Introduction
Traumatic spinal cord injury (SCI) is a potentially devastating event for individuals. Given the vast impact of SCI on individuals and society combined with the economic burden, it is clear that effective therapies are urgently needed. Because current treatment options are limited and provide either negative or modest effects, the development of new strategies to treat SCI are required.
A comprehensive understanding of SCI pathophysiology can lead to potentially promising treatment modalities. The current concepts of the injury pathophysiology indicate that the primary insult, typically caused by rapid spinal cord contusion with subsequent compression, can initiate a signaling cascade of neural damage and hypoxic sequelae known as the secondary injury. Preventing these secondary mechanisms offers the opportunity for neuroprotection and potentially supports reduced tissue destruction and improved neurological outcomes after initial spinal cord trauma.
A growing number of neuroprotective therapies have established some promise in preclinical experimental models. Concurrently, a rapid evolution of stem cell biology and application to treat SCI is occurring. Many of these experimental therapeutic strategies over the past 30 years have reached the point of translation into human evaluation and some have already gone into clinical trials. Despite their passage into clinical trials, evaluating the efficacy of suggested therapeutic strategies is still extremely challenging. The overall complexity is based on the infrequent nature of these injuries, heterogeneous clinical presentation, and the difficulty with classification and categorization of injuries.
In this chapter, we will focus on the pathophysiology of SCI and describe the most studied neuroprotective, neuroregenerative, and cell-based therapies used in SCI trials. Additionally, we will briefly review the current body of preclinical literature that might support the translation into human clinical trials.
Spinal Cord Injury Epidemiology: Demographics and Baseline Features
Data indicate that traumatic SCI is mostly prevalent among males aged 18 to 32 years and in developed countries, highly influenced by aging and elderly populations. Global estimates conducted in 2007 report that approximately 133,000 and 226,000 incident cases of traumatic SCI occurred as a result of accidents and self-inflicted harm, respectively. Gaining insight into the incidence and prevalence rates of SCI is crucial because of the large effect such an injury has on personal resources and the health care industry. Furthermore, the frequency of injury implies the necessity of enhanced prevention.
Published reports of SCI incidence within the United States describe 25 to 40 new cases per million each year. Estimates reveal that SCI-related costs in the United States are about $9.7 million per year. A multicenter, prospective study determined the spectrum, incidence, and severity of complications during initial hospitalization of patients with SCI and found that 79% of the patients included were male and of an average age of 44.6 years (range, 18 to 87 years). Additionally, 25% of patients were 29 years or younger and 25% were older than 57 years. Finally, the primary etiologies included falls (37%), motor vehicle accidents (28%), and sports or recreation (14%). Of all injuries, 4% were caused by penetrating injuries. Among persons involved in a review supplemented by inception cohort study, data found that the mean age of injury increased from 28.3 years during the 1970s to 37.1 years between 2005 and 2008 and directly reflects the overall increasing median age of the general U.S. population.
A literature survey aimed at revealing data about the incidence, prevalence, and epidemiology of SCI concluded that the young, male patients were more likely paraplegic, complete or incomplete. A review reported that 55.7% of new injuries enrolled in a combined U.S. data set since 2000 were injuries to the cervical spinal cord and that this percentage increased from 50.7% in the 1970s. The increase in cervical injuries is directly influenced by higher rates in C1-C4 lesions, 12.3% to 27.2%, and to a doubling in the percentage of patients being discharged as ventilator dependent: 1.5% in the 1970s to 5.4% between 2000 and 2004. The above-mentioned multicenter study indicated that of the participants recorded, the levels of injury were 78% for cervical, 18% for thoracic, and 4% for lumbar/sacral, and 1% were SCI without radiographic abnormality (SCIWORA).
The preliminary neurological assessment on admission indicated a bimodal distribution of the American Spinal Injury Association (ASIA) grade of severity of neurological injury so that the incidence of grade A was 40% and that of grade D was 29%. Not surprisingly, the severity of the injury is directly in proportion to a higher incidence of complications. Specifically, of the 126 patients with ASIA grade A, 106 (84.1%) incurred complications. While an extensive amount of effort is focused on the prevention and treatment of acute events that are most ubiquitous among SCI populations, complications still arise. These include pneumonia, deep venous thrombosis (DVT), pleural effusion, severe bradycardia, shock, cardiac arrest, respiratory failure, septicemia, pulmonary embolus, and external events. In particular, half of all complications occur within the first week of hospitalization and three-fourths within 2 weeks. Since the 1970s, a remarkable amount of advancement has been achieved toward significantly diminishing the mortality rate during the first year after SCI. Information relating to the gravity of particular impediments following SCI will definitely facilitate earlier recognition, effective treatment, and prevention.
The Pathophysiology of Spinal Cord Injury: Primary and Secondary Injury
In general terms, mechanical trauma to the spinal cord induces tissue necrosis and functional loss ( Fig. 31-1 ). Any neurologic damage incurred at the moment of impact is the primary injury and occurs after concussion, contusion, laceration, transection, or intraparenchymal hemorrhage. There are four characteristic mechanisms of primary injury: (1) impact plus persistent compression, (2) impact alone with transient compression, (3) distraction; and (4) laceration and transection ( Table 31-1 ). Out of those four, the most frequent mechanism of injury involves impact plus persistent compression. The central gray matter is primarily damaged after the initial mechanical insult, while the peripherally located white matter is relatively spared. Studies have suggested that irreversible damage to the gray matter transpires within the first hour after SCI, whereas the white matter is irreversibly damaged within 72 hours after SCI.
| Primary Injury Types | Characteristics | Examples |
|---|---|---|
| Impact with constant compression | Most common; compression arising from fractures or ruptures | Burst fractures with retropulsed bone fragments compressing the cord; fracture-dislocations; acute disc ruptures |
| Impact alone | May involve transient compression | Hyperextension injuries as seen in patients with degenerative cervical spine disease |
| Distraction | Forcible stretching or shearing of the spinal column | Flexion, extension, rotation, or dislocation |
| Laceration/transection | Varying degrees of injury, from minor injury to complete transection | Missile injury, sharp bone fragment dislocation, severe distraction |
Other pathophysiological events in the spinal cord that commence after the primary injury include hemorrhage, edema, disrupted microcirculation, local infarction (caused by hypoxia and ischemia), loss of autoregulation, vasospasm, neuronal damage, and disrupted nerve transmission. Together, this interdependent cascade of systemic and cellular events initiated after the primary insult is referred to as the secondary injury and may occur within minutes after SCI ( Table 31-2 ). Mechanical disruption of the microvasculature sets in motion a series of pathways and interrelated processes that inevitably contribute to cellular necrosis and apoptosis within the spinal cord. These events can be further divided into (1) neurogenic shock, (2) vascular abnormalities, (3) free radical and lipid peroxidation, (4) excitotoxicity and electrolyte imbalance, (5) necrotic and apoptotic cell death, and (6) inflammatory and immunologic responses.
| Secondary Injury Events | Characteristics |
|---|---|
| Neurogenic shock | Bradycardia, hypotension, reduced peripheral resistance, decreased cardiac output, ischemia |
| Vascular disruption | Hemorrhagic and ischemic damage, disrupted microcirculation, hemorrhagic necrosis, vasospasm |
| Free radical generation and lipid peroxidation | Free radical production, oxidative stress, oxidation of proteins, lipids and nucleic acids, inactivation of mitochondrial respiratory chain enzymes, inhibited Na + -K + ATPase, Na + channel inactivation |
| Excitotoxicity and electrolyte imbalance | Excessive release of glutamate, NMDAR and AMPAR activation, cytotoxic edema, intracellular acidosis, accumulation of intracellular Ca 2+ |
| Necrotic and apoptotic cell death | Swelling, damaged organelles, lysis, cellular shrinkage, nuclear fragmentation |
| Inflammation and immunologic response | Neutrophil accumulation, macrophage and microglia migration, demyelination, wallerian degeneration, scarring, mitochondrial damage, cytochrome c release, caspase activation |
Neurogenic shock is essentially inadequate tissue perfusion, resulting from paralysis of vasomotor input that ultimately produces deleterious disturbances of the balance between vasodilation and vasoconstriction. Clinical characteristics include bradycardia, hypotension, and decreased cardiac output. The resultant effects may result in further neurological damage if left unchecked. Vascular insults include hemorrhage and ischemia-reperfusion and are thought to be one of the most crucial features of secondary injury. Mechanical interruptions to the microvasculature, loss of microcirculation, and disrupted autoregulation produces petechial hemorrhage and intravascular thrombosis, which in combination with vasospasm of intact vessels and edema at the injury site, leads to local hypoperfusion and ischemia. Postmortem studies of human spinal cords have reported a significantly higher amount of vascular perfusion in the gray matter than in the white matter and that this difference may be due to the disruption and/or thrombosis of the sulcal arterial network that supplies the gray matter. Further exacerbating the microcircuitry injuries is the spreading of the damage beyond the initial site of injury into a wider zone of destruction. Eventually this ischemic damage spreads rostrally and caudally. Once this occurs, the amount of available oxygen decreases, anaerobic cellular respiration commences, and both lactic acid and free radicals are generated. Oxygen-derived free radicals are produced during ischemia and are comprised of unpaired electrons. These molecules include superoxide, hydroxyl radicals, nitric oxide, and peroxynitrite oxidants; are highly reactive to lipids, proteins, and DNA; and contribute to oxidative stress. Free radicals cause a progressive oxidation of fatty acids in cell membranes (lipid peroxidation) so that the oxidation process creates more free radicals to further propagate the reaction across the cellular surface. During neurotrauma, the level of oxidative stress surpasses the normal level of protective cellular antioxidant capacity and leads to a net production of reactive molecules that progressively oxidize proteins, lipids, and nucleic acids. Oxidative stress also negatively impacts significant mitochondrial respiratory chain enzymes, alters DNA and DNA-associated proteins, and inhibits sodium-potassium adenosine triphosphatase (Na + -K + ATPase) that essentially precipitates metabolic collapse and cellular apoptosis and necrosis.
While anatomically intact fiber tracts remain after SCI, there is still a loss of impulse conduction that has been attributed to modified intracellular and extracellular concentrations of key ions, biochemical derangements, and simultaneous fluid-electrolyte disturbances that inevitably lead to excitotoxicity and electrolyte imbalance . To respond to the primary and secondary injuries, excitatory neurotransmitters are released but rapidly accumulate to toxic concentrations producing additional direct damage to spinal cord tissue.
Specifically, glutamate is excessively released and quickly accumulates after SCI, activating ionotropic and metabotropic receptors such as N -methyl- d -aspartate (NMDA) and α-amino-3-hydroxyl-5-methyl-isoxazolopropionate (AMPA)/kainate receptors and inducing neuronal injury via excitotoxicity. Glutamate-mediated NMDA receptor activation promotes extracellular calcium (Ca 2+ ) and sodium (Na + ) to move down a concentration gradient into the cell, where the levels of calcium are usually very low. Changes in the intracellular concentrations of Na + and Ca 2+ create profound physiological modifications and further damage such as cytotoxic edema, intracellular acidosis, activation of lytic enzymes, free radical production, inhibition of Na + -K + ATPase activity, inactivation of membrane Na + channels, and dysregulation of mitochondrial oxidative phosphorylation. An additional consequence of electrolyte imbalance includes augmented extracellular potassium (K + ) concentration, resulting in excessive neuronal depolarization, abnormal conduction, and possibly spinal shock. Finally, magnesium depletion from intracellular stores can negatively impact glycolysis, oxidative phosphorylation, and protein synthesis.
Necrotic and apoptotic cell death transpire after SCI and are prompted by ischemia, oxidative stress, and excitotoxicity. Necrotic cell death arises after disrupted homeostatic mechanisms and leads to membrane and organelle damage, decreased adenosine triphosphate (ATP) generation, and passive cell swelling. Conversely, apoptosis occurs when specific extrinsic or intrinsic traumas activate intracellular signaling cascades, activating caspase enzymes and dismantling of the cell. Apoptosis has been shown to significantly contribute to SCI as it is found to influence neurons, oligodendrocytes, microglia, and possibly astrocytes. Neuronal apoptosis contributes to cell loss and has obvious implications on outcome after SCI. SCI-mediated neuronal apoptosis transpires extrinsically, mediated by the Fas ligand and receptor and/or inducible nitric oxide synthase production and intrinsically through direct caspase-3 proenzyme activation, mitochondrial damage, release of cytochrome c, and activation of the inducer caspase-9.
After SCI, the inflammatory process is instantly activated and continues for several days postinjury. The inflammatory and immunologic response to injury within the central nervous system (CNS) is immensely varied when compared to other tissue because of the involvement of neutrophils, macrophage, T cells, cytokines, prostaglandins, and complement. The response involves endothelial damage, the release of inflammatory mediators, changes in vascular permeability, development of edema, permeation of peripheral inflammatory cells, microglial activation, and phagocytosis of injured tissue.
The functional significance of particular key immunological cells after SCI is controversial. Numerous investigations indicated that macrophage and/or microglia have positive contributions and detrimental consequences after injury. Specifically, the activated microglia and monocytes represent the greater part of all inflammatory cells located at the injury site so that there is debate as to whether these cells help or hinder. Clearly the inflammatory response is thought to be neurotoxic and neuroprotective, the early phases being injurious and the latter being protective.
The grade of SCI is contingent on the extent of mechanical damage inflicted on the cord during the primary event but is also influenced by the secondary phase of injury. Additionally, the degrees of both primary and secondary injuries are directly influenced by the amount of energy delivered to the spinal cord at the moment of impact. The extent of secondary injuries extends radially and longitudinally along the spinal cord in a rostral-to-caudal manner. The final outcome is central gray matter cavitation with loss of adjacent white matter tracts. Numerous surgical and pharmacological strategies are now focused on stabilizing the injured cord and minimizing additional damage initiated by the secondary trauma.
Immediate Therapeutic Approaches
The treatment of SCI focuses on minimizing secondary injury. This must begin immediately. Namely, focus should be on maintaining adequate tissue perfusion and oxygenation. Hypotension following traumatic injury has been noted to result in worse outcomes compared to a more normal blood pressure. This may especially be true in patients presenting in spinal shock. There may be bradycardia, hypotension, and warm flushed extremities. Patients with cervical spinal cord injuries may present with reduced inspiratory and expiratory capacity. This may be caused by loss of accessory muscles for respiration and/or paralysis of the diaphragm. Either may result in hypoxia.
It is imperative that patients are managed in a setting where blood pressure and respiratory status may be monitored and also treated appropriately, namely an intensive care unit. Consideration should be given to early intubation, especially in those patients with high-cervical spinal cord injuries. Early treatment of blood pressure should involve fluid resuscitation followed by pressor agents if needed. The choice of the agent to use is dependent on many factors and beyond discussion in this chapter. The goal should be to maintain mean arterial blood pressure greater than 85 mm Hg and continue this goal for at least 7 days postinjury. This recommendation is based on class III literature and is reported in the Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries.
Initial Closed Reduction
The authors believe that, at times, there should be an initial attempt at closed reduction of cervical spine dislocations. At times, closed reduction is skipped and the patient taken emergently to the operating room for open reduction and fixation. Closed reduction is most often used for unilateral and bilateral facet dislocations. Reduction appears possible in more than 80% of patients. Authors have reported improved outcomes following urgent reduction; however, no class I or II data have been presented confirming these findings.
Early Decompression Surgery
The existing preclinical evidence supports that decompression surgery of the spinal cord after SCI attenuates secondary injury and improves neurological recovery. This neuroprotective effect seems to vary inversely with the time elapsed from injury to decompression and also the magnitude of compression. The impact of timing of decompression and stabilization following SCI has been difficult to establish in clinical trials. Vaccaro and colleagues published a randomized, prospective, controlled study on 64 patients with acute cervical SCI. Patients were randomized into either an early surgical decompression group (surgery performed <72 hours after SCI) or a late surgical group (surgery performed >5 days after SCI). The results showed that there was no significant benefit in terms of neurological or functional level in patients treated less than 72 hours compared to those treated more than 5 days after cervical SCI. In contrast, a systematic review by LaRosa and colleagues reported that early decompression (within 24 hours after SCI) resulted in improved outcomes compared to both delayed decompression and conservative therapy. In 2010, the Spine Trauma Study Group defined 24 hours as the cutoff to differentiate early versus late decompression surgery after SCI. Recently, a multicenter prospective cohort study was conducted on 313 patients with acute cervical SCI. Of these, 182 underwent early surgical decompression (<24 hours after injury), while the remaining 131 patients underwent late surgery (>24 hours after injury). Results demonstrated that 19.8% of patients treated with early surgery showed a grade II or higher improvement in the ASIA Impairment Scale at 6 months’ follow-up compared to 8.8% in the late decompression group.
Therapeutic Hypothermia
Numerous clinical investigations have indicated that hypothermia is an effective neuroprotective treatment, shown to decrease pathophysiological complications associated with cardiac arrest, traumatic brain injury, stroke, aortic aneurysm, and neonatal hypoxic-ischemic encephalopathy. Because of the benefits associated with this option, the potential application in SCI is now being examined. Specifically, hypothermia is known to decrease axonal swelling, lower tissue hemorrhaging and microglia accumulation, diminish oxidative stress, apoptosis, and reduce glutamate release so that SCI-induced ischemia may be treated in patients by cooling. Studies have reported that systemic (surface and intravascular) hypothermia (89.6°–93.2° F [32°–34° C]) offers the most neuroprotective benefits that overcome harmful effects often associated with subphysiological temperatures.
A retrospective analysis of 14 patients with acute cervical SCI graded as ASIA A, who received systemic hypothermia for 48 hours, found an associated conversion rate of 42.8% and specifically that 3 patients improved to ASIA grade B, 2 progressed to ASIA grade C, and 1 patient recovered to ASIA grade D. Additionally patients exhibited respiratory and infectious complications but failed to demonstrate adverse effects such as coagulopathy, DVT, and pulmonary embolism in comparison to control patients. A single case report described an NFL football player who sustained a C3-C4 fracture-dislocation, which resulted in an ASIA A SCI. The individual underwent surgical decompression, intravenous methylprednisolone therapy, and systemic hypothermia and demonstrated significant and rapid neurologic improvement within weeks of the injury. Furthermore, the patient eventually progressed to ASIA D. While the degree of contribution from hypothermia to recovery remains to be determined, these results demonstrate the need for additional preclinical and clinical investigations focused on hypothermia as a treatment for acute SCI. Recently, a meta-analysis of 16 publications sought to examine the efficacy of hypothermia on functional outcome, mean outcome, and variance and reported that regional cooling is neuroprotective when cord ischemia is present. Overall, the authors suggest great translational potential for hypothermia and recommend further clinical studies.
Pharmacological Management: Methylprednisolone Sodium Succinate
One strategy that has been explored in an acute SCI environment is the use of corticosteroids. The application of these antiinflammatory agents originated more than 30 years ago and was based on findings that application reduced spinal cord edema. The neuroprotective influences of corticosteroids include attenuated lipid peroxidation, inhibition of inflammatory cytokines, reduced calcium influx, reduced posttraumatic axonal dieback, and improved vascular perfusion. Due to the accrual of promising preclinical data in animal models of SCI, the effectiveness of the corticosteroid methylprednisolone sodium succinate (MPSS) was examined in five prospective acute SCI trials in humans.
The widespread use of MPSS in the clinical setting has been largely influenced by three large-scale prospective randomized double-blinded multicenter clinical trials reported as the North American Spinal Cord Injury Studies (NASCIS) I, II, and III. In brief, NASCIS I investigated the efficacy of 10 daily doses of either a moderate (1000 mg) or low (100 mg) dose of MPSS administered within 48 hours of SCI. Data analysis indicated that there was no significant difference in the neurological outcomes between the two groups when examined at 6 weeks, 6 months, and 1 year. Although neurological improvement showed no significant difference between the groups, wound infection, gastrointestinal (GI) hemorrhage, sepsis, pulmonary embolism, delayed wound healing, and death were all significantly higher for patients receiving the moderate dosage. NASCIS II examined the difference between a high-dose application of MPSS (initial bolus of 30 mg/kg followed by a 23-hour infusion of 5.4 mg/kg per hour), naloxone (an opioid receptor antagonist), or placebo administered within 24 hours. A post hoc analysis indicated that the group who received MPSS within 8 hours of injury demonstrated statistically significant sensory and motor recovery and that these improvements were visible at 1.5, 6, and 12 months postinjury. The NASCIS III trial examined the efficacy of high-dose MPSS application (30 mg/kg bolus) for 48 versus 24 hours. Data analysis indicated that patients had significant neurological functional recovery when they received MPSS within 3 to 8 hours and were treated for 48 hours; improvements were visible at 6 weeks and 6 months but not 1 year.
The variability of clinical efficacy, as well as complications associated with and the propensity toward adverse effects have inevitably generated a great deal of controversy surrounding the use of MPSS in SCI cases. While MPSS is currently an accepted clinical option, there is still a need for additional neuroprotective agents with improved and consistent efficacy.
Neuroprotective and Neuroregenerative Approaches to Treating the Injured Spinal Cord
Current medical and surgical interventions are currently focused on minimizing the extent of secondary injury and protecting the neural components that survived the primary mechanical injury. For example, postmortem studies of patients diagnosed as having “complete” injuries have indicated that the cord is rarely completely transected after blunt injuries. While it is not known how much is remaining, intact spinal cord is needed to mediate significant distal neurologic function; data suggest that minimal motor function has been demonstrated in an incompletely paralyzed patient with around 7% of the normal number of axons below the level of injury. Therefore, there is great potential in the idea that some progress toward neuroprotection and preservation after SCI may somehow significantly impact functionally relevant neurological recovery.
Monosialotetrahexosylganglioside
Gangliosides are sialic acid-containing glycosphingolipids that are abundant in the outer surface of neuronal membranes. A number of experimental CNS injury studies indicated that the systemic administration of monosialotetrahexosylganglioside (GM-1) resulted in neuroprotective effects that included neural repair, functional recovery, inhibition of excitotoxicity, and prevention of apoptosis. A single-center prospective double-blinded randomized trial of SCI patients administered 100 mg of intramuscular GM-1 for 30 days reported statistically significant improvement in ASIA motor score for the treatment group. These positive results prompted a prospective clinical trial that randomized 797 patients into placebo, low-dose GM-1 (300 mg loading dose, followed by 100 mg/day for 56 days) or high-dose GM-1 (600 mg loading dose, followed with 200 mg/day for 56 days). Data indicated that the experimental group did not demonstrate statistically significant recovery at 26 weeks but analysis did suggest a trend toward improved motor and sensory scores and augmented bowel and bladder function. These improvements were especially evident in patients with incomplete spinal cord injuries and suggest that there may be a potential benefit for subjects living with incomplete paraplegia.
Minocycline
Minocycline is a tetracycline family derivative that is often employed in the treatment of acne and rosacea and has been demonstrated as being neuroprotective in animal models of stroke, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Additionally, a multitude of studies have shown that minocycline lessens secondary injury and supports functional recovery in animal models of SCI. The range of activities include inhibition of microglial activation and proliferation, decreased excitotoxicity, stabilization of mitochondria, reduced apoptosis, neutralization of free oxygen radicals, inhibition of nitric oxide synthase, decreased inflammation, and Ca 2+ chelation.
Taking the preclinical findings into consideration, a phase II placebo-controlled randomized trial of minocycline in acute SCI was conducted. In brief, patients who presented within 12 hours in injury were stratified into three groups according to their severity, and were given intravenous administration of minocycline for 7 days. Data analysis indicates that patients treated with minocycline demonstrated 6 points greater motor recovery than the placebo group but that no difference was evident for thoracic SCI. A change of 14 motor points was detected in patients with cervical injury and with cervical motor-incomplete injuries; results approached significance.
While the clinical data do not report statistically significant results, improvements in motor output suggest a potential therapeutic advantage. Furthermore, minocycline possesses pharmacological and mechanistic promise that supports additional efficacy investigations.
Cethrin
Rho guanosine triphosphatase (GTPase) is one of five members of the Ras superfamily that primarily functions as a molecular modulator of signal transduction pathways in eukaryotic cells. In general, the Rho family regulates numerous actin-mediated processes that include morphogenesis, endocytosis, phagocytosis, and motility. Within the nervous system, Rho family members are essential components of axonal growth and guidance. Rho activation mediates neuronal responses to repulsive cues, induces growth cone collapse and neurite retraction so that inhibition of Rho support axonal growth. Experimental investigations have indicated that Rho activity is increased following SCI in neurons, astrocytes, and oligodendrocytes and suggests that Rho signaling influences SCI pathophysiology such as neuronal apoptosis and glial plasticity. Because Rho is involved in an inhibitory signaling cascade that supports growth cone collapse and inhibition of neurite and axonal outgrowth, discovering a pharmacological means to inhibit Rho activation may prevent the downregulation of axon regeneration.
A phase I/II clinical trial compared the effectiveness of a single dose (0.3, 1, 3, 6, and 9 mg) of Cethrin on neurological improvement in patients with thoracic and cervical SCI. Patients received Cethrin within 1 week of injury during a decompression surgery and delivery was as follows: Cethrin was combined with a fibrin sealant and directly applied to the dura mater at the injury site. Data indicated that 66% of patients with cervical SCI, who received a dose of 3 mg, improved from ASIA grade A to ASIA grade C or D and that only 6% of those with thoracic SCI demonstrated similar recovery. These encouraging findings support the use of Cethrin as a safe and effective means to promote functional recovery after SCI.
Autologous Macrophage
Activated autologous macrophage was the first cellular substrate transplanted into patients after SCI. This study was based on an early animal model of SCI whereby the ex vivo activation of autologous macrophage, injected into the injured spinal cord, promoted the functional recovery and augmented the synthesis of beneficial trophic factors. An early clinical trial enrolled eight patients with complete SCI and transplanted the macrophage within 14 days of injury. The investigation reported improvement from ASIA grade A to ASIA grade C in 3 of 8 patients. A phase II randomized controlled multicenter trial expanded this study to 43 patients with either cervical or thoracic SCI and did not reveal statistically significant functional recovery between the two groups. Therefore, the data indicate that the application of autologous incubated macrophage to the injured spinal cord was not an effective therapeutic option.
Riluzole
An extensive array of data has demonstrated that voltage-gated sodium channels become constitutively activated during the secondary injury cascade. Amplified intracellular sodium (Na + ) levels induce cellular swelling, intracellular acidosis, increased calcium influx, and glutamate excitotoxicity. To target the neuronal ionic imbalance, pharmacological therapies have focused on inhibiting Na + channel activation. By using various Na + channel antagonists, preclinical studies have displayed neural tissue preservation and behavioral improvement following SCI.
Of particular interest to both preclinical and clinical SCI studies is riluzole, a neuroprotective agent approved for the treatment of ALS patients. Experimental investigations have indicated that riluzole-treated animals exhibit significant tissue preservation and improved neurobehavioral outcomes when compared to control animals. The promising preclinical data coupled with the clinical efficacy of ALS treatment has prompted a prospective, multicenter phase I trial by the North American Clinical Trials Network (NACTN) to establish the pharmacokinetics and safety of riluzole treatment on acute SCI. The trial enrolled 36 patients (ASIA grades A through C) and was designed as a single-arm, open-labeled, matched comparison study that had an end point follow-up set to 6 months with neurological, functional, and pain assessments continued out to 12 months postinjury. In brief, patients received their first dose of riluzole (50 mg) within 12 hours of injury and were administered treatment every 12 hours for 2 weeks. Data indicate that the most significant mean motor score improvements were present in grade B patients. Additionally, pinprick scores were 10 points higher for riluzole-treated patients compared to registry participants. While the pilot data suggest a beneficial trend on motor function, additionally studies (phase II trial) are needed to completely define neurological outcomes.
Improving Axonal Conduction in the Injured Spinal Cord
Fampridine
A traditional viewpoint of myelin is that it plays a significant role in signal transduction so that any mechanical insult likely decreases conduction velocity. Following SCI, although some nerve fibers remain uninterrupted across the injury, there is an overall redistribution of sodium (Na + ) and potassium (K + ) channels across the axon caused by myelin disruption. Reports indicate that 6 to 8 weeks following SCI, voltage-gated K + channels demonstrate altered distribution on axons following demyelination. Specifically, rapidly activating K + channels that were once obscured by myelin show increased activity, drive the membrane potential close to the K + equilibrium potential, and support blockade of axonal conduction.
To inhibit the exposed fast K + channels on demyelinated axons, researchers have used 4-aminopyridine (4-AP) to promote the facilitation of axonal conduction, broaden action potentials, and augment synaptic transmission. Laboratory investigations have shown that 4-AP treatment improves conduction in rat spinal nerve roots, supports conduction in demyelinated rat sciatic nerves, and promotes functional motor behavior in a chronic SCI model. Together these studies demonstrate that 4-AP application not only suppresses fast-acting K + channels but also improves conduction along demyelinated axons after SCI.
The success of the in vitro studies prompted investigators to determine if 4-AP enhances motor function and sensation in the clinical setting after injury. An early clinical trial examining the efficacy of 4-AP in chronic SCI patients revealed neurological improvements that included increased motor control and sensory ability and reduced chronic pain and spasticity after application. These advancements lasted 48 hours postinfusion and prompted studies aimed at using sustained release 4-AP. An oral fampridine-SR (sustained release 4-AP) exploratory trial demonstrated that treating patients with incomplete SCI resulted in improved sensory scores, augmented motor function, and decreased spasticity. While variations in the amount and frequency of fampridine delivery have generated additional clinical studies, data suggest that patients receiving drug treatment demonstrate functional improvement.
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