Pathophysiology

Acute traumatic injury to the spinal cord can come in the form of a blunt mechanism, such as an acrobat falling onto a hard surface or a person thrown from a car during an automobile collision, or a penetrating injury such as a stab or gunshot wound. The forces involved in each of these events are transmitted to the spinal column and if great enough result in disruption of the bony and ligamentous structures and in damage to the neural elements. Damage to the spinal cord or the exiting nerve roots can result in motor, sensory, or autonomic dysfunction. In an attempt to delineate the precise cause of neurological dysfunction researchers have divided the temporal sequence of destructive events into primary and secondary injury. Primary injury refers to the destructive forces that directly damage the neural structures such as the shear force tearing an axon or direct compressive force occluding a blood vessel, resulting in ischemia. These destructive primary mechanisms not only result in instantaneous damage to neurons and blood vessels but also initiate a cascade of cellular mechanisms that result in ongoing damage to the neural structures, termed secondary injury. In fact, in cases of ongoing primary injury, for example, in the setting of a fracture dislocation where the bony spinal column is displaced and physically pushed up against the spinal cord, these cellular mechanisms are thought to be locked into the “on” position until such physical forces are removed either by closed reduction or surgically. Secondary injury may persist from hours to weeks to years following primary injury. A great deal of work has gone into the detailed understanding of these cellular cascades and along with this work has come an appreciation for the destructive effects of the mechanisms and the role of potential therapeutics to halt these cascades. In the remainder of this section we will highlight the most important secondary mechanisms of injury (Fig. 27.1) and in the section titled “Translational Research” we will discuss some of the therapeutic targets that resulted from these basic science discoveries.

FIGURE 27.1 Following a primary mechanical injury, numerous secondary mechanisms result in ongoing damage to the spinal cord and minimize the chance for recovery.

Secondary injury stems from any aberrant physiological or physical force and results in further tissue damage and potential exacerbation of primary injury. Two of the easiest physiological parameters to recognize are hypotension and hypoxia. Both of these conditions are relatively common in trauma patients, who often sustain concomitant injuries and blood loss. Both are also amenable to medical management shortly after the patient arrives at the hospital. Specific treatment options will be discussed later; here we highlight the importance of these two causes of secondary injury and the fact that they further exacerbate secondary cellular cascades. Both global hypotension and hypoxia add to the overall effect of hypoperfusion to the damaged area of the spinal cord. Several other mechanisms add to hypoperfusion including disruption of the microvasculature, loss of normal autoregulatory mechanisms, and increased interstitial pressure.^5–7 The effects of this ischemic insult are cytotoxic cell swelling of both neurons and glial cells; as a downstream effect of this, blockade of action potentials has been demonstrated as a result of axonal swelling.⁸

Ionic dysregulation and excitotoxicity are closely linked events that contribute to tissue damage. Calcium dysregulation in particular has been widely linked to cell death through a number of different processes including calpain activation, mitochondrial dysfunction, and free radical production.⁹ Whether calcium dysregulation or disruption of other ionic gradients occurs, loss of ionic homeostasis is central to both necrotic and apoptotic cellular death. Excitotoxicity results from activation of glutamate receptors via the influx of both sodium and calcium ions. As cell death occurs, either through the process of necrosis or apoptosis, extracellular glutamate levels rise presumably due to the failure of energy-dependent transporters such as the Na⁺/K⁺-ATPase membrane transporter.¹⁰ In the next section we will discuss how antagonists of NMDA (N-methyl-D-aspartic acid) receptors are potential targets of translational research in order to minimize cellular death.

Free radical–mediated secondary injury occurs through the process of lipid peroxidation that ultimately results in disruption of axons and death of both neurons and glial cells. Considering the mechanism of free radical damage, peroxynitrite and other reactive oxygen species act through a chain reaction that ultimately destroys cellular membranes and leads to cell lysis, organelle dysfunction. and calcium dysregulation.¹¹ This, in turn, adds to the ionic dysregulation described in the preceding paragraph. Free radicals have been measured in the damaged tissue of experimental models and are found to be elevated for approximately 1 week following injury, returning to preinjury baseline only after 4 to 5 weeks.¹² Examples of these free radicals include hydrogen peroxide, hydroxyl radical, nitric oxide, and the superoxide radical. Specific radicals, such as peroxynitrite, have been directly liked to the activation of apoptotic cascades in rat SCI models.¹³ As with NMDA receptors, free radical oxygen species become a potential target of translational research. If one is theoretically able to mediate the level of these dangerous compounds, could one not prevent the degree of secondary damage that occurs following SCI? This idea will be expanded on in the translational research section below.

Tight junctions between endothelial cells act as an interface between the systemic circulation and the central nervous system. Known as the blood-brain barrier (BBB), it also functions in the spinal cord and acts as a selective barrier that allows passage of solutes such as glucose while maintaining impermeability to macromolecules and infectious agents such as bacteria. Endothelial cells and astrocytes are normally bridged by tight junctions and are interspersed with very selective transmembrane proteins to allow the passage of vital molecules and ions. With the destructive forces that accompany SCI comes the destruction of the BBB. This can result either from direct mechanical destruction, such as damaged blood vessels and spinal cord parenchyma, or from destruction at a cellular level. The latter is best understood as a result of the effects of numerous inflammatory mediators on the endothelial cells that disrupt the normally impermeable barrier. One way researchers have studied this effect is through the use of a compound called horseradish peroxidase. When injected into the peripheral circulation of a normal animal, this compound does not cross the fortress of the BBB and remains in the systemic tissues. When injected into animal models of SCI, the compound was found to permeate into the CNS at a peak time of 24 hours following injury. Such permeability was persistent for up to 2 weeks following injury.¹⁴ A number of compounds have been identified that are thought to contribute to this ongoing permeability following injury, each of which is related to the secondary mechanisms of SCI. Inflammatory mediators affecting vascular permeability include tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) and both have been shown to be unregulated following SCI.^15,16 Other compounds that play a role include matrix metalloproteinases, histamine, and reactive oxygen species including nitric oxide.¹²

The inflammatory reaction following SCI has received a renewed interest in recent years largely because of what is thought of as the dual nature of the immune response. On the one hand inflammatory mediators seem to be responsible for the ongoing destruction of tissue, and on the other hand they seem to be clearing cellular debris and optimizing the environment for regenerative growth. Several noncellular mediators are involved in the cascade, the most prominent of which are TNF-α, interferons, and interleukins.¹⁷ Cellular mediators following SCI include both resident microglia and peripheral inflammatory cells. A few of the well-characterized examples, mainly from studies in the rodent population, include astrocytes, T cells, neutrophils, and invading monocytes.¹⁸ A great example of this dual nature of protection and destruction comes from studies involving TNF-α, which has been demonstrated to be significantly unregulated following SCI.¹⁹ Subsequent studies involved the application of neutralizing antibodies to TNF-α following experimental injury, resulting in improved neurological function.²⁰ However, TNF-α-deficient mice have been shown to have higher numbers of apoptotic cells, increased lesion size, and worse function following SCI when compared to wild-type mice.²¹ This demonstrates the complexity of the inflammatory cascade in SCI and should point the novice reader in the direction of thinking beyond the notion of one type of molecule causing destruction; rather, one must view the many players as acting in a complex pattern, some of which may aid in optimizing function and others that may result in ongoing destruction. The role of research in this field is to tease out these details and provide specific targets for translational research that aim to optimize the potential for recovery.

Cellular death via the apoptotic pathway is thought to play little role in the fate of neurons²² but a considerable role in the fate of oligodendrocytes²³ following SCI. Although it may be difficult to demonstrate the apoptotic mechanism of neuronal death in human SCI, there is some evidence for its role in animal models.²⁴ In contrast, the apoptotic mechanism of oligodendrocyte death has been convincingly demonstrated and its mechanism at least partially elucidated. Following SCI, microglia are activated within the first 2 to 48 hours and express the Fas ligand.²⁵ This ligand has a receptor largely expressed on the oligodendrocyte, and communication occurs via the p75 neurotrophin receptor.²⁶ The interaction of the Fas ligand and its receptor initiate apoptosis by way of the caspase cascade that ultimately results in proteolysis, DNA cleavage, and cellular death. This pathway has been the target of translational research strategies and will be expanded on in the next section.

In contrast, cellular death via the necrotic pathway has been demonstrated in both the neuronal and non-neuronal cell populations. Several of the secondary mechanisms of injury previously discussed, such as hypoperfusion and excitotoxicity, culminate in the necrotic death of neurons. Oligodendrocytes are also susceptible to this death pathway and the loss of this cell type has the consequence of axonal demyelination. This demyelination, in combination with other insults on the neuronal processes such as lipid peroxidation and ischemic swelling, results in death of the associated neuronal cell bodies.²⁷ Animal studies have provided evidence that preserved axons represent a critical therapeutic target in order to regain neurological function.²⁸ In stark contrast to this, postmortem human studies have failed to identify demyelinated axons²⁹ and may represent an important disconnect between animal and human pathology following SCI.

Primary and secondary injuries are conceptual frameworks that divide the temporal sequence of events following SCI. This framework provides a basis for research into the complex pathways that are activated in response to trauma, some of which may result in optimizing the local environment for neurological recovery and others that have deleterious side effects. The pathological processes that occur at the cellular level include ischemia, vasospasm, ion-mediated cellular damage, excitotoxicity, oxidative cellular damage, neuroinflammation, and cellular death. Each of these processes involves complex cascades of events. As research continues into each of these cascades different targets for intervention are discovered. In the paragraphs to follow we will highlight some of these targets and explain how they may eventually prove to be beneficial in treating persons that suffer an SCI.

Translational Research

As previously stated, an in-depth understanding of secondary mechanisms of SCI has led to identification of numerous possible targets for prevention of this secondary damage and possible regeneration of partially damaged neural circuits. Here we will review a number of agents that are currently under investigation. Broad categories include neuroprotective agents (minocycline and riluzole), myelin-associated inhibitors of neural regeneration (ATI355 and Cethrin), and cellular transplantation strategies (activated autologous macrophages, bone marrow stromal cells, and human embryonic stem cells). This list is by no means exhaustive. Numerous other strategies have been attempted in the past and many lessons have been learned—both positive and negative. Readers interested in a recent history of translational research in the field of SCI are referred to a recently published open source review.³⁰ Alongside developments in neurobiology have come advances in clinical management and operative strategies. In a similar fashion to the scrutiny of drug delivery trials, these clinical and surgical options have also been the focus of clinical trials and extensive review to determine if their effects provide better outcomes for patients. Research that has gone into blood pressure management, methylprednisolone therapy, closed reduction of bilateral locked facets, and early surgical decompression will be discussed in the following section on clinical management.