The optimal radiologic method for assessing spinal canal compromise and cord compression in patients with cervical spinal cord injury. Part II: Results of a multicenter study.

An evidence-based analysis of published radiologic criteria for assessing spinal canal compromise and cord compression in patients with acute cervical spinal cord injury. This study was conducted to determine whether literature-based guidelines could be established for accurate and objective assessment of spinal canal compromise and spinal cord compression after cervical spinal cord injury. Before conducting multicenter trials to determine the efficacy of surgical decompression in cervical spinal cord injury, reliable and objective radiographic criteria to define and quantify spinal cord compression must be established. A computer-based search of the published English, German, and French language literature from 1966 through 1997 was performed using MEDLINE (U.S. National Library of Medicine database) to identify studies in which cervical spinal canal and cord size were radiographically assessed in a quantitative manner. Thirty-seven references were included for critical analysis. Most studies dealt with degenerative disease, spondylosis, and stenosis; only 13 included patients with acute cervical spinal cord injury. Standard lateral radiographs were the most frequent imaging method used (23 studies). T1- and T2-weighted magnetic resonance imaging were used to assess spinal cord compression in only 7 and 4 studies, respectively. Spinal cord size or compression were not precisely measured in any of the cervical trauma studies. Interobserver or intraobserver reliability of the radiologic measurements was assessed in only 7 (19%) of the 37 studies. To date, there are few quantitative, reliable radiologic outcome measures for assessing spinal canal compromise or cord compression in patients with acute cervical spinal cord injury.

Prospective, blinded validation study of an objective, quantitative measure to assess maximum canal compromise (MCC) and maximum spinal cord compression (MSCC) in individuals with acute cervical spinal cord injury (SCI). To examine the intraobserver and interobserver reliability of MCC and MSCC in individuals with acute traumatic cervical SCI. To date, few quantitative reliable radiologic methods for assessing the extent of spinal cord compression in the setting of acute SCI have been reported. MCC and MSCC, as assessed on mid-sagittal CT and T2-weighted MR images, respectively, appear to have potential clinical and prognostic value. To date, the validation of these assessment tools has been limited to a small number of observers at a single institution. However, to date no study has focused on the reliability of these radiologic parameters among a large cohort of spine surgeons from North America and abroad. This type of validation is critical to allow the broader use of these outcome measures in research studies and in clinical practice. Mid-sagittal MRI and CT images of cervical spine were selected from 10 individuals with acute traumatic cervical SCI. A total of 28 spine surgeons independently estimated CT MCC, T1-weighted MRI MCC, and T2-weighted MRI MSCC on two occasions using a calibrated ruler. In the first round of measurements, the observers estimated the radiologic parameters using only written instructions. The second measurement set was obtained after an interactive teaching session on the methodology. The order of the images was altered for the second set of measurements. Analysis using parametric and nonparametric statistics indicated high intraobserver reliability for CT MCC, T1-weighted MRI MCC, and T2-weighted MSCC with interclass correlation coefficients (ICCs) of 0.92, 0.95, and 0.97, respectively. The interobserver reliability for all three radiologic parameters was considered moderate with ICCs ranging from 0.35 to 0.56. Our results indicate that the intraobserver reliability for the MCC and MSCC was high. Although the interobserver reliability for all three radiologic parameters in the present study was below 0.75, the observed differences were small and largely accounted for by the limitations in the precision of the calibrated ruler. For cases with minimal cord compression, the measurement of canal stenosis (MCC) proved more accurate. In contrast, in cases with severe cord compression, the assessment of MSCC was more accurate. It is anticipated that the use of digital imaging technologies will further enhance the precision of these outcome measures.

Spinal cord injury results in permanent neurological impairment and disability due to the absence of spontaneous regeneration. NG101, a recombinant human antibody, neutralises the neurite growth-inhibiting protein Nogo-A, promoting neural repair and motor recovery in animal models of spinal cord injury. We aimed to evaluate the efficacy of intrathecal NG101 on recovery in patients with acute cervical traumatic spinal cord injury. This randomised, double-blind, placebo-controlled phase 2b clinical trial was done at 13 hospitals in the Czech Republic, Germany, Spain, and Switzerland. Patients aged 18-70 years with acute, complete or incomplete cervical spinal cord injury (neurological level of injury C1-C8) within 4-28 days of injury were eligible for inclusion. Participants were initially randomly assigned 1:1 to intrathecal treatment with 45 mg NG101 or placebo (phosphate-buffered saline); 18 months into the study, the ratio was adjusted to 3:1 to achieve a final distribution of 2:1 to improve enrolment and drug exposure. Randomisation was done using a centralised, computer-based randomisation system and was stratified according to nine distinct outcome categories with a validated upper extremity motor score (UEMS) prediction model based on clinical parameters at screening. Six intrathecal injections were administered every 5 days over 4 weeks, starting within 28 days of injury. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was change in UEMS at 6 months, analysed alongside safety in the full analysis set. The completed trial was registered at ClinicalTrials.gov, NCT03935321. From May 20, 2019, to July 20, 2022, 463 patients with acute traumatic cervical spinal cord injury were screened, 334 were deemed ineligible and excluded, and 129 were randomly assigned to an intervention (80 patients in the NG101 group and 49 in the placebo group). The full analysis set comprised 78 patients from the NG101 group and 48 patients from the placebo group. 107 (85%) patients were male and 19 (15%) patients were female, with a median age of 51·5 years (IQR 30·0-60·0). Across all patients, the primary endpoint showed no significant difference between groups (with UEMS change at 6 months 1·37 [95% CI -1·44 to 4·18]; placebo group mean 19·20 [SD 11·78] at baseline and 30·91 [SD 15·49] at day 168; NG101 group mean 18·23 [SD 15·14] at baseline and 31·31 [19·54] at day 168). Treatment-related adverse events were similar between groups (nine in the NG101 group and six in the placebo group). 25 severe adverse events were reported: 18 in 11 (14%) patients in the NG101 group and seven in six (13%) patients in the placebo group. Although no treatment-related fatalities were reported in the NG101 group, one fatality not related to treatment occurred in the placebo group. Infections were the most common adverse event affecting 44 (92%) patients in the placebo group and 65 (83%) patients in the NG101 group. NG101 did not improve UEMS in patients with acute spinal cord injury. Post-hoc subgroup analyses assessing UEMS and Spinal Cord Independence Measure of self-care in patients with motor-incomplete injury indicated potential beneficial effects that require investigation in future studies. EU program Horizon2020; Swiss State Secretariat for Education, Research and Innovation; Wings for Life; the Swiss Paraplegic Foundation; and the CeNeReg project of Wyss Zurich (University of Zurich and Eidgenössische Technische Hochschule Zurich).

Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries

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

The goal of this study was to determine the prognostic and clinical value of magnetic resonance imaging (MRI) performed within hours after cervical spinal cord injuries in human patients. Fifty-five patients with acute cervical vertebral column and spinal cord injuries underwent MRI as part of their initial treatment at the University of Michigan Medical Center. All images were obtained within 21 hours after injury (mean, 7.8 h) and were interpreted by an attending neuroradiologist who was blinded to the clinical status of the patients. Neurological function at presentation and in long-term follow-up examinations was compared with MRI characteristics assessed immediately after the injury. The presence and rostrocaudal length of intra-axial hematoma, the rostrocaudal length of spinal cord edema, the presence of spinal cord compression, and spinal cord compression by extra-axial hematoma were each significantly associated with poor neurological function at presentation and in long-term follow-up examinations. Although the best single predictor of long-term improvement in neurological function was the neurological function at presentation, four MRI characteristics, i.e., the presence of intra-axial hematoma, the extent of spinal cord hematoma, the extent of spinal cord edema, and spinal cord compression by extra-axial hematoma, provided significant additional prognostic information. MRI data demonstrated spinal cord compression for 27 of 55 patients (49%), leading to emergency surgery. Among patients who underwent imaging after restoration of normal vertebral alignment using closed cervical traction, 13 of 26 (50%) underwent emergency surgery for treatment of persistent, MRI-demonstrated, spinal cord compression. Emergency MRI after spinal cord injury provides accurate prognostic information regarding neurological function and aids in the diagnosis and treatment of persistent spinal cord compression after vertebral realignment.

AANS: American Association of Neurological Surgeons AIS: Abbreviated Injury Scale ASIA: American Spinal Injury Association CNS: Congress of Neurological Surgeons CSFD: cerebrospinal fluid drainage FDA: Food and Drug Administration FGF: fibroblast growth factor G-CSF: granulocyte colony-stimulating factor HGF: hepatocyte growth factor IL: interleukin iPSC: induced pluripotent stem cell MAP: mean arterial blood pressure MPSS: methylprednisolone sodium succinate MSC: mesenchymal stem cell NASCIS: National Acute Spinal Cord Injury Studies Nogo: neurite outgrowth inhibitor NgR: Nogo receptor NPC: neural precursor cell NSS: Neuro-Spinal Scaffold OEC: olfactory ensheathing cell OPC: oligodendrocyte progenitor cell PEG: polyethylene glycol PLGA: poly(lactic-co-glycolic acid) SCI: spinal cord injury TH: therapeutic hypothermia TNF: tumor necrosis factor Traumatic spinal cord injury (SCI) is a devastating event caused by trauma to the spine which leads to mechanical disruption of the spinal cord. The incidence of SCI varies worldwide. Focusing on developed regions, North America (39 per million) has a higher annual incidence than Australia (16 per million) or Western Europe (15 per million).1 Direct costs for lifetime patient care reach $1.1 to 4.6 million per patient, which further underscores the need for the development of effective SCI treatments.2 Substantial research effort has been dedicated to uncovering the pathophysiology of SCI. This has led to the development of pharmacologic and cell-based therapies, which are now demonstrating functional motor recovery in animal models. Among these, several promising therapeutic agents are already being investigated in clinical trials for SCI. This review will summarize the pathophysiology and current evidence-based clinical strategies to manage an acute spinal cord injury followed by a discussion of key emerging treatments including pharmacological approaches, cell-based therapies, biomaterials and physiological approaches. PATHOPHYSIOLOGY Phases of SCI Tissue damage after SCI has been divided into primary and secondary injury phases.3,4 The physical forces of the initial trauma cause the primary injury and this is the main determinant of the severity of SCI. The axons, blood vessels, and cell membranes are disrupted by physical forces such as compression, shearing, laceration, and acute stretch. Secondary injury refers to delayed, progressive damage which continues after the primary injury and represents an additional important determinant of neurological deficits (Figure).5,6 Due to the disruption of the blood–spinal cord barrier following the primary injury, infiltration of inflammatory cells such as macrophages, microglia, T-cells, and neutrophils can be observed. Inflammatory cytokines such as tumor necrosis factor (TNF) α, interleukin (IL)-1α, IL-1β, and IL-6 are released by these cells, with levels of these cytokines peaking 6 to 12 h after injury and remaining elevated up to 4 d after injury.7 Increases in intracellular calcium are caused by the disruption of ionic homeostasis after SCI and activates calcium-dependent proteases (eg, phospholipases, calpain, caspase, and nitric oxide synthase). These proteases trigger dysfunction of mitochondria which leads to cell death.8 Oligodendrocytes are highly susceptible to apoptotic loss and apoptosis has been observed, not only at the lesion epicenter, but also distant from the epicenter leading to demyelination of preserved axons.9-11 Furthermore, delayed necrosis and apoptosis are induced by reactive oxygen species which are released by phagocytic inflammatory cells.12-14 Moreover, the disrupted cells release excitatory amino acids (eg, glutamate and asparate) after SCI15,16 and the excessive activation of excitatory amino acid receptors causes further loss of neurons and glia by both necrotic and apoptotic cell death.17 To achieve repair and regeneration of the injured spinal cord, researchers have attempted to disrupt elements of the secondary injury pathway with the aim of neural preservation, inhibition of the barriers to axonal regeneration, and replacement of the damaged cells by cell transplantation therapy. From a pathophysiological perspective, it is likely that the optimal therapy will be a combinatorial one consisting of administration of drugs to reduce secondary injury at the acute phase, followed by cell transplantation or other regenerative therapies to regenerate the damaged spinal cord tissue in the subacute to chronic phases.18,19 These therapies are discussed in greater detail below.FIGURE: Three pathophysiological phases after SCI including acute (eg, hemorrhage, edema, and inflammation), subacute (eg, demyelination and axonal dieback), and chronic (eg, cavity formation) phases. Primary injury is caused by the physical forces of the initial traumatic event. Secondary injury refers to delayed, progressive damage which includes inflammation, loss of ionic homeostasis, oxidative damage, excitotoxicity, apoptosis, and necrosis. Oligodendrocytes are highly susceptible to apoptotic loss resulting in axonal demyelination. Cystic cavitation forms in the center of the spinal cord, with surrounding glial scar in the subacute and chronic phases. Nonastrocyte cells mainly form a chemical barrier by secreting growth inhibitory CSPGs.Barriers to Regeneration The adult mammalian Congress of Neurological Surgeons (CNS), including the spinal cord, has generally been considered to have limited regenerative capacity due to the finite number of available regenerative cells and the restricted plasticity of the adult CNS.20 While recent research has shown that the spinal cord has more regenerative capacity than was previously thought,21,22 compared with the peripheral nervous system, the regenerative capacity of the CNS is lower and it gradually decreases with increasing age.23 Schwab et al24 reported the inhibitory nature of CNS myelin in 1985. Myelin-associated proteins, such as neurite outgrowth inhibitor A (Nogo A),25,26 oligodendrocyte-myelin glycoprotein,27 and myelin-associated glycoprotein28,29 function through Nogo receptors (NgR). The NgRs lack an intracellular signaling domain and transduce inhibitory signals by forming coreceptor complexes with TNF receptor family proteins (eg, p75, TROY, and LIGO-1) to activate the GTPase Rho A. The downstream effector of Rho A is Rho-associated protein kinase which affects changes in the actin cytoskeleton and leads to growth cone collapse of regenerating axons, neurite retraction, and increasing apoptosis. SCI is accompanied by mechanically induced and excitotoxic cell death, with associated demyelination. The lost parenchyma is replaced by cystic cavitation and regeneration is often hindered by the presence of this cystic cavity which lacks the substrate to support axonal growth and cell migration.30 Furthermore, at the site of injury, glial and fibrotic scarring is also present (Figure). Glial and fibrotic scarring results when pericytes, hypertrophied astrocytes, fibroblast lineage cells, and inflammatory cells form a physical barrier, walling off injured tissue from healthy tissue.31,32 Recent research has shown that both astrocytes and nonastrocyte cells can form a physical and chemical barrier by secreting growth inhibitory chondroitin sulfate proteoglycans (CSPGs) such as neurocan, versican, brevican, phosphacan, and NG2.33 A fibroblast-derived scar can also be located in the perilesional region and is associated with the deposition of inhibitory extracellular matrix molecules. Similar to myelin-associated inhibitors, these molecules act as chemical barriers to the regeneration of axons. CURRENT CLINICAL STRATEGIES Early Surgical Intervention To reduce the effects of cord compression and resultant ischemia, early bony and ligamentous surgical decompression is performed to provide relief from the mechanical pressure. To elucidate the effectiveness of early decompression, a prospective cohort study, The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) was conducted with 313 cervical SCI patients.34 After adjusting for confounders, the early decompression group (<24 h after SCI) was 2.8 times as likely to demonstrate an Abbreviated Injury Scale (AIS) improvement of 2 or more grades at 6 mo after SCI compared with the late decompression group (≥24 h after SCI). A subsequent prospective Canadian cohort study (including cervical, thoracic, and lumbar SCI, n = 84) also revealed that early decompression was associated with a 2 or more grade AIS improvement at the time of rehabilitation facility discharge.35 The findings of these studies support the concept of "Time is Spine" which emphasizes the importance of early diagnosis and intervention to improve long-term outcomes. Central Cord Syndrome Central cord injury is characterized by greater weakness in the upper extremities than the lower extremities, variable sensory loss, variable bowel/bladder dysfunction, and, usually, early rapid improvements in neurological function. Early decompression has traditionally been avoided in cases of central cord injury with patients being allowed to plateau in their recovery over a number of weeks before any intervention.36 However, for patients with pre-existing canal stenosis, recent evidence suggests that early surgery may improve long-term outcomes. A systematic review demonstrated that patients undergoing early decompression (<24 h after SCI) had American Spinal Injury Association (ASIA) motor scores that were 6.31 points higher, and a greater chance of improvement in ASIA grade (odds ratio of 2.81) at 12-mo follow-up than those undergoing late decompression (≥24 h after SCI).37 Although the prospective randomized controlled Comparing Surgical Decompression Versus Conservative Treatment in Incomplete Spinal Cord Injury (COSMIC, NCT01367405) trial was initiated in 2013, it was terminated in 2016 due to difficulties in enrolling patients. Blood Pressure Augmentation The neuroprotective effects of blood pressure augmentation act through enhancing systemic perfusion. Several studies have shown that high-normal mean arterial blood pressures (MAPs) of 85 to 90 mm Hg may improve outcomes in SCI patients.38-40 The guidelines of the American Association of Neurological Surgeons (AANS) and (CNS) recommend MAP targets of 85 to 90 mm Hg as an option in SCI to be initiated as early as possible and maintained for 7 d after injury.41 This MAP elevation requires invasive blood pressure monitoring, maintenance of slightly hypervolemic state, and central venous access for continuous infusion of vasopressors. A noninferiority trial named Mean Arterial Blood Pressure Treatment for Acute Spinal Cord Injury (MAPS; NCT02232165) comparing MAP ≥ 85 mm Hg and MAP ≥ 65 mm Hg has been developed to assess the efficacy of lower targets. ASIA motor scores at 1 yr postinjury will be evaluated, and this trial is expected to complete in March 2017. Steroids for SCI Methylprednisolone sodium succinate (MPSS) is the only agent from completed clinical trials that has entered clinical use. It acts by reducing oxidative stress to enhance neural cell survival in animal models of traumatic SCI. Three landmark National Acute Spinal Cord Injury Studies (NASCIS) examined the use of MPSS for acute SCI.42-47 Although no neurological benefit in the MPSS-treated group was observed in the overall analyses of these studies, a subgroup analysis in the NASCIS II and III trials demonstrated that use of the drug in a higher dosing regimen than that used in NASCIS I within 8 h of injury resulted in neurological improvement, and that MPSS bolus 3 to 8 h after injury improved neurological function when it was administered for 48 h rather than 24 h.44-47 Recent evidence further supports the use of MPSS for SCI. A 2012 Cochrane meta-analysis and review demonstrated a 4 point greater ASIA motor score improvement in the group that received MPSS for acute SCI and that its administration was not associated with a significant increase in the risk of complications.48 Nevertheless, the 2013 AANS/CNS Section on Disorders of the Spine and Peripheral Nerves guideline provided a level I recommendation against the administration of MPSS which represents a marked change from the previous version despite little change in the evidence considered. Accordingly, an updated AOSpine guideline suggests that 24 h of MPSS IV be administered within 8 h of SCI to patients without medical contraindication.49 Emerging Therapies for SCI Key emerging technologies for SCI treatment include pharmacological approaches, cell-based therapies, biomaterials, and physiological approaches. A summary of these technologies is provided in Table.TABLE: Key Emerging Technologies for Acute SCIPharmacological Approaches Riluzole Riluzole is a benzothiazole antiepileptic which acts via sodium channel blockade. It is approved by the US Food and Drug Administration (FDA), European Medicines Agency, and Health Canada for the treatment of amyotrophic lateral sclerosis.50,51 Its role in neuroprotection stems from its ability to mitigate excitotoxicity and block sodium influx to neurons in addition to restricting the presynaptic release of glutamate.52 In animal studies, Riluzole has been shown to reduce neuronal loss and cavity size which led to improvements in motor function and electrophysiology.53-55 In the phase I trial for acute SCI was recently completed, and 36 patients were enrolled.56 Although elevations of liver enzyme levels were observed temporarily, no serious adverse events were attributed to the drug. Regarding the neurological outcomes, cervical SCI patients treated with riluzole showed the better improvement in ASIA motor score compared with non-riluzole treated patients matched from an historical registry cohort. The phase II/III RCT entitled riluzole in Spinal Cord Injury Study (RISCIS; NCT01597518) is recruiting patients with acute C4-8 injuries with ASIA grade A, B, or C and will compare riluzole versus placebo and assess AIS, Spinal Cord Independence Measure, and brief pain inventory. This study which was initiated in 2014 has to date recruited 70 patients and is expected to conclude in 2020. Minocycline Minocycline is a second-generation semisynthetic tetracycline antibiotic that has the ability to cross the blood–brain barrier. It also has potent anti-inflammatory properties and inhibits microglial activation, TNF-α, IL-1β, cyclooxygenase-2, and matrix metalloproteinases.57-60 In animal studies, minocycline treatment after acute SCI has been shown to protect against neuron loss and reduce the lesion size.61,62 A phase II study showed that patients with incomplete cervical SCI (n = 25) demonstrated an ASIA score improvement of 14 points with minocycline treatment compared to placebo (P = .05).63 The follow-up Phase III Minocycline in Acute Spinal Cord Injury (MASC; NCT01828203) study will compare IV minocycline for 7 d and is expected to conclude in 2018. VX-210 (Cethrin) The Rho pathway is known to negatively impact axonal and neurite growth.64 A toxin produced by Clostridium botulinum, C3 transferase (cethrin), has been shown to inhibit Rho-mediated inhibition of axonal growth which promoted neural regeneration and motor function recovery in rodent SCI models.65 Cethrin is a permeable material intended for application to the dura mater at the site of SCI during decompressive surgery in the acute phase. A phase I/IIa multicenter, dose-escalation human trial evaluating this drug in a human population was published in 201166; no serious adverse events were attributed to the drug.66 Cervical patients treated with 3 mg of cethrin showed improvement in ASIA motor score at 12 mo and this was shown to be superior to historical recovery rates. A phase IIb/III study of cethrin has commenced in cervical SCI patients in 2016 and is expected to conclude in 2018. Anti-Nogo-A antibody (ATI-355) A monoclonal antibody of major inhibitory fractions within CNS myelin, IN-1, has been shown to promote axonal sprouting and functional recovery following SCI in animal models.67 The humanized anti-Nogo antibody, ATI-355, has been shown to promote axonal sprouting and functional recovery following SCI in numerous animal models and is a rare therapeutic in that it has been demonstrated to improve functional outcomes in a primate model.26 A phase I human trial of humanized anti-Nogo antibody (ATI-355) was completed in Europe, rather than the US, as the FDA expressed concerns with the infusion pump. Although this trial has been completed, it has not been published. A phase II study of ATI-355 is about to commence in Europe. Granulocyte Colony Stimulating Factor Granulocyte colony-stimulating factor (G-CSF) has been shown to increase the mobilization of bone marrow stromal cells from the bone marrow and to increase their presence at the site of SCI. In a rodent model, G-CSF enhances neurogenesis, reduces apoptosis, and decreases expression of TNF-α and IL-1β. These positive effects are associated with white matter sparing and improved hind-limb function.68 The phase I/IIa trials, which were nonrandomized, showed no increase in serious adverse events with G-CSF administration alongside AIS grade improvement.69,70 G-CSF is currently in a phases III clinical trial in Japan with results expected in 2018. Hepatocyte Growth Factor Hepatocyte growth factor (HGF) is mainly secreted by mesenchymal cells and promotes cellular growth and motility. HGF enhances neuron survival, decreases lesion size, and reduces oligodendrocyte apoptosis to improve behavioral outcomes in rodent models.71 Moreover, in a primate model of cervical SCI, HGF improved hand dexterity which is one of the most important key functions of the upper limb.72 A phase I/II clinical trial (NCT02193334) comparing intrathecal HGF (KP100IT) versus placebo is now underway with results expected in 2017. Magnesium (AC105) Magnesium is a physiological antagonist of NMDA receptors which decreases excitotoxicity and also functions as an anti-inflammatory agent. Magnesium with polyethylene glycol (PEG) improves cerebrospinal fluid levels without requiring large magnesium doses.73-75 The use of magnesium with PEG in the treatment of animal models of SCI has been shown to enhance tissue sparing and improve motor functional recovery.76,77 However, a phase I/II clinical trial (NCT01750684) of magnesium with PEG (AC105) was terminated in 2015 due to difficulties in enrolling patients. Fibroblast Growth Factor Fibroblast growth factor (FGF) plays a key role in preserving motor neurons adjacent to the SCI site and reduces acute respiratory deficits resulting from the loss of ventral horn neurons by reducing glutamate-mediated excitotoxicity in animal models.78,79 Although a phase I/II trial (NCT01502631) of the FGF-analog (SUN13837) has been completed, the results have not been published to date. Cell-Based Therapies Regenerative therapies based on transplanted multipotent and differentiated cells are an exciting therapeutic approach showing promising results in translational studies. Initial research focused on embryonic stem cell lines derived from aborted early-stage embryos, however, ethical considerations and limited numbers of donor cells created challenges. More recently, the discovery of induced pluripotent stem cells (iPSCs), which can be derived within weeks from any somatic cell source, has revolutionized the field by providing a nearly limitless source of pluripotent cells for research and therapeutic purposes.80 Furthermore, iPSCs can potentially be derived from autologous tissue reducing or eliminating the risk of graft rejection.80 While unforeseen challenges in iPSC technology, such as epigenetic memory and early senescence, have been found, they continue to be a substantial technological advance in spinal cord regeneration.81 The most translationally relevant cell therapies derived from pluripotent stem cells or harvested from adult tissue are discussed cells are known to peripheral regeneration by providing a and support to axons. In rodent models of SCI, have been shown to reduce lesion size, axons, and provide motor The to has a phase trial (n = to assess for patients with chronic AIS grade injuries in the cervical or The study is expected to conclude in 2018. additional phase I trial (n = of derived for AIS grade A injuries has with results expected in ensheathing cells olfactory neurons and provide from and the In animal models of SCI, they have been to enhance neurite outgrowth and resulting in significant functional the are now and for chronic While a meta-analysis of several of these trials (n = no increase in serious adverse efficacy has to be due to concerns within the A previous study showed the of transplanted on from the into the spinal clinical trials of for chronic SCI have been completed and in a meta-analysis which no significant increase in to the stem cells are multipotent tissue cells of into and to repair ability to the and systemic inflammatory led to their application in SCI they were to promote tissue sparing through signaling and of is now a Phase II/III randomized trial of autologous via and intrathecal for patients with AIS grade cervical SCI within 12 mo of The study is expected to conclude in precursor cells are multipotent CNS cells of to astrocytes, and to lost cells and provide are most the central canal of the spinal cord and after however, their numbers are limited of or stem a promising In animal models of cervical and SCI, transplanted have been shown to reduce cystic axons, and improve behavioral outcomes over In 2 phase II trials led by were terminated early due to The studies were the effects of human CNS stem cell for and cervical The results of these trials have not been however, provide evidence that cell are in on emerging it is likely that further to the transplanted cells their will be to enhance motor outcomes. progenitor cells have multipotent to but they to to axons. Several studies have and functional recovery after A phase I/II trial (n = is now underway by to assess with results expected by have the of several of biomaterials with to SCI. These can be with stem cells, to growth and can be to over Moreover, they are being to cavitation with a that the extracellular In rodent biomaterials such as and have been shown to improve and behavioral to clinical Neuro-Spinal Scaffold is a and poly(lactic-co-glycolic currently in phase III trial by n = The trial will the effects of in with AIS grade A injuries and no as a was provided by the FDA this a The study is expected to conclude by Approaches to to via a of has been shown to reduce CNS injury after and These reduce the of the CNS and the systemic inflammatory to SCI, is tissue sparing and improvements in behavioral recovery in the In patients with AIS grade A a study (n = early therapeutic hypothermia to be associated with better neurological A phase II/III trial by the to entitled for Traumatic of the currently The study will assess of initiated within 6 h of injury to both efficacy and treatment is known to be a of the secondary injury Similar to MAP cerebrospinal fluid drainage to improve early spinal cord pressure to reduce the While an initial trial (n = to recent studies have that drainage and MAP augmentation can act to enhance spinal cord blood A phase (n = randomized trial and MAP elevation is now underway to the treatment can improve neurological outcomes for patients with acute AIS grade A, B, or C injuries from The study is expected to conclude in The of SCI research is and findings are being with from SCI clinical To achieve in clinical trials in SCI, the of and to In with to level of injury as as ASIA grade have been in of the clinical trials including the cethrin and riluzole The of SCI is likely to the administration of drugs to mitigate the secondary injury at the acute phase, followed by cell transplantation therapy to regenerate damaged spinal cord tissue from subacute to chronic that the therapeutic discussed in this review and the continuous in and clinical research are a to regenerative for SCI. This is by Canadian of Health AOSpine North in and and The support from the in and Regeneration and the is a for and and a for The other have no or in any of the or in this for this

Introduction to the Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries

Intradural spinal cord compression impairs perfusion pressure and is putatively rate-limiting for recovery after traumatic spinal cord injury (tSCI). After cervical tSCI, even minimally improved tissue preservation may help promote neurological recovery. To assess the nature and extent of spinal cord swelling and compression post-acute cervical tSCI, we evaluated several baseline MRI parameters including BASIC score, intramedullary lesion (IML) length, maximal canal compromise (MCC), maximal spinal cord compression (MSCC), extent of cord compression (ECC), maximal swollen anteroposterior diameter adjacent to injury site (Dmax), and maximal cord swelling (MCS) in 169 consecutive patients across 2 centers. In patients with either primarily intradural or combined (MSCC ≤5% or >5%, respectively) cord compression, we examined the predictive value of clinical and imaging admission parameters on American Spinal Injury Association Impairment Scale (AIS) severity and conversion up to 1-year follow-up. 37 (21.9%) patients presented with primarily intradural while 132 (78.1%) had combined cord compression. MSCC, MCS, and Dmax values differed significantly between the two groups (p < 0.0001, < 0.01 and < 0.001, respectively). MSCC was associated with age, MCC and MCS at baseline, while MCS was associated with age, MSCC and Dmax, on multivariable analysis. Logistic regression analysis of areas under receiver operating characteristic curve (AUROC) confirmed ECC (AUC 0.678) and MCS (AUC 0.922) as good and excellent predictors, respectively of AIS-conversion at 1-year for intradural compression participants. Additionally, MCS was significantly more accurate in predicting AIS-conversion in intradural group and the probability of AIS-conversion significantly decreased with each 1% increase in MCS (p = 0.003; OR 0.949), for both compression subtypes. In conclusion, baseline measures of cord swelling predict AIS-conversion likelihood up to 1-year. The deleterious effects of intradural cord compression, either isolated or presenting with extradural compression, may benefit from supplemental decompression strategies in addition to current standard-of-care.

A modified Delphi study. To assess current practice patterns in the management of cervical spinal cord injury (SCI) and develop a simplified, practical classification system which offers ease of use in the acute setting, incorporates modern diagnostic tools and provides utility in determining treatment strategies for cervical SCI. A three-phase modified Delphi procedure was performed between April 2020 and December 2021. During the first phase, members of the AOSpine SCI Knowledge forum proposed variables of importance for classifying and treating cervical SCI. The second phase involved an international survey of spine surgeons gauging practices surrounding the role and timing of surgery for cervical SCI and opinions regarding factors which most influence these practices. For the third phase, information obtained from phases 1 and 2 were used to draft a new classification system. 396 surgeons responded to the survey. Neurological status, spinal stability and cord compression were the most important variables influencing decisions surrounding the role and timing of surgery. The majority (>50%) of respondents preferred to perform surgery within 24hours post-SCI in clinical scenarios in which there was instability, severe cord compression or severe neurology. Situations in which <50% of respondents were inclined to operate early included: SCI with mild neurological impairments, with cord compression but without instability (with or without medical comorbidities), and SCI without cord compression or instability. Spinal stability, cord compression and neurological status are the most important variables influencing surgeons' practices surrounding the surgical management of cervical SCI. Based on these results, a simplified classification system for acute cervical SCI has been proposed.

Breaking Down Silos to Protect the Spinal Cord

Cervical spinal cord injury results in severe cardiorespiratory impairments due to interruptions of bulbospinal pathways innervating to phrenic motoneurons and thoracic sympathetic preganglionic neurons. Additionally, the injury substantially impacts spinal cord blood flow, attributed to damage to the spinal vessels and the blood–spinal cord barrier. Current clinical guidelines suggest maintaining the mean arterial pressure between 85–90 mmHg during the acute phase of spinal cord injury; however, there is no preclinical animal evidence to examine the optimal timing and effect of hemodynamic management on respiratory function and spinal microcirculation following injury. Accordingly, the present study aimed to comprehensively investigate the therapeutic efficacy of hemodynamic agent (i.e., norepinephrine) on cardiorespiratory function and spinal cord blood flow during compression vs. decompression phases of acute cervical spinal cord injury. Adult male rats underwent mid-cervical spinal cord compression followed by decompression were received an intravenous infusion of 1) saline (7 ml/kg/hr), 2) norepinephrine (125 μg/kg/hr) during compression, or 3) norepinephrine during decompression. Respiratory and cardiovascular patterns were measured in conjunction with monitoring of spinal cord blood flow utilizing a laser speckle contrast imaging device. There are three major findings in the present study. First, saline infusion during cervical spinal cord compression resulted in a significant reduction in the minute ventilation (45 ± 10% of baseline, p&lt;0.01) and the mean arterial blood pressure (71 ± 10% of baseline, p&lt;0.01), which is accompanied by a hypoperfusion of spinal cord blood flow (62 ± 11% of baseline, p&lt;0.01). Second, infusion of norepinephrine during compression significantly enhanced the minute ventilation (75 ± 21% of baseline, p&lt;0.01) and improved spinal cord blood flow (92 ± 22% of baseline, p&lt;0.01), with mean arterial blood pressure returning to the normal values. The improvement of physiological function could be still maintained even norepinephrine was no longer administrated during decompression phase. Importantly, the ischemia-reperfusion rebound of spinal cord blood flow during the decompression phase was significantly mitigated by infusion of norepinephrine during compression. Third, norepinephrine infusion during decompression was surprisingly unable to improve the minute ventilation despite the mean arterial blood pressure could be maintained at the normal level. Furthermore, the ischemia-reperfusion effect on spinal cord blood flow was significantly exaggerated (136 ± 17% of baseline, p&lt;0.01). These data indicated that norepinephrine exerts differential effects on the cardiorespiratory function and spinal cord blood flow depending on the time point of administration. Our results suggest that infusion of norepinephrine during compression is beneficial for functional improvement, while norepinephrine may aggravate ischemia reperfusion injury when infusing during decompression. This study provides essential pre-clinical evidence underscoring the importance of determining the optimal timepoint of hemodynamic management to achieve the maximal therapeutic efficacy and prevent the potential side effects during acute cervical spinal cord injury. Support for this work was provided by grants from the National Science and Technology Council (NSTC 112-2628-B-110-003-MY3). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

3:51 118. Correlation of Qualitative and Quantitative MRI Findings With Neurological Outcome after C-Spine Trauma: A Multi-Center Prospective Study of 100 Patients With Acute Cervical Spinal Cord Injury

Background and PurposeTo assess the relationship between early MRI biomarkers after acute cervical spinal cord injury (SCI) and to evaluate their predictive validity of neurologic impairment.Materials and MethodsWe performed a retrospective cohort study of 95 patients with acute SCI and pre-operative MRI within 24 hours of injury. American Spinal Injury Association Impairment Scale (AIS) was used to define neurological impairment as our primary outcome measure. We assessed several MRI features of injury including axial grade (BASIC score), sagittal grade, length of injury, maximum canal compromise (MCC), and maximum spinal cord compression (MSCC). Data-driven non-linear principal component analysis (NL-PCA) was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment.ResultsNL-PCA identified two clusters of MRI variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MRI measures of intrinsic cord signal abnormality, with axial grade (BASIC score) representing the most statistically significant and accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression.ConclusionsThis study demonstrates the utility of applying NL-PCA for defining the relationship between MRI biomarkers in a complex clinical syndrome of cervical SCI. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute SCI, highlighting the value of axial T2 MRI.

Context: Traumatic spinal cord injury (TSCI) is a devastating disease, hence the need to identify clinical and radiological injury features that can predict neurological improvement. Aims: This study aims to identify magnetic resonant imaging (MRI) features in cervical TSCI that correlates with neurological status at admission, and also predict early neurological improvement. Settings and Design: This was a prospective cohort study. Subjects and Methods: Admission MRI features of 47 patients with cervical TSCI and their neurological assessments at admission and 3 months post-injury were reviewed prospectively over a period of 18 months. Correlational and regression analyses were done using SPSS® version 25 software. P < 0.05 was used as the level of significance. Results: Spinal cord oedema and cord contusion (78.0%) constitute the majority of injury patterns seen on MRI. There was a significant association between spinal cord contusion and cord oedema on MRI and incomplete TSCI. Likewise, spinal cord haemorrhage, compression and transection were associated with complete TSCI. Maximum canal compromise (MCC), maximum spinal cord compression (MSCC) and length of cord lesion significantly correlate with American Spinal Injury Association Impairment Scale at admission (P = 0.033, P = 0.015 and P < 0.001, respectively). Increasing values of these variables were found to be independent predictors of complete TSCI. However, length of cord lesion was the only independent predictor of neurological improvement, 3 months post-injury (P = 0.025). Conclusions: Spinal cord haemorrhage, compression, transection and higher values of MCC, MSCC and increased length of cord lesion were predictive of complete TSCI. However, the length of spinal cord lesion was a better predictor of early neurological improvement.