EPIDEMIOLOGY AND IMPACT OF SPINAL CORD INJURY
Spinal cord injury (SCI) is a relatively rare event that represents a significant medical problem for patients, health care providers and the health care system. In the United States there are ~1.3 million people living with SCI.1 Every year ~40 out of every 1 million people suffer from SCI.1 The majority of those affected are young male individuals which account for 80.7% of injuries and have an average age of 28 years.1 SCI is most commonly caused by motor vehicle accidents and falls.1 The total cost of caring for patients living with SCI in the United States is ~$7 billion per year with average cost per patient range ranging from $1.1 to $4.6 million per year.1
The management and treatment of acute SCI remains controversial as clinicians and researchers continue to search and identify ways to improve patient outcomes (Table 1). There are several phases of care that affect each patient with acute SCI, which include the initial trauma management, acute surgical intervention, and perioperative medical management. Each phase of care requires the work of an interdisciplinary team focused on providing effective and efficient medical care to maximize patient outcomes. The purpose of this review is to provide an overview of SCI care with a focus on the postoperative medical management.
PATHOPHYSIOLOGY OF SCI
SCI encompasses a cascade of events that typically begins with a mechanical injury. The process can be divided into 2 components, the mechanical injury and the acute inflammatory response. There are several mechanisms that may result in neurological insult such as compression, laceration, distraction, and shearing.2,3 The initial injury results in damage to the microvasculature of the spinal cord leading to hemorrhage, ischemia, and local acidosis.2–4 After the mechanical insult is the acute inflammatory response that lasts from minutes after the injury to several days or weeks. During the inflammatory phase proapoptotic signaling and vasogenic edema contribute to ongoing ischemia and lead to expansion of the zone of injury.5,6 A disruption of the blood spinal cord barrier leads to an influx of vasoactive peptides, inflammatory cells, and cytokines including tumor necrosis factor-α, interleukin-1α (IL-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Subsequently the by-products of cellular necrosis are released including ATP, DNA, and potassium which lead to a cytotoxic environment and therefore leads to further recruitment of phagocytes.2 Macrophages and polymorphonuclear leukocytes infiltrate the zone of injury and produce oxygen-free radicals and cytotoxic by-products.2,3 One such by-product is the release of excess glutamate which results in excitoxic damage of surrounding neurons.7,8
The management of patients with acute SCI requires a multidisciplinary team-based approach that provides a streamlined pathway for the initial evaluation, work-up, and treatment. Initial evaluation of SCI patients begins with the basic trauma principles of airway, breathing, and circulation. Patients with spinal cord injuries may present with a variety of cardiopulmonary issues depending on the level of neurological injury. Once the airway has been secured, a temporary cervical spine stabilization device should be placed such as a rigid cervical spine collar and spinal precautions should be implemented. Once the cervical spine is stabilized the patient should undergo radiographic evaluation including a computed tomography scan of the cervical, thoracic, and lumbar spine to ensure any noncontiguous injuries are detected. Following computed tomography scan all areas of injury or concern should have dedicated magnetic resonance imaging performed to evaluate the spinal cord itself.
Patients with spinal cord injuries should be transferred to an intensive care unit for resuscitation and close monitoring of their hemodynamic stability with particular attention given to their mean arterial pressure (MAP). One area of controversy surrounding the initial management of SCI patients is the role of hypotension and the maintenance of MAP. In 2014 the American Association of Neurosurgeons and Congress of Neurosurgeons provided a Level II recommendation to avoid hypotension and suggested maintaining MAPs between 85 and 90 mm Hg for 7 days after the injury. Hypotension was defined as a systolic blood pressure <90 mm Hg.1 Hawryluk and colleagues evaluated 74 patients with acute SCI that had their MAPs maintained >85 mm Hg for 5 days after injury and subsequently all patients were followed for 30 days. They discovered 23 of 74 patients that had a one level or greater improvement in their American Spinal Injury Association (ASIA) score.9 Those patients had higher MAPs on average and fewer episodes of hypotension than patients who failed to have neurological improvement.9 Martin and colleagues in a prospective analysis studied 105 patients with cervical and thoracic acute SCI demonstrated that the number of episodes of hypotension did not affect the ASIA score.10 This analysis questions the value of using pharmacologic agents to artificially elevate MAPs which present their own set on side effects.11 In addition, Kepler et al12 demonstrated in a retrospective review of 92 patients that chronic hypertension was an independent risk factor for poor early neurological recovery. Further investigation is needed into the correlation of MAP and its effect of neurological recovery.
An important aspect of the initial management is early optimization of the patient for surgical decompression and stabilization. The time for surgical intervention for SCI is critical to maximize potential outcomes. The Surgical Treatment of Acute Spinal Cord Injury Study (STASCIS) prospectively evaluated 313 patients with a cervical SCI comparing outcomes of early surgical intervention, within 24 hours, versus late intervention. They demonstrated that the early decompression group experienced 2.8 times greater likelihood of experiencing an ASIA impairment sale improvement of at least 2 grades at 6 months compared with patients who underwent surgery >24 hours after injury.13 In addition, these results have been corroborated by Wilson et al14 who evaluated early versus late surgical intervention in patients with cervical, thoracic, and lumbar spinal cord injuries and found that patients who underwent early decompression had a statistically significant greater improvement in ASIA motor score at the time of discharge. Lastly, early decompression has been correlated with clinically significant findings such as reduced incidence of acute hospital complications and shorter length of stay.8
Methylprednisolone therapy remains an area of controversy in the treatment algorithm of acute spinal cord injuries (Table 2). The use of steroids after SCI is intended to decrease the inflammatory response that occurs in the zone injury and limit secondary damage to the spinal cord. The National Acute Spinal Cord Injury Study (NASCIS) series demonstrated the potential benefits of methylprednisolone therapy and complications. The first study published in 1984 failed to demonstrate a significant difference in patient outcomes, but did demonstrate that the group randomized to methylprednisolone therapy had higher rate wound complications.21 The second NASCIS trial reevaluated the efficacy of methylprednisolone and demonstrated improved outcomes if treatment was started within 8 hours of the injury.5,22 The NASCIS III trial demonstrated improved patient outcomes when methylprednisolone therapy was initiated within 3 to 8 hours after injury and administered over 48 hours.23 However, the NASCIS III trial also demonstrated a higher rate of sepsis and pneumonia. In 2012 a Cochrane review of 6 randomized, controlled trials and several observational studies recommended the use of methylprednisolone within 8 hours of injury.6 In 2013, the American Academy of Neurosurgeons recommended against the use of methylprednisolone in acute SCI patients. However, in 2016 the AOSpine guidelines recommended the use of the methylprednisolone therapy within 8 hours of injury. Use of methylprednisolone therapy in SCI remains controversial.
The use of GM1 ganglioside has demonstrated significant improvements in neurological recovery in preclinical animal studies. GM1 is a molecule that is found in cell membranes that enhances neural plasticity and regeneration through activation of a tyrosine kinase pathway.24 In addition GM1 is also believed to reduce excitoxicity activity, and reduce neural apoptosis, enhance neural growth factors, and promote neuritic sprouting.24 In a rat model those that received GM1 ganglioside had improvements in their motor scores within 3 to 5 days of injury compared to the control group.25 In 1991, Geisler and colleagues reported the results of a phase II pilot investigating GM1 Ganglioside effect on patients with acute SCI. The results of 34 patients treated with GM1 gangioside at 1 year had significant improvement in Frankel grade from baseline and significantly improved ASIA motor scores compared with the control group.24 This study led to a phase-III multicenter trial involving 28 neurotrauma centers and recruited 797 patients to be randomized to treatment with GM1 ganglioside or placebo. Patients randomized to the GM1 gangiolside treatment group received a dose of 100 to 200 mg intravenously for a total of 56 days.26 In addition, patients in both groups received methylprednisolone within 8 hours of injury. Results of the phase III study failed to demonstrate any significant difference in patient outcomes between the placebo group and the group. The use of GM1 ganglioside has not been widely adopted since the results of the phase III trial.26
Riluzole is under investigation in the treatment of acute SCI. This medication is primarily used to treat amyotrophic lateral sclerosis, which is currently its only FDA-approved use. Riluzole works as a sodium channel blocker that is neuroprotective by reducing the amount of calcium ion influx after an axonal injury and thus decreasing the rate of apoptosis (Fig. 1).27,28 In addition, it has been shown to decrease glutamate release, prevent glutamate receptor hypofunction, and activate glutamate receptors to increase glutamate uptake.27 Preclinical studies have demonstrated its ability as a neuroprotective agent, particularly at the injury site epicenter.29 In a Phase I clinical trial performed by Wu and colleagues, rats were treated with either riluzole (8 mg/kg) at 1 hour and 3 hours after SCI or with drug vehicle. Rats initially given riluzole postinjury were treated with riluzole (6 mg/kg) every 12 hours for 7 days. The findings of the Phase I trial demonstrated an overall larger locomotor score improvement in the group treated with Rilozule 1 hour after SCI compared with the control cohort (P=0.003).30 Currently, Phase II and Phase III clinical trials are underway. In a double-blind, multicenter, placebo-controlled study, patients are being treated with 100 mg bid of riluzole in the first 24 hours followed by 50 mg bid of riluzole for the next 13 days after injury. The objective of the study is to measure neurological motor outcomes in participants assigned riluzole versus participants assigned a placebo from neurological level C4 to C8.27
Minocycline is a tetracycline antibiotic with anti-inflammatory properties that is currently being investigated as neuroprotective agent in acute SCI patients. It has demonstrated neuroprotective qualities in preclinical studies in other neurological disease such as Huntington and multiple sclerosis.31 Minocycline has been shown to inhibit tumor necrosis factor alpha, IL-1β, cyclooxygenase-2 (COX2), nitric oxide synthase, and microglial activation all of which are neuroprotective.31 Preclinical rat models evaluating minocyclines effect on SCI demonstrated a statistically significant improvement in motor function from 7 to 28 days as compared with a tetracycline control group.31 A phase II clinical trial of minocycline in acute SCI demonstrated a significant improvement in motor function scores compared with the control group.7 This difference was primarily seen in patients with cervical spine injury. A phase III clinical trial is currently underway.
Granulocyte Colony Stimulating Factor
Granulocyte colony stimulating factor (G-CSF) is an endogenous glycoprotein that promotes cell proliferation, survival, and mobilization.32 It has been shown to improve cellular survival after ischemic insult in the central nervous system (CNS). G-CSF also decreases inflammatory cytokine expression such tumor necrosis factor alpha, IL-1β. Preclinical studies have demonstrated recovery of hindlimb function and significant suppression of apoptosis.33 The first clinical trial evaluating the effect of G-CSF on acute SCI demonstrated neurological improvement of all 16 participating patients treated with G-CSF within 48 hours of injury.34 Of the 16 patients treated with G-CSF, 9 (56%) demonstrated a 1 grade increase in their AISA score.34 A second clinical trial compared the results of G-CSF with those of methylprednisolone in the NASCIS II trial.35 This study identified superior motor score improvements in the G-CSF.35
Neuroprotective Therapies in Preclinical Investigation
Several other therapies are under investigation in preclinical trials to identify their efficacy in the treatment of acute SCI. Magnesium has been demonstrated to be a neuroprotective agent through its ability to decrease excitotoxicity.2 It has been used in the treatment and prevention of several other neurological disorders such as in the prevention of seizures secondary to eclampsia during pregnancy. Preclinical studies evaluating magnesium in SCI have demonstrated enhanced tissues sparing and behavioral recovery.2 Fibroblast growth factor has also been evaluated in preclinical studies to treat SCI. Fibroblast growth factor decreases oxygen-free radicals and neuronal excitotoxicty.2 Animal models have demonstrated reduced motor neuron loss and improved respiratory deficits.2 Additional studies have evaluated the effect of hepatocyte growth factor in the treatment of SCI in animal models. Hepatocyte growth factor improves neuron survival and decreases apoptosis of oligodendrocytes resulting in improved outcomes.2 A primate cervical spine injury model demonstrated enhanced angiogenesis and upper limb recovery.2
It is important to recognize current investigations into neuroregenerative agents. Most current agents used in the treatment of acute SCI listed above are neuroprotective; however, there are several studies evaluating medications to promote neuronal proliferation. Inhibition of the Rho-ROCK pathway is the target of many neuroregenerative agents. The Rho-ROCK pathway is a signaling pathway that produces inhibitory signals that block neuron regeneration (Fig. 2).2,36 Neuron regeneration in the CNS is limited secondary to the presence of myelin-associated growth inhibitors such as Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein.36 The blockade of the Rho-ROCK pathway inhibits the actions of these myelin-associated axon growth inhibitors thus promoting regeneration.36 An example of treatments that target the Rho-Rock pathway is BA-210 (Cethrin), which is a direct RHO inhibitor that is applied as a fibrin glue sealant intraoperatively to the epidural space. In phase I and phase II trials testing Cethrin as a direct Rho inhibitor, 48 patients with acute, complete SCI of the thoracic (32) or cervical (16) region of the spine were enrolled. Each patient was scheduled to undergo surgery within 7 days of injury and placed into one of 5 dosing groups; 0.3, 1, 3, 6, and 9 mg. The study demonstrated an increase in ASIA motor scores in cervical SCI patients 12 months postop when treated with Cethrin. The greatest average improvement in ASIA score was 21.3 and 27.3 in the 1 and 3 mg dosing groups, respectively. These results prompted a phase III trial that was recently stopped due to futility.37,38 Another potential target to improve neuronal recovery after SCI is the utilization of an antibody to Nogo-A, which inhibits myelin growth. Anti-Nogo-A is a monoclonal antibody that targets Nogo-A. In an animal model of stroke, adult rats were administered 250 μg of anti-Nogo-A versus anti-IgG (control) after suffering a white matter injury. Rats who were administered 250 μg of anti-Nogo-A had significantly higher tract integrity, axonal sprouting, and functional recovery.38 Clinical trials have not yet begun investigating anti-Nogo.
In addition to therapies that target the Rho-ROCK pathway, there are many investigations into stem cell and cellular-based therapies for the treatment of acute and chronic SCI. Such investigations include the use of mesenchymal stem cells, Schwann cells, and olfactory ensheathing cells. Schwann cells are a major factor in neuron regeneration in the peripheral nervous system. The transplantation of Schwann cells into the CNS in animal models demonstrated remyelination axons, reduced cystic cavitation, and enhanced recover. Olfactory ensheathing cells protect olfactory neurons from the harsh conditions of the nasal mucosa. They have been studied in patients with chronic SCI numerous times and in animal models. The results of several animal models have demonstrated neurite outgrowth and endogenous remyelination that promoted substantial behavioral improvement. Clinical trials have failed to demonstrate efficacy in humans. Mesenchymal stem cells are multipotent cells capable of differentiating into myocytes, osteoblasts, chondrocytes, and adipocytes. Several studies have investigated their ability to treat acute SCI both as a regenerative and a neuroprotective agent. Clinical trials of mesenchymal stem cells have demonstrated significant heterogeneity and have failed to demonstrate a significant difference.
Acute SCI is a devastating and life altering event for patients and their families. It results in longstanding functional limitation and significant societal cost. The mainstay of treatment of SCI remains early surgical intervention. At this point in time, the medical and pharmacologic management SCI treatment remains relatively controversial. Currently the most substantial and agreed upon recommendation is to avoid hypotension in patients with acute SCI. There is some consensus supporting the use of methylprednisolone with 8 hours of injury, however, this remains an area of debate. Ongoing clinical investigations into pharmacologic and cellular based therapies will continue to dominate the clinical landscape for the foreseeable future.
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