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Executive Summary
Among the most exciting frontiers in medicine is the repair of traumatic injuries to the spinal cord. Improvements in treatment are helping many more people survive spinal cord injury. Yet most spinal cord injuries still cause lifelong disability, and continued research is critically needed. To explore new directions for research on spinal cord injury, the National Institutes of Health sponsored a scientific workshop on September 30 - October 1, 1996. The workshop, Spinal Cord Injury: Emerging Concepts, brought together experts from the field of spinal cord injury research and leaders from other fields such as development, immunology, and stroke.

Current Understanding and Treatment
The normal spinal cord coordinates movement and sensation in the body. It is a complex organ containing nerve cells, supporting cells, and nerve fibers to and from the brain. The spinal cord is arranged in segments, with higher segments controlling movement and sensation in upper parts of the body and lower segments controlling the lower parts of the body. The consequences of injury reflect this organization.

The types of disability associated with spinal cord injury vary greatly depending on the type and severity of the injury, the level of the cord at which the injury occurs, and the nerve fiber pathways that are damaged. Severe injury to the spinal cord causes paralysis and complete loss of sensation to the parts of the body controlled by the spinal cord segments below the point of injury. Spinal cord injuries also can lead to many complications, including pressure sores and increased susceptibility to respiratory diseases.

Clinical management of spinal cord injury has advanced greatly in the last 50 years. Recent advances include improved imaging of damage to the spinal cord and vertebrae and development of the first effective drug therapy for use in the hours just after injury. Current management of acute spinal cord injury involves diagnosing and relieving gross misalignments and other structural problems of the spine, minimizing cellular-level damage, and stabilizing the vertebrae to prevent further injury. Once a patient is stabilized, supportive care and rehabilitation strategies promote long-term recovery.

Secondary Damage
Damage to the spinal cord does not stop immediately after the initial injury, but continues in the hours following trauma. These delayed injury processes present windows of opportunity for treatments aimed at reducing the extent of disability resulting from spinal cord injury.

Most types of immune cells enter the spinal cord only rarely. However, when the spinal cord is damaged by trauma or disease, immune cells engulf the area, eliminating debris and releasing a host of powerful regulatory chemicals, both beneficial and harmful. Scientists know little about the role of these immune cells after spinal cord injury.

Following spinal cord injury, highly reactive chemicals called oxidants or "free radicals" are released. These chemicals attack the body's natural defenses and critical cell structures. Trauma also causes release of excess neurotransmitters, leading to excitotoxicity, or secondary damage from overexcited nerve cells. Understanding how to block oxidative damage and excitotoxicity may provide avenues for reducing damage following spinal cord injury.

New insights about how cells die are affecting many areas of disease research, including spinal cord injury. Until recently, most cell death in spinal cord injury was attributed to necrosis, the common, uncontrolled form of cell death in which cells swell and break open. Recent experiments have shown that some cells die as a result of apoptosis, a form of "cell suicide" in which damaged cells eliminate themselves with less harm to their neighbors. Blocking apoptosis appears to improve recovery after spinal cord injury in rodents.

Damage to axons - nerve fibers that signal to other cells - causes most of the problems associated with spinal cord injury. Until recently, most researchers assumed that the physical forces of spinal cord trauma immediately tear axons. New evidence suggests that many axons deteriorate more slowly because the vital transport of molecules and cell components to and from the ends of axons is disrupted. This delay in axon loss allows time for intervention.

Following injury, nerve cells in the spinal cord below the lesion may die, disrupting spinal cord circuits that help control movement and interpret sensory information. Understanding these changes will be essential for obtaining useful recovery of function following regeneration.

For successful regeneration to occur following spinal cord injury, damaged nerve cells must survive or be replaced, and axons must regrow and find appropriate targets. Axons and their targets must then interact to construct synapses, the specialized structures that act as the functional connections between nerve cells.

Although conditions in the injured adult spinal cord are significantly different from those occurring during development, the requirements for regeneration are similar to those for development. Scientists are beginning to learn how cells specialize, how axons find their correct targets, and how synapses form in the developing spinal cord. Physicians may ultimately be able to manipulate developmental signals to control regeneration.

Central nervous system neurons require combinations of natural chemicals called trophic factors to survive and grow. Understanding which trophic factors are important and how cells respond to these molecules may enable researchers to use trophic factors to foster regeneration after spinal cord injury. Research on ways to administer these factors and avoid side effects will be necessary before they can be used for human spinal cord injury. Scientists are currently studying how nerve cells' innate ability to grow, and the environment that surrounds them, affect regeneration following injury. For example, investigators recently discovered a gene that prevents nerve cells from growing in adults. Methods that control this innate ability to grow may eventually complement other therapies.

Researchers are beginning to apply new knowledge about regeneration in animal models of spinal cord injury. Strategies include grafting of peripheral nerve pieces and fetal tissue into the damaged spinal cord, administering growth factors, genetically manipulating cell death programs, and neutralizing or bypassing natural growth-inhibiting substances. Combinations of such therapies have produced the first evidence that some functional regeneration of completely severed spinal cords in adult mammals is possible.

Current Interventions
Effective drug therapy for spinal cord injury first became a reality in 1990 with the finding that the steroid drug methylprednisolone can significantly improve recovery. Clinical trials of methylprednisolone demonstrated that there is an 8-hour window of opportunity for treatment after injury. This trial also showed that health care systems can provide the rapid treatment necessary in spinal cord injury, and it serves as a model for efficient clinical trials of other therapies. Methylprednisolone has now moved from clinical trials to standard use.

Neural prostheses present another approach for improving the quality of life after spinal cord injury. These electronic and mechanical devices, such as hand-grasp prostheses, connect with the nervous system to supplement or replace lost motor or sensory function. Devices such as prostheses to control bladder function and to help people stand are now in development or planning stages.

Rehabilitation can greatly improve patients' health and quality of life. New knowledge about the factors underlying spasticity, muscle weakness, and incoordination may lead to innovative ways of reducing these problems. In some cases, drugs available for other purposes may be effective for treating problems associated with spinal cord injury.

Preclinical and Clinical Testing of New Therapies
Animal studies point to several avenues for developing new therapies for spinal cord injury, including drugs that promote regeneration and transplantation strategies. Each of the mechanisms of secondary damage offers targets for intervention.

Efficient preclinical tests can ensure that the most promising potential therapies proceed rapidly to clinical testing. New animal models, innovative approaches to testing, and reliable outcome assessments are essential to this process.

Randomized, controlled, clinical trials are the gold standard for revealing the benefits and drawbacks of a particular therapy, but practical and ethical constraints limit large-scale trials to the most promising therapies. Good preclinical data is essential so that researchers can predict which treatments and doses are most useful and which patients might benefit. Combination therapies present special challenges that must be overcome when designing clinical trials for promising therapies.

Spinal cord injury research has now come of age. Because of general progress in neuroscience, as well as specific advances in spinal cord injury research, researchers can now test new ideas about how changes in molecules, cells, and their complex interactions in the living body determine the outcome of spinal cord injury. One of the most exciting messages from the workshop was the confirmation that findings from other fields, such as development, immunology, and stroke research, can be applied to the study of spinal cord injury.

Researchers are wary of giving people false hope that a "magic bullet" for curing spinal cord injury is just around the corner. However, with accelerating progress in basic and applied research, there is renewed vitality and growing optimism among investigators that, with continued effort, the problems of spinal cord injury will be overcome.