairment scale [AIS] A, B, C). We assessed preoperative and postoperative SCI severity (AIS grade), surgical data, use of steroids, and early magnetic resonance imaging (MRI) findings (preoperatively in 27 patients), including axial T2 MRI grade (Brain and Spinal Injury Center score). RESULTS: The presence of MEPs significantly predicted AIS at discharge (P< .001). In the group of severe SCI (ie, AIS A, B, C) patients with elicitable MEPs, AIS improved by an average of 1.5 grades (median = 1), as compared to the patients without elicitable MEP who improved on average 0.5 grades (median = 0, P< .05). In addition, axial MRI grade significantly correlated with MEP status. Patients without MEPs had a significantly higher axial MRI grade in comparison to the patients with MEPs (P< .001). CONCLUSION: In patients with severe SCI, MEPs predicted neurological improvement and correlated with axial MRI grade. These significant findings warrant future prospective studies of MEPs as a prognostic tool in SCI.

A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

The p75 neurotrophin receptor is important in multiple physiological actions including neuronal survival and neurite outgrowth during development, and after central nervous system injury. We have discovered a novel piperazine-derived compound, EVT901, which interferes with p75 neurotrophin receptor oligomerization through direct interaction with the first cysteine-rich domain of the extracellular region. Using ligand binding assays with cysteine-rich domains-fused p75 neurotrophin receptor, we confirmed that EVT901 interferes with oligomerization of full-length p75 neurotrophin receptor in a dose-dependent manner. Here we report that EVT901 reduces binding of pro-nerve growth factor to p75 neurotrophin receptor, blocks pro-nerve growth factor induced apoptosis in cells expressing p75 neurotrophin receptor, and enhances neurite outgrowth in vitro Furthermore, we demonstrate that EVT901 abrogates p75 neurotrophin receptor signalling by other ligands, such as prion peptide and amyloid-ß. To test the efficacy of EVT901 in vivo, we evaluated the outcome in two models of traumatic brain injury. We generated controlled cortical impacts in adult rats. Using unbiased stereological analysis, we found that EVT901 delivered intravenously daily for 1 week after injury, reduced lesion size, protected cortical neurons and oligodendrocytes, and had a positive effect on neurological function. After lateral fluid percussion injury in adult rats, oral treatment with EVT901 reduced neuronal death in the hippocampus and thalamus, reduced long-term cognitive deficits, and reduced the occurrence of post-traumatic seizure activity. Together, these studies provide a new reagent for altering p75 neurotrophin receptor actions after injury and suggest that EVT901 may be useful in treatment of central nervous system trauma and other neurological disorders where p75 neurotrophin receptor signalling is affected.

Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome.

OBJECT The optimal mean arterial pressure (MAP) for spinal cord perfusion after trauma remains unclear. Although there are published data on MAP goals after spinal cord injury (SCI), the specific blood pressure management for acute traumatic central cord syndrome (ATCCS) and the implications of these interventions have yet to be elucidated. Additionally, the complications of specific vasopressors have not been fully explored in this injury condition. METHODS The present study is a retrospective cohort analysis of 34 patients with ATCCS who received any vasopressor to maintain blood pressure above predetermined MAP goals at a single Level 1 trauma center. The collected variables were American Spinal Injury Association (ASIA) grades at admission and discharge, administered vasopressor and associated complications, other interventions and complications, and timing of surgery. The relationship between the 2 most common vasopressors-dopamine and phenylephrine-and complications within the cohort as a whole were explored, and again after stratification by age. RESULTS The mean age of the ATCCS patients was 62 years. Dopamine was the most commonly used primary vasopressor (91% of patients), followed by phenylephrine (65%). Vasopressors were administered to maintain MAP goals fora mean of 101 hours. Neurological status improved by a median of 1 ASIA grade in all patients, regardless of the choice of vasopressor. Sixty-four percent of surgical patients underwent decompression within 24 hours. There was no observed relationship between the timing of surgical intervention and the complication rate. Cardiogenic complications associated with vasopressor usage were notable in 68% of patients who received dopamine and 46% of patients who received phenylephrine. These differences were not statistically significant (OR with dopamine 2.50 [95% CI 0.82-7.78], p = 0.105). However, in the subgroup of patients > 55 years, dopamine produced statistically significant increases in the complication rates when compared with phenylephrine (83% vs 50% for dopamine and phenylephrine, respectively; OR with dopamine 5.0 [95% CI 0.99-25.34], p = 0.044). CONCLUSIONS Vasopressor usage in ATCCS patients is associated with complication rates that are similar to the reported literature for SCI. Dopamine was associated with a higher risk of complications in patients > 55 years. Given the increased incidence of ATCCS in older populations, determination of MAP goals and vasopressor administration should be carefully considered in these patients. While a randomized control trial on this topic may not be practical, a multiinstitutional prospective study for SCI that includes ATCCS patients as a subpopulation would be useful for examining MAP goals in this population.

Development of a locomotor rating scale for testing motor function in sheep.

BACKGROUND/PURPOSE: Research to cure paralysis associated with myelomeningocele (MMC) is ongoing using the fetal sheep model of MMC. Despite decades of research using this model, no standardized motor function assessment exists. The purpose of this study is to develop a sensitive and reliable locomotor scale for assessing the functional status of sheep. METHODS: Twenty lambs were used to develop and validate the locomotor scale. Lambs (n=15) underwent a surgically created MMC defect at gestational age (GA) 75 days, followed by repair with various methods at GA 100. One lamb underwent a sham operation (n=1). Normal lambs (n=4) served as controls. All lambs were born via spontaneous vaginal delivery, and motor function was assessed for 24 hours. A locomotor rating scale was developed based on behavioral observations of lambs. Inter-rater reliability testing was performed to determine if the scale could be reliably applied by different raters. RESULTS: Observations led to the definition of 7 categories of locomotor recovery. A scoring system was developed to rank these categories. The scale captured a wide variety of neurologic outcomes. Inter-rater reliability revealed minimal variability between examiners (average standard deviation ±0.431). The average score for all raters was within 1 point of the consensus score 100% of the time. CONCLUSIONS: The sheep locomotor rating scale is capable of capturing subtle differences in neurologic function with minimal inter-rater variability. We propose a standardized rating scale for neurologic outcomes and believe this is a critical component for assessing the validity of experimental treatments to cure paralysis in MMC.

Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele.

UNLABELLED: Myelomeningocele (MMC)-commonly known as spina bifida-is a congenital birth defect that causes lifelong paralysis, incontinence, musculoskeletal deformities, and severe cognitive disabilities. The recent landmark Management of Myelomeningocele Study (MOMS) demonstrated for the first time in humans that in utero surgical repair of the MMC defect improves lower limb motor function, suggesting a capacity for improved neurologic outcomes in this disorder. However, functional recovery was incomplete, and 58% of the treated children were unable to walk independently at 30 months of age. In the present study, we demonstrate that using early gestation human placenta-derived mesenchymal stromal cells (PMSCs) to augment in utero repair of MMC results in significant and consistent improvement in neurologic function at birth in the rigorous fetal ovine model of MMC. In vitro, human PMSCs express characteristic MSC markers and trilineage differentiation potential. Protein array assays and enzyme-linked immunosorbent assay show that PMSCs secrete a variety of immunomodulatory and angiogenic cytokines. Compared with adult bone marrow MSCs, PMSCs secrete significantly higher levels of brain-derived neurotrophic factor and hepatocyte growth factor, both of which have known neuroprotective capabilities. In vivo, functional and histopathologic analysis demonstrated that human PMSCs mediate a significant, clinically relevant improvement in motor function in MMC lambs and increase the preservation of large neurons within the spinal cord. These preclinical results in the well-established fetal ovine model of MMC provide promising early support for translating in utero stem cell therapy for MMC into clinical application for patients. SIGNIFICANCE: This study presents placenta-derived mesenchymal stromal cell (PMSC) treatment as a potential therapy for myelomeningocele (MMC). Application of PMSCs can augment current in utero surgical repair in the well-established and rigorously applied fetal lamb model of MMC. Treatment with human PMSCs significantly and dramatically improved neurologic function and preserved spinal cord neuron density in experimental animals. Sixty-seven percent of the PMSC-treated lambs were able to ambulate independently, with two exhibiting no motor deficits whatsoever. In contrast, none of the lambs treated with the vehicle alone were capable of ambulation. The locomotor rescue demonstrated in PMSC-treated lambs indicates great promise for future clinical trials to improve paralysis in children afflicted with MMC.

Leveraging biomedical informatics for assessing plasticity and repair in primate spinal cord injury.

Recent preclinical advances highlight the therapeutic potential of treatments aimed at boosting regeneration and plasticity of spinal circuitry damaged by spinal cord injury (SCI). With several promising candidates being considered for translation into clinical trials, the SCI community has called for a non-human primate model as a crucial validation step to test efficacy and validity of these therapies prior to human testing. The present paper reviews the previous and ongoing efforts of the California Spinal Cord Consortium (CSCC), a multidisciplinary team of experts from 5 University of California medical and research centers, to develop this crucial translational SCI model. We focus on the growing volumes of high resolution data collected by the CSCC, and our efforts to develop a biomedical informatics framework aimed at leveraging multidimensional data to monitor plasticity and repair targeting recovery of hand and arm function. Although the main focus of many researchers is the restoration of voluntary motor control, we also describe our ongoing efforts to add assessments of sensory function, including pain, vital signs during surgery, and recovery of bladder and bowel function. By pooling our multidimensional data resources and building a unified database infrastructure for this clinically relevant translational model of SCI, we are now in a unique position to test promising therapeutic strategies' efficacy on the entire syndrome of SCI. We review analyses highlighting the intersection between motor, sensory, autonomic and pathological contributions to the overall restoration of function. This article is part of a Special Issue entitled SI: Spinal cord injury.

In utero repair of myelomeningocele with autologous amniotic membrane in the fetal lamb model.

BACKGROUND: Despite advances in prenatal repair, myelomeningocele (MMC) still produces devastating neurologic deficits. The amniotic membranes (AM) are a biologically active tissue that has been used anecdotally for human fetal MMC repair. This study evaluated the use of autologous AM compared to skin closure in an established fetal MMC model. METHODS: Seven fetal lambs underwent surgical creation of MMC at gestational age of 75days followed by in utero repair at gestational age of 100days. Lambs were repaired with an autologous AM patch followed by skin closure (n=4) or skin closure alone (n=3). Gross necropsy and histopathology of the spinal cords were performed at term to assess neuronal preservation at the lesion. RESULTS: An increase in preserved motor neurons and a larger area of spinal cord tissue were seen in AM-repaired lambs, as was decreased wound healing of the overlying skin. Loss of nearly all spinal cord tissue with limited motor neuron preservation was seen in skin only-repaired lambs. CONCLUSIONS: AM-repaired lambs showed increased protection of spinal cord tissue compared to skin only-repaired lambs, but the overlying skin failed to close in AM-repaired lambs. These results suggest a potential role for AM in fetal MMC repair that warrants further study.

Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough?

Cellular therapies represent a novel treatment approach for spinal cord injury (SCI), with many different cellular substrates showing promise in preclinical animal models of SCI. Considerable interest therefore exists to translate such cellular interventions into human clinical trials. Balanced against the urgency for clinical translation is the desire to establish the robustness of a cellular therapy's efficacy in preclinical studies, thereby optimizing its chances of succeeding in human trials. Uncertainty exists, however, on the extent to which a therapy needs to demonstrate efficacy in the preclinical setting in order to justify the initiation of a lengthy, expensive, and potentially risky clinical trial. The purpose of this initiative was to seek perspectives on the level of evidence required in experimental studies of cellular therapies before proceeding with clinical trials of SCI. We conducted a survey of 27 SCI researchers actively involved in either preclinical and/or clinical research of cellular interventions for SCI, and then held a focus group meeting to facilitate more in-depth discussion around a number of translational issues. These included: the use of animal models, the use of injury models and mechanisms, the window for demonstrating efficacy, independent replication, defining "relevant, meaningful efficacy" in preclinical studies, and the expectation of therapeutic benefits for cellular interventions. Here we present the key findings from both the survey and focus group meeting in order to summarize and underscore the areas of consensus and disagreement amongst the sampled researchers. It is anticipated that the knowledge generated from this initiative will help to incite future scientific discussions and expert guidelines towards translation of a cell therapy for persons with SCI.