The end result is a complex state of disrepair. Axons that have been damaged become useless stumps, connected to nothing, and their severed terminals disintegrate. Often many axons remain intact but are rendered useless by loss of their insulating myelin. A fluid-filled cavity, or cyst, sits where neurons, other cells and axons used to be. And glial cells proliferate abnormally, creating clusters termed glial scars. Together the cyst and scars pose a formidable barrier to any cut axons that might somehow try to regrow and connect to cells they once innervated. A few axons may remain whole, myelinated and able to carry signals up or down the spine, but often their numbers are too small to convey useful directives to the brain or muscles.
First, Contain the Damage
If all these changes had to be fully reversed to help patients, the prospects for new treatments would be grim. Fortunately, it appears that salvaging normal activity in as little as 10 percent of the standard axon complement would sometimes make walking possible for people who would otherwise lack that capacity. In addition, lowering the level of injury by just a single segment (about half an inch) can make an important difference to a person’s quality of life. People with a C6 injury have no power over their arms, save some ability to move their shoulders and flex their elbows. But individuals with a lower, C7 injury can move the shoulders and elbow joints and extend the wrists; with training and sometimes a tendon transfer, they can make some use of their arms and hands.
Because so much damage arises after the initial injury, clarifying how that secondary destruction occurs and blocking those processes are critical. The added wreckage has been found to result from many interacting mechanisms.
Within minutes of the trauma, small hemorrhages from broken blood vessels appear, and the spinal cord swells. The blood vessel damage and swelling prevent the normal delivery of nutrients and oxygen to cells, causing many of them to starve to death.
Meanwhile damaged cells, axons and blood vessels release toxic chemicals that go to work on intact neighboring cells. One of these chemicals in particular triggers a highly disruptive process known as excitotoxicity. In the healthy cord the end tips of many axons secrete minute amounts of glutamate. When this chemical binds to receptors on target neurons, it stimulates those cells to fire impulses. But when spinal neurons, axons or astrocytes are injured, they release a flood of glutamate. The high levels overexcite neighboring neurons, inducing them to admit waves of ions that then trigger a series of destructive events in the cells—including production of free radicals. These highly reactive molecules can attack membranes and other components of formerly healthy neurons and kill them.
Until about a year ago, such excitotoxicity, also seen after a stroke, was thought to be lethal to neurons alone, but new results suggest it kills oligodendrocytes (the myelin producers) as well. This effect may help explain why even unsevered axons become demyelinated, and thus unable to conduct impulses, after spinal cord trauma.
Prolonged inflammation, marked by an influx of certain immune system cells, can exacerbate these effects and last for days. Normally, immune cells stay in the blood, unable to enter tissues of the central nervous system. But they can flow in readily where blood vessels are damaged. As they and microglia become activated in response to an injury, the activated cells release still more free radicals and other toxic substances.
Methylprednisolone, the first drug found to limit spinal cord damage in humans, may act in part by reducing swelling, inflammation, the release of glutamate and the accumulation of free radicals. The precise details of how it helps patients remain unclear, however.