three phases of injury depends on which nerve cells and fiber tracts die, which remain intact, and which regenerate or form new branching patterns to compensate for the losses.

The elucidation of the distinct phases of injury—and the cellular and molecular events underlying them—comes largely from animal models. As events unfold, many of the cellular and molecular events designed to heal the injury can paradoxically lead to further neuronal injury or death. The site of injury may spread to adjacent areas of the spinal cord, sometimes extending four spinal segments above and below the initial site (Crowe et al., 1997; Liu et al., 1997). The affected area becomes filled with immune cells, and a “scar” is formed. The details of the pathophysiology continue to evolve.

Acute Phase

The acute phase, which begins within seconds of the injury, is marked by systemic as well as local events (Tator et al., 1998; Hulsebosch, 2002). The foremost systemic event, after a fleeting increase in blood pressure, is a prolonged decrease in blood pressure (hypotension) that sometimes coincides with a decrease in blood volume. Systemic hypoxia, a reduction of the oxygen supply to the tissues, occurs if, during the injury, respiration is compromised by airway obstruction or by paralysis of diaphragm muscles. Failure of the spinal cord to function for the first 2 to 24 hours after injury, a condition known as spinal shock, results from inadequate flow of oxygen and nutrients into the tissue.

Numerous local events within the spinal cord occur immediately after the injury and also contribute to spinal shock. Direct trauma from injury causes necrosis (cell death) to spinal cord neurons and to the endothelial cells lining the blood vessels of the spinal cord. The surviving neurons at the site of injury respond with a procession of electrical impulses, known as action potentials. Because action potentials require the influx and efflux of ions across the neuron’s membrane, the barrage of action potentials creates significant local shifts in ion levels. Higher ion levels are also produced by the mechanical shearing of nerve cells, causing their membranes to rupture and release their contents. Ion buildups can reach levels toxic enough to kill nearby neurons. Similarly, the barrage of action potentials causes the release of excess amounts of neurotransmitters, which then accumulate in the synapses between nerve cells. The accumulation of certain neurotransmitters (e.g., glutamate) can cause the death of nearby neurons through a mechanism called excitotoxicity (Faden and Simon, 1988). Neuron death, by whatever mechanism, contributes to the losses of sensory, motor, and autonomic functions that occur after spinal cord injury.

Direct trauma to the spinal cord causes its small blood vessels to hem-



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