Spinal cord injuries represent one of the most survivable, yet disabling injuries known to man. An estimated 10,000 North American people are injured in the spinal cord each year, most of whom are younger than 30 years of age.1 The personal and psychological costs to these individuals, who are often otherwise healthy and in the most productive years of their lives, are incalculable. Over a decade ago, the estimated costs associated with the medical, surgical, and rehabilitative care of spinal cord injured patients exceeded $4 billion per annum, a figure that is undoubtedly much higher today.2 Tremendous effort and resources have been expended to develop therapeutic strategies to improve the neurologic function of paralyzed individuals, and many promising experimental treatments are emerging from basic science research in this area.
The annual incidence of spinal cord injury in the United States is estimated to be 40 to 50 per million people (or approximately 10,000 per year).1,3 This figure does not include what is estimated to be a comparable number of victims of spinal cord injury who die at the scene of the accident or upon arrival at the hospital.4 Motor vehicle accidents constitute the most common etiology of spinal cord injuries, followed by acts of violence, falls, and sporting injuries. Male patients outnumber females by a ratio of approximately 4:1. The mean age of individuals who suffer a spinal cord injury is 35.3 years, although nearly two-thirds of these cases occur in individuals younger than 30.3 In the United States, estimates of the prevalence of spinal cord injury indicate that between 183,000 to 230,000 individuals live with spinal cord paralysis, representing a large population of chronically injured individuals.
Improvements in the initial triage, resuscitation, and clinical management of spinal cord injured patients are likely responsible for a decreasing proportion of individuals with complete paraplegia. Currently, approximately 45% of spinal cord injured patients have a complete injury, while four decades ago, this number was approximately two-thirds.5 Patients with suspected spinal injuries must be carefully immobilized in the field and transported rapidly to a hospital facility where resuscitation measures in adherance to the advanced trauma life support (ATLS) protocols are initiated. Acute life-threatening chest and abdominal injuries must be identified and addressed. Airway management with strict control of the cervical spine, maintenance of vascular perfusion with aggressive volume repletion, careful log-rolling and transport, a thorough neurologic examination, and comprehensive radiographic imaging of the spinal axis are important aspects of the ATLS protocol that have particular relevance to spinal cord injured patients. Microvascular hypoperfusion and ischemia are considered significant contributors to the acute pathophysiology of spinal cord injury.6 Spinal cord injured patients should receive supplemental oxygen to maximize their oxygen saturation, and it has been proposed that mean arterial pressure be maintained at or above 90 mm Hg.7
Neurogenic shock is a unique hemodynamic alteration in patients with spinal cord injuries who have their sympathetic outflow disrupted in addition to the interruption of the motor and sensory pathways. The loss of sympathetic tone to the heart and peripheral vasculature leads to bradycardia and hypotension. In the setting of hypotension after spinal cord injury, particularly in multi-trauma patients, one must first consider other conditions that may cause hypovolemic shock (eg, chest and abdominal injuries) and treat these with aggressive fluid resuscitation. Treatment of neurogenic shock includes judicious intravenous fluids, Trendelenburg positioning, vasopressors such as dopamine to increase systemic resistance, and atropine to increase heart rate.
Methylprednisolone is currently the only accepted pharmacologic agent for the acute treatment of spinal cord injury. The use of methylprednisolone was popularized by the large North American Spinal Cord Injury Studies (NASCIS) performed in the 1980s and 1990s. The results of NASCIS II found significant motor and sensory improvement in patients who were treated within 8 hours of injury with a methylprednisolone bolus of 30 mg/kg, followed by an infusion of 5.4 mg/kg per hour for 24 hours.8 The results of NASCIS III proposed that patients in whom the 30 mg/kg bolus was initiated within 3 hours receive the 5.4 mg/kg per hour infusion for 24 hours, while in patients in whom the bolus was started within 3 to 8 hours receive the infusion for 48 hours.9 Most centers in North America adhere to these protocols, although a number of authors have questioned the validity and interpretation of NASCIS II and III,10-12 leading to an extensively debated and as yet unresolved controversy over the use of high dose steroids in acute spinal cord injury. Some Canadian centers have discontinued the use of methylprednisolone after spinal cord injury,13 but despite questions over the true efficacy of this agent, the medicolegal atmosphere facing physicians (particularly in the United States) will likely lead to its continued use until a more effective alternative is found.
The characterization of neurologic injury for patients with spinal cord injuries is performed by motor and sensory evaluation and by deep tendon and spinal cord reflexes. Initially, a patient may be in spinal shock, which refers to the absence of spinal reflexes below a cord injury and is manifested by the loss of the bulbocavernosus reflex. The cause of spinal shock is somewhat undefined, and its end is heralded by the return of the bulbocavernosus reflex. Until a patient emerges from spinal shock (usually within 24 to 48 hours), it is not possible to truly characterize the severity and prognosticate neurologic recovery after spinal cord injury.
Most centers quantify a patient’s neurologic deficit according to the standards described by the American Spinal Injury Association (ASIA). The scoring scheme is shown in Slide 1. In summary, key motor groups in the upper and lower extremity are tested and graded according to the Medical Research Council scale of muscle strength (0-5), and a total motor score out of 100 is achieved. Light touch and pinprick sensation is evaluated throughout all dermatomes, leading to a sensory score for each out of 112. Important elements of the ASIA assessment are the evaluation of perianal sensation and voluntary anal sphincter contraction and sensation because these have significant prognostic implications. Patients are graded ASIA A to E based on this examination (Table 1). Generally, the amount of motor recovery achieved is worse for ASIA A injuries and best for ASIA C injuries. Patients with ASIA B injuries are most variable in their recovery, while the amount of motor recovery achieved by ASIA D injuries is limited by ceiling effects (they often improve to "normal", but this improvement is often minimal).
Table 1. The American Spinal Injury Association Grades of Spinal Cord Injury (From the International Standards for Neurological Classification of Spinal Cord Injury, 2000)
| || |
|A (Complete) ||No motor or sensory function preserved in the sacral segments S4-S5|
|B (Incomplete) ||Sensory but not motor function is preserved below the neurologic level* and includes the sacral segments S4-S5|
|C (Incomplete) ||Motor function is preserved below the neurologic level and more than half of the key muscles below the neurologic level have a muscle grade less than 3 (Grades 0-2)|
|D (Incomplete) ||Motor function is preserved below the neurologic level and at least half of the key muscles below the neurologic level have a muscle grade greater than or equal to 3|
|E (Normal) ||Sensory and motor function are normal|
|* For example, patients are often described as being a "C6 quadriplegic." This refers to the "neurologic level" of injury, which, according to the ASIA standards, is the most caudal segment of the spinal cord with normal sensory and motor function on both sides of the body. Normal motor function, in this context, is defined as having a grade of at least 3, as long as the key rostral muscles are judged to have full strength of 5. Technically speaking, a motor level and sensory level can be defined for both sides of the body.|
Spinal Cord Injury Syndromes
The patterns of neurologic deficits sustained by patients with incomplete spinal cord injuries can often be characterized into certain syndromes, reflecting the parts of the spinal cord that sustain the most damage given the particular osteoligamentous injury.
Probably the most common incomplete spinal cord injury syndrome is central cord syndrome. Central cord syndrome often occurs as a result of a pinching of the spinal cord in elderly patients who have a narrowed spinal canal as the result of degenerative spondylosis. It is a pattern of disproportionately severe upper extremity motor and sensory changes as compared to lower extremity findings. The term central cord comes from observations that the central part of the cord is most damaged. The neurologic findings of upper versus lower extremity weakness has been explained by the damage to the more centrally positioned corticospinal axons targeting the upper extremity compared to the sparing of the more peripherally positioned axons targeting the lower extremity. This theory of the somatotopic organization of corticospinal fibers has, however, been refuted, and it may simply be that the upper extremity dysfunction in central cord patients reflects the greater involvement of the corticospinal tract in upper extremity innervation compared to the lower extremity.14
Other syndromes include anterior cord syndrome, which produces variable loss of motor function and pain and temperature sensation but spares the posterior columns, leaving proprioception intact. Posterior cord syndrome is somewhat the opposite, with the posterior columns most affected.
Brown-Sequard syndrome results from a unilateral spinal cord lesion, causing ipsilateral motor weakness and proprioceptive loss, and contralateral pain and temperature sensory loss.
At the thoracolumbar junction, injuries can affect the caudal tip of the spinal cord where innervation to the bowel and bladder emerges. This conus medullaris syndrome can cause extremely disabling problems with bowel and bladder incontinence, despite leaving fairly intact lower extremity motor function. Conus medullaris syndrome can be difficult to distinguish initially from cauda equina syndrome. Many unstable injuries at the thoracolumbar junction injure a combination of the spinal cord (conus) and peripheral roots (cauda equina), thus creating a mixed neurologic picture of upper and lower motor neuron dysfunction.
A discussion of the various surgical options for stabilizing the spinal column is beyond the scope of this tutorial, as fractures and dislocations of the cervical and thoracic spine are covered elsewhere. The primary role of surgical management in the spinal cord-injured patient is mainly focused on stabilization of the spinal column. The role of operatively decompressing the neural elements is less well defined. In the setting of a compressed spinal cord, decompressing the neural elements and rigidly stabilizing the spine to prevent further displacement provide for the optimal environment for neurologic recovery. In patients with incomplete spinal cord injuries, such decompression significantly improves distal neurologic function.15
The return of meaningful neurologic function for patients with complete spinal cord injuries, however, is far less likely.16 One of the unresolved controversies in the surgical management of spinal cord-injured patients is the timing with which decompression and stabilization should be performed. One would assume that the earlier the neural elements are decompressed, the more likely it would be for neurologic recovery to occur. A host of animal literature supports such a contention but proving this in the human setting has been challenging.
A number of studies that have observed the neurologic recovery after an early versus a late decompression have not been able to show an improvement in neurologic function with early decompression.17-19 To more definitively address this question, the Surgical Treatment for Acute Spinal Cord Injury Study (STASCIS) group was formed in 1992, and a large-scale prospective, randomized, controlled trial of early (less than 12 hours) versus late (more than 24 hours) has been initiated. This study will evaluate both complete and incomplete spinal cord injured-patients with magnetic resonance image or computed tomography myelographic evidence of cord compression after a cervical or thoracolumbar injury, and is expected to be completed within the next 5 years.
Spinal Cord Regeneration Strategies
The permanent devastation of a spinal cord injury has prompted tremendous efforts to develop therapies that will enhance neurologic function. As a reflection of the interest in this endeavour, in 2000 the National Institutes of Health and private donations funded approximately $100 million of spinal cord research and American investigators published more than 500 articles on the topic.20 Strategies to improve the neurologic function of patients with spinal cord injuries can be broadly divided into those that provide neuroprotection, and those that promote axonal regeneration and spinal cord plasticity.
The concept of neuroprotection is based on the knowledge that at the moment of injury, the spinal cord sustains an impact that only partially destroys the local parenchyma (the primary injury). This is then rapidly followed by a host of pathophysiologic events, including alterations in vascular perfusion, loss of membrane homeostasis, free radical release and oxidative stress, inflammation, and apoptotic (programmed) cell death.21 This secondary injury is thought to claim the surrounding spinal cord tissue that escapes the initial impact. Attenuating these pathophysiologic processes is hoped to minimize further damage to the spinal cord and thus optimize neurologic function.
The only widely accepted neuroprotective agent is methylprednisolone and, as described above, some controversy surrounds its efficacy. Corticosteroids are thought to act on a number of pathways to potentially reduce secondary spinal cord damage (Table 2). GM1-ganglioside is another neuroprotective agent that was recently studied in a large-scale prospective human clinical trial. Although it was not found to significantly improve motor and sensory function over placebo, in a post hoc analysis GM1-ganglioside appeared beneficial in patients with incomplete spinal cord injuries.22 Because the primary outcome of this study was negative, GM-1 ganglioside did not achieve US Food and Drug Administration approval.
Table 2. Potential Mechanisms of Action of Corticosteroids after Spinal Cord Injury
|Inhibition of lipid peroxidation|
|Improved microvascular perfusion|
|Prevention of calcium influx into cells|
|Suppression of pro-inflammatory cytokine expression|
|Attenuation of the effects of inflammatory cytokines|
|Inhibition of nitric oxide production|
|Inhibition of apoptosis|
Other neuroprotective pharmacologic agents that have been evaluated in human studies include tirilazad (a lipid peroxidation inhibitor), nimodipine (calcium channel blocker), naloxone (opioid antagonist), and gacyclidine (an N-methyl-D-aspartate receptor antagonist). The rationale for the use of these agents has come from promising results in animal models of spinal cord injury, in which their inhibition of specific pathophysiologic processes has resulted in favorable neurologic outcomes. The results in human trials have been universally less promising.
Other neuroprotective agents, some that are in common clinical use for other contexts, are now emerging. Such drugs include cyclooxygenase (COX) inhibitors, minocycline, and erythropoietin. While the current debate about whether the incremental neurologic benefits accrued by methylprednisolone are clinically (or even statistically) significant, the controversy has pointed to the need for better, more obviously efficacious neuroprotective strategies.
Axonal Regeneration Strategies
The permanence of paralysis after spinal cord injury is a reflection of the paucity of axonal regeneration that occurs after central nervous system (CNS) injury. Conversely, the regenerative properties of the peripheral nervous system are apparent, and the ability of peripheral nerves to regenerate axons is recognized in the clinical practice of repairing completely transected peripheral nerves. So why does similar axonal growth not occur in the injured CNS? Conceptually, this failure of axonal growth is related to both the poor intrinsic capacity of neurons within the CNS to regenerate injured axons and to the biomolecular environment within the CNS that is inhibitory to axonal growth.23 Strategies to promote axonal regeneration attempt to address these issues. Neurotrophic factors, for example, promote cell survival and axonal growth. The list of trophic factors with potential therapeutic benefit is long and includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF).
Scientists are utilizing gene therapy strategies to create cells capable of secreting large quantities of such trophic factors after being transplanted into the injured spinal cord.24 After the initial injury, the spinal cord injury site typically matures into a glial scar-lined cystic cavity. The glial scar and the injured CNS myelin possess numerous molecules that are inhibitory to axonal growth. For example, chondroitin sulfate proteoglycans are thought to be an important inhibitory component of the glial scar. Treating the spinal cord with an enzyme to degrade this (chondroitinase ABC) has been shown in animal models to promote axonal regeneration and functional recovery.25,26 Similarly, antibodies that block specific myelin proteins that are inhibitory to axonal growth promote axonal regeneration and functional recovery in animal models.27
Much interest has also been directed at cellular transplantation strategies to provide a bridge for axons to grow across the spinal cord injury site. Candidates for such cellular transplantation therapies include Schwann cells, olfactory ensheathing cells, embryonic stem cells, and fetal spinal cord tissue segments. Fetal spinal cord tissue transplants have been performed in humans with syringomyelia. Recent reports from a small cohort of patients suggest that this procedure is safe, but little neurologic recovery was seen.
Spinal cord injuries frequently cause devastating paralysis in young, otherwise healthy individuals. The clinical treatment begins with careful immobilization and transport from the field, followed by aggressive hemodynamic resuscitation upon arrival at an emergency facility. Such measures are probably responsible for the improved neurologic function in spinal cord-injured patients today compared to 40 years ago. The entire spinal axis must be carefully examined. Surgery may be necessary for mechanical stabilization and for the decompression of neural elements. Much research is underway to develop more effective neuroprotective agents to minimize secondary spinal cord damage and to find ways of promoting axonal regeneration across the injury site.
- Nobunaga AI, Go BK, Karunas RB. Recent demographic and injury trends in people served by the Model Spinal Cord Injury Care Systems. Arch Phys Med Rehabil. 1999; 80:1372-1382.
- Stripling T. The cost of economic consequences of traumatic spinal cord injury. Paraplegia News. 1990; 8:50-54.
- Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine. 2001; 26(24 Suppl):S2-12.
- Kraus JF, Franti CE, Riggins RS, Richards D, Borhani NO. Incidence of traumatic spinal cord lesions. J Chronic Dis. 1975; 28:471-492.
- Tator CH, Duncan EG, Edmonds VE, Lapczak LI, Andrews DF. Changes in epidemiology of acute spinal cord injury from 1947 to 1981. Surg Neurol. 1993; 40:207-215.
- Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 1991; 75:15-26.
- Levi L, Wolf A, Belzberg H. Hemodynamic parameters in patients with acute cervical cord trauma: Description, intervention, and prediction of outcome. Neurosurgery. 1993; 33:1007-1016.
- Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990; 322:1405-1411.
- Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA. 1997; 277:1597-1604.
- Hurlbert RJ. Methylprednisolone for acute spinal cord injury: An inappropriate standard of care. J Neurosurg. 2000; 93(1 Suppl):1-7.
- Coleman WP, Benzel D, Cahill DW, Ducker T, Geisler F, Green B, et al. A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury. J Spinal Disord. 2000; 13:185-199.
- Short DJ, El Masry WS, Jones PW. High dose methylprednisolone in the management of acute spinal cord injury — a systematic review from a clinical perspective. Spinal Cord. 2000; 38:273-286.
- Hurlbert RJ. The role of steroids in acute spinal cord injury: An evidence-based analysis. Spine. 2001; 26(24 Suppl):S39-S46.
- Levi AD, Tator CH, Bunge RP. Clinical syndromes associated with disproportionate weakness of the upper versus the lower extremities after cervical spinal cord injury. Neurosurgery. 1996; 38:179-183.
- Bohlman HH, Anderson PA. Anterior decompression and arthrodesis of the cervical spine: Long-term motor improvement. Part I: Improvement in incomplete traumatic quadriparesis. J Bone Joint Surg Am. 1992; 74:671-682.
- Anderson PA, Bohlman HH. Anterior decompression and arthrodesis of the cervical spine: Long-term motor improvement. Part II: Improvement in complete traumatic quadriplegia. J Bone Joint Surg Am. 1992; 74:683-692.
- Fehlings MG, Tator CH. An evidence-based review of decompressive surgery in acute spinal cord injury: Rationale, indications, and timing based on experimental and clinical studies. J Neurosurg. 1999; 91(1 Suppl):1-11.
- Vale FL, Burns J, Jackson AB, Hadley MN. Combined medical and surgical treatment after acute spinal cord injury: Results of a prospective pilot study to assess the merits of aggressive medical resuscitation and blood pressure management. J Neurosurg. 1997; 87:239-246.
- Vaccaro AR, Daugherty RJ, Sheehan TP, Dante SJ, Cotler JM, Balderston RA, et al. Neurologic outcome of early versus late surgery for cervical spinal cord injury. Spine. 1997; 22:2609-2613.
- Young W. A cost analysis of spinal cord injury research. Available at: http://carecure.edu/spinewire/Articles/SCIResearchCost.html.
- Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, et al. Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clin Neuropharmacol. 2001; 24:254-264.
- Geisler FH, Coleman WP, Grieco G, Poonian D. The Sygen multicenter acute spinal cord injury study. Spine. 2001; 26(24 Suppl):S87-S98.
- Horner PJ, Gage FH. Regenerating the damaged central nervous system. Nature. 2000; 407:963-970.
- Jones LL, Oudega M, Bunge MB, Tuszynski MH. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol. 2001; 533:83-89.
- Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002; 416:636-640.
- Moon LD, Asher RA, Rhodes KE, Fawcett JW. Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci. 2001; 4:465-466.
- Bregman BS, Kunkel-Bagden E, Schnell L, Dai HN, Gao D, Schwab ME. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature. 1995; 378:498-501.