Translational Advances in the Management of Acute Spinal Cord Injury

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 = The follow-up III Minocycline in Acute Spinal Cord Injury study will compare IV minocycline for 7 d and is expected to conclude in The Rho pathway is to axonal and neurite A by has been shown to inhibition of axonal growth which neural regeneration and motor function recovery in SCI is a for to the at the site of SCI surgery in the acute A phase trial this drug in a was in no serious adverse events were attributed to the patients treated with 3 of showed improvement in ASIA motor score at 12 mo and this was shown to be to historical recovery A phase study of has in cervical SCI patients in 2016 and is expected to conclude in A of inhibitory within CNS has been shown to axonal and functional recovery following SCI in animal The has been shown to axonal and functional recovery following SCI in animal models and is a therapeutic in that it has been demonstrated to improve functional outcomes in a A phase I trial of was completed in rather than the as the with the infusion Although this trial has been completed, it has not been A phase II study of is to in colony-stimulating factor has been shown to increase the of cells from the and to increase their presence at the site of SCI. In a apoptosis, and decreases of and These effects are associated with and improved The phase which were showed no increase in serious adverse events with administration AIS grade is in a phases III clinical trial in with results expected in growth factor is mainly by mesenchymal cells and growth and neuron decreases lesion and oligodendrocyte apoptosis to improve outcomes in Moreover, in a of cervical SCI, improved which is one of the important key of the upper A phase clinical trial comparing versus placebo is now with results expected in 2017. is a physiological of receptors which decreases excitotoxicity and also as an anti-inflammatory with polyethylene glycol cerebrospinal fluid levels without The use of with in the treatment of animal models of SCI has been shown to enhance tissue and improve motor functional However, a phase clinical trial of with was terminated in due to difficulties in enrolling patients. growth factor a key role in motor neurons to the SCI site and acute deficits resulting from the loss of neurons by reducing excitotoxicity in animal Although a phase trial of the has been completed, the results have not been to Therapies therapies on and cells are an therapeutic promising results in research on stem cell from and limited of cells the of induced pluripotent stem cells which can be within weeks from any cell has the by a of pluripotent cells for research and therapeutic Furthermore, can be from tissue reducing or the risk of While in such as and early have been to be a in spinal cord The cell therapies from pluripotent stem cells or from adult tissue are discussed cells are to peripheral regeneration by a and support to axons. In models of SCI, have been shown to reduce lesion 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 additional phase I trial (n = of for AIS grade A injuries has with results expected in ensheathing cells olfactory neurons and provide from and the In animal models of SCI, 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 within the A previous study showed the of 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 tissue cells of into and to repair ability to the and systemic inflammatory led to their in SCI were to tissue through signaling and of is now a II/III randomized trial of via and for patients with AIS grade cervical SCI within 12 mo of The study is expected to conclude in precursor cells are CNS cells of to astrocytes, and to lost cells and provide are the central canal of the spinal cord and after their are limited of or stem a promising In animal models of cervical and SCI, have been shown to reduce cystic axons, and improve outcomes over In 2 phase II trials led by were terminated early due to The studies were the effects of CNS stem cell for and cervical The results of these trials have not been provide evidence that cell are in on emerging it is likely that further to the cells their will be to enhance motor outcomes. progenitor cells have to but to to axons. Several studies have and functional recovery after A phase trial (n = is now 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, are being to cavitation with a that the extracellular In biomaterials such as and have been shown to improve and to clinical Neuro-Spinal Scaffold is a and poly(lactic-co-glycolic 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 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 and improvements in 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 The study will assess of initiated within 6 h of injury to both efficacy and treatment is 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 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 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. 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