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Pathophysiology and Early Management of Spinal Cord Injury


Introduction

Traumatic spinal cord injury (SCI) is a devastating neurologic entity and a life-altering event. SCI affects approximately 1.4 million North Americans, with a disproportionate number of patients who are younger than 30 years of age. Injury results in the development of substantial motor, sensory, and autonomic deficits or even permanent loss of neurologic function. SCI may occur anywhere in the spine, and the location of injury will largely dictate the level of postinjury function and influence the risk of developing postinjury complications. Furthermore, the financial and psychosocial well-being of patients and their caregivers are affected. To date, effective therapies for functional recovery from SCI have not been established. Because existing treatment options are limited, with negligible or no effect, the development of novel strategies to treat SCI is warranted.

A thorough understanding of SCI pathophysiology is imperative because it may lead to the development of promising treatment modalities and the prevention of further injury. The primary insult resulting in SCI is typically due to physical trauma, such as motor vehicle accidents, falls, sports-related injuries, or gunshot injuries, that results in rapid spinal cord contusion and/or tissue destruction. This leads to a signaling cascade of neuronal damage and hypoxic sequelae known as secondary injury that further induces neurologic deterioration due to ongoing tissue damage. Prevention of these secondary mechanisms that cause posttraumatic degeneration of the spinal cord can provide the opportunity for neuroprotection and impede tissue destruction, thus promoting improved neurologic outcomes after initial spinal cord trauma.

The advancement of neuroprotective therapies to prevent secondary injury has been well documented in preclinical experimental models. However, translation into human subjects and the overall efficacy of these therapies have been largely unsuccessful to date. The complexity of extrapolating therapeutic promise is based on the rarity of SCI, varied clinical presentations, the heterogeneous nature of the injury, the myriad cellular and biochemical reactions that occur, and the difficulty of categorizing of injuries.

In this chapter, we focus on the pathophysiology of SCI, both primary and secondary injury, and highlight emerging therapies for neuroprotection. Additionally, we review early versus late surgical management of SCI and briefly review the literature regarding current SCI trials. Of note, current and emerging treatment options regarding regenerative strategies for SCI treatment will not be addressed in this writing.

Key Points

  • The most common causes of SCI are motor vehicle accidents, gunshot injuries, falls, and sports-related injuries.

  • SCI not only impairs independence and physical function but also includes many complications from the injury.

  • Neurogenic bladder and bowel, urinary tract infections, pressure ulcers, deep vein thrombosis, spasticity, and autonomic dysreflexia are frequent complications after SCI.

  • The treatment and rehabilitation period is extensive and strenuous.

  • The mainstay of treatment in SCI is early rehabilitation to maintain remaining functionality after injury.

Pathophysiology of Spinal Cord Injury

Traumatic insult to the spine may result in various anatomic changes that disrupt the functionality and homeostasis of the spinal cord ( Fig. 29.1 ). Bony fractures and facet joint dislocation that apply an outer compressive effect and/or damage the spinal cord can significantly disrupt arterial flow, thus driving ischemia and tissue death. The severity of these changes and time to intervention determine the grade of injury and functional impairment. When there is continued compression of the spinal cord, many spine surgeons categorize treatment as an urgent priority because there is a common acceptance that the initial traumatic event leading to neurologic injury only partially contributes to the total neurologic deficit a patient with SCI endures.

Fig. 29.1, Pathophysiology of spinal cord injury (SCI). The diagram shows the pathologic events occurring after SCI. The primary and secondary injury mechanisms involve hemorrhage, edema, inflammation, apoptosis, necrosis, excitotoxicity, blood vessel occlusion, ischemia and/or vasospasm, axonal demyelination, disruption of synaptic transmission, and hypertrophic astrocytes and macrophages, which aid in the composition of the glial scar.

Traumatic SCI can be classified into primary and secondary phases. Primary injury results from the offense of the direct, mechanical injury that causes a traumatic event, and secondary injury represents an immense inflammatory cascade and biochemical events succeeding the primary injury ( Fig. 29.2 ). The underlying pathophysiology that occurs in the setting of traumatic SCI is exceedingly complex, with much detail remaining unknown. This cascade of events is characterized by ischemia, proapoptotic signaling, and the infiltration of inflammatory cells. The arrival of inflammatory cells results in the release of proinflammatory cytokines and cytotoxic debris, such as DNA, adenosine triphosphate (ATP), and reactive oxygen species (ROS), that further disseminate tissue damage. This adds to the harsh preinjury microenvironment that is adverse for healing. As the traumatized neuronal tissue matures over time, an astroglial-mediated fibrous scar with surrounding cystic cavities develops. The chronic inflammatory state results in the severe impedance of neural regeneration. To this end, there continues to be a great effort in determining the inciting process and factors that inhibit conservation or promotion of neurologic function.

Fig. 29.2, (A) Primary and secondary mechanisms of injury determining the final extent of spinal cord damage. The primary injury event starts a pathobiologic cascade of secondary injury mechanisms that unfold in different phases within seconds of the primary trauma and continue for several weeks thereafter. (B) Longitudinal section of the spinal cord after injury. The epicenter of the injury progressively expands after the primary trauma as a consequence of secondary injury events. This expansion causes an increased region of tissue cavitation and, ultimately, worsened long-term outcomes. Within and adjacent to the injury epicenter are severed and demyelinated axons. The neuroprotective agents listed act to subvert specific secondary injuries and prevent neural damage, and the neuroregenerative agents act to promote axonal regrowth once damage has occurred. ATP, Adenosine triphosphate.

Primary Injury

Primary SCI injury results from the physical forces of the initial traumatic event and often dictates the severity of injury. Mechanical trauma to the spinal cord invokes tissue death and functional loss. Physical forces are characteristically due to an external source and include those sustained from a motor vehicle accident or fall from significant height. These physical forces result in compression, contusion, distraction, laceration, transection, or intraparenchymal hemorrhage of spinal cord tissue. There are four mechanisms of primary injury: (1) impact with persistent compression, (2) impact alone with transient compression, (3) distraction, and (4) laceration and transection ( Table 29.1 ). Of these categories, the most frequent form of acute SCI mechanism involves impact with persistent compression due to displaced components of the vertebral column, including bone and intervertebral disk that exert force on the spinal cord, causing immediate traumatic injury and sustained compression. After the primary injury event, there is a complex cascade of multiple pathophysiologic mechanisms that induces secondary injury, further propagates neural tissue injury and destruction, and intensifies neurologic deficits.

Table 29.1
Summarized Description and Examples of the Primary Mechanisms of Spinal Cord Injury
Adapted from Dumont RJ, Okonkwo DO, Verma S, et al. Acute spinal cord injury. Part I. Pathophysiologic mechanisms. Clin Neuropharmacol . 2001;24:254–264.
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 disk 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

Secondary Injury

Secondary injury occurs after the initial traumatic event and compounds the original neurologic deficit by causing progressive tissue damage. Further neurologic deterioration commences due to multiple pathophysiologic events that occur in the spinal cord after the primary injury, including edema, disrupted microcirculation, loss of autoregulation, neuronal damage, and disordered nerve transmission ( Table 29.2 ). Acute cell death and dysfunction after the initial injury disrupt cell permeability and initiate a proapoptotic signaling cascade. Additionally, disruption of the blood–spinal cord barrier exposes the damaged cord to inflammatory cells, cytokines, and vasoactive peptides that promote additional injury. These interrelated processes signal cascading systemic and cellular events that compose the secondary insult (see Table 29.2 ).

Table 29.2
Summarized Description of the Secondary Injuries Associated With Spinal Cord Injury
Adapted from Dumont RJ, Okonkwo DO, Verma S, et al. Acute spinal cord injury. Part I. Pathophysiologic mechanisms. Clin Neuropharmacol . 2001;24:254–264; Kwon BK, Tetzlaff W, Grauer JN, et al. Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J. 2004;4:451–464.
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
Na + -K + ATPase, Sodium- and potassium-activated adenosine triphosphatase.

At the center of this process is the inflammatory cell migration of macrophages, microglial cells, T cells, and neutrophils that infiltrate the injury site due to disruption in the blood–spinal cord barrier. These inflammatory cells release cytokines, such as tumor necrosis factor-α (TNF-α) and interleukins (ILs) IL-1α, IL-1β, and IL-6 that mediate further inflammatory processes and present a harsh environment for the survival of neural tissue. Peak levels of these cytokines are attained 6 to 12 hours postinjury, and levels remain elevated up to 4 days after injury. Phagocytic and inflammatory cells release ROS, which causes DNA damage, protein oxidation, and lipid peroxidation. This insult further induces necrosis, apoptosis, and neurologic deficit.

Loss of ionic homeostasis results in intracellular hypercalcemia, which in turn activates calcium-dependent proteases and causes mitochondrial dysfunction and subsequent apoptotic cell death. Oligodendrocytes, the myelin-producing cells of the central nervous system (CNS), are particularly susceptible to apoptotic loss and have demonstrated apoptotic death both at the initial injury site and in distant surrounding areas. After acute SCI, there is an amplified release of excitatory amino acids, such as glutamate and aspartate, from injured cells. Excessive stimulation of excitatory amino acid receptors produces excitotoxicity and further propagation of neuron death by both necrotic and apoptotic events.

Concepts of Neuroprotection

Understanding of the specific secondary injury mechanisms that contribute to further neural tissue destruction and reduction of neurologic recovery is critical because much SCI research has focused on identifying pharmaceutical and cellular agents that can abate this process. An enhanced understanding of SCI pathobiology has permitted investigation into therapies targeting specific elements of this pathologic cascade. The strategy behind neuroprotection involves modulating the pathomechanisms of SCI. Pharmaceutical agents have been investigated from a neurobiology standpoint to determine whether drug administration could improve outcomes after SCI. These agents have been applied in both the preclinical and clinical setting to determine whether there are any benefits, such as halting the loss of or regaining neurologic function.

It is known that continuous activation of neuronal voltage-gated sodium channels promotes increased rates of cell loss through the development of cellular swelling, acidosis, and glutaminergic excitotoxicity. Common agents evaluated to provide neuroprotective effects after traumatic SCI include methylprednisolone, riluzole, minocycline, magnesium, and monosialotetrahexosylganglioside (GM-1). None of these has shown improved patient outcomes, except for methylprednisolone implemented within 8 hours of injury onset, although this treatment remains controversial. Of interest, these drugs did show preclinical efficacy, and therefore the limited amount of negative results has not yet definitively excluded their efficacy.

Pharmacologic Therapies

Riluzole

Riluzole is a benzothiazole anticonvulsant agent that is approved by the US Food and Drug Administration for the treatment of amyotrophic lateral sclerosis. It has been demonstrated in preclinical SCI studies to exhibit efficacy in reducing the extent of sodium- and glutamate-mediated secondary injury. The mechanism of action of riluzole involves inhibition of pathologic glutamatergic transmission in the synapses of neurons via sodium channel blockade. In animal SCI models, there is evidence that riluzole diminishes neuronal tissue destruction and promotes functional recovery.

A multicenter phase 1 trial conducted by the North American Clinical Trials Network (NACTN) evaluated the pharmacokinetics and safety of riluzole treatment of acute SCI. The trial included 36 patients, American Spinal Injury Association (ASIA) grades A through C ( Table 29.3 ) and was designed as a single-arm, open-labeled, matched comparison study. Patients received the first dose of riluzole (50 mg) within 12 hours of injury and then twice daily for 2 weeks. The endpoint for follow-up was fixed at 6 months, with neurologic, functional, and pain assessments continuing until 12 months. Results suggested that the most significant mean motor score improvements were present in grade B patients. Pinprick scores were 10 points higher for riluzole-treated patients compared with registry participants. RISCIS (Riluzole in Acute Spinal Cord Injury Study), an international, multicenter clinical trial, is currently in phase 2/3 trials evaluating the use of riluzole in patients with SCI.

Table 29.3
American Spinal Injury Association Impairment Scale
From American Spinal Injury Association. International standards for neurological classification of spinal cord injury (ICOS), revised April 2011. Available at: http://www.asia-spinalinjury.org/elearning/ISNCSCI_Exam_Sheet_r4.pdf .
A Complete: No motor or sensory function is 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 key muscles below the neurologic level have a muscle grade less than 3.
D Incomplete: Motor function is preserved below the neurologic level, and at least half of key muscles below the neurologic level have a muscle grade of 3 or more.
E Normal: Motor and sensory function are normal.

Methylprednisolone Sodium Succinate

The use of corticosteroids in the treatment of acute SCI was based on the initial findings that the application of an antiinflammatory agent reduced spinal cord edema. Although limited benefits were demonstrated in the NASCIS II (National Acute Spinal Cord Injury Studies) trial, administration of corticosteroids beyond 8 hours after injury remains hugely controversial.

NASCIS II assessed the difference between a high-dose regimen of methylprednisolone sodium succinate (MPSS; initial bolus of 30 mg/kg followed by a 23-hour infusion of 5.4 mg/kg/hr), naloxone, or placebo administered within 24 hours of injury. Post hoc analysis showed that the MPSS group within 8 hours of injury demonstrated statistically significant sensory and motor recovery at 1.5, 6, and 12 months postinjury. The Congress of Neurologic Surgeons critically reviewed the present evidence about the use of methylprednisolone in the setting of SCI. After a thorough review, the authors did not recommend the administration of methylprednisolone for the treatment of acute SCI because high-dose steroids are associated with harmful side effects.

Fehlings et al. conducted a systematic review in 2017 to assess the comparative effectiveness and safety of high-dose MPSS versus no pharmacologic treatment in patients with traumatic SCI. A total of 13 articles met the inclusion criteria, 7 of which were previous systematic reviews. Results revealed moderate evidence that the 24-hour NASCIS II MPSS regimen had no impact on long-term neurologic recovery when all postinjury time points were considered. There was moderate evidence that patients receiving the same MPSS regimen within 8 hours of injury gained an additional 3.2 points of motor recovery compared with patients receiving placebo or no treatment. The authors concluded that, although safe to administer, a 24-hour NASCIS II MPSS regimen had no impact on indices of long-term neurologic recovery when all postinjury time points were considered. However, a high-dose 24-hour regimen of MPSS conferred a small benefit on long-term motor recovery when commenced within 8 hours of injury.

Minocycline

Minocycline, a second-generation bacteriostatic tetracycline antibiotic, has demonstrated neuroprotective properties in preclinical models of CNS disorders. Through its CNS-penetrating effects, it is thought to provide substantial antiinflammatory effects mediated by inhibition of microglial activation, IL-1β, TNF-α, cyclooxygenase-2, and matrix metalloproteinases. Animal studies evaluating administration of minocycline after acute SCI have demonstrated reduced lesion size and promotion of tissue sparing. A phase 2 trial demonstrated that patients with incomplete acute cervical SCI may benefit from early administration of minocycline; the authors found a 14-point ASIA motor score improvement compared with placebo ( P = 0.05). A phase 3 trial, Minocycline in Acute Spinal Cord Injury, is currently being conducted to assess intravenously administrated minocycline for 7 days versus placebo.

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