Current Interventions 2004

Published: February 4, 2004  |  Source: ninds.nih.gov
101

Drug Therapy

Effective drug therapy for spinal cord injury first became a reality in 1990, when methylprednisolone, the first drug shown to improve recovery from spinal cord injury, moved from clinical trials to standard use. The NASCIS II (National Acute Spinal Cord Injury Study II) trial, a multicenter clinical trial comparing methylprednisolone to placebo and to the drug naloxone, showed that methylprednisolone given within 8 hours after injury significantly improves recovery in humans. Completely paralyzed patients given methylprednisolone recovered an average of about 20 percent of their lost Motor function, compared to 8 percent recovery of function in untreated patients. Paretic (partially paralyzed) patients recovered an average of 75 percent of their function, compared to 59 percent in people who did not receive the drug. Patients treated with naloxone, or treated with methylprednisolone more than 8 hours after injury, did not improve significantly more than patients given a placebo.

The successful clinical trial of methylprednisolone revolutionized thinking in the medical community. The trial showed conclusively that there is a window of opportunity for acute treatment of spinal cord injury. Some doctors are now using this idea to guide surgical treatment as well as drug therapy. Today, most patients with spinal cord injuries receive methylprednisolone within 3 hours after injury, especially if the injury is severe. This shows that emergency rooms and acute care facilities are aware of the drug’s value and are capable of providing rapid treatment for spinal cord trauma. Success in delivering this drug on a widespread basis shows that health care systems are capable of providing rapid treatment. The NASCIS II trial also proves that well-designed trials of acute therapies for spinal cord injury are feasible and provides a model for testing other interventions.

Other drugs are now being tested in clinical trials. A recently completed trial suggested that 48-hour regimen of methylprednisolone may be warranted in some patients. Preliminary clinical trials of another agent, GM-1 Ganglioside, have shown that it is useful in preventing secondary damage in acute spinal cord injury, and other studies suggest that it may also improve neurological recovery from spinal cord injury during Rehabilitation.

Neural Prostheses

While it may eventually become possible to help injured spinal cords regrow their connections, another approach is to compensate for lost function by using neural prostheses to circumvent the damage. These sophisticated electrical and mechanical devices connect with the nervous system to supplement or replace lost motor and sensory functions. Neural prostheses for deafness, known as cochlear implants, are now in widespread use in humans and have had a dramatic impact on the lives of some people. The first prostheses for spinal cord injured patients are now being tested in humans. One device, a neural Prosthesis that allows rudimentary hand control, was recently approved by the United States Food and Drug Administration (FDA). This prosthesis has been experimentally implanted in more than 60 people. Patients control the device using shoulder muscles. With training, most patients with this device can open and close their hand in two different grasping movements and lock the grasp in place by moving their shoulder in different ways. These simple movements allow the patients to perform many activities of daily life that they would otherwise be unable to perform, such as using silverware, pouring a drink, answering a telephone, and writing a note.

Neural prostheses are complex and contain many intricate components, such as implantable stimulators, electrodes, leads and connectors, sensors, and programming systems. There are many technical considerations in selecting each component. The electronic components must be as small as possible. Biocompatibility between electrodes and body tissue is also necessary to prevent the person from being harmed by contact with the device and to prevent the device from being harmed by contact with the person. Other challenges include finding ways to safely send currents into the body, to reliably record neural activity, and to cope with changes in muscle properties due to the injury. Neural prostheses also must be evaluated for usefulness and long-term safety.

Although many years of intensive study have contributed to the development of the prostheses now being tested, they are really the first generation of useful devices. Better materials and enhanced technology can refine these devices to provide much better function. Among the recent technical advances are extremely small probes that fit 16 electrodes on a shaft finer than a human hair. Integrated into a neural prosthesis, this type of electrode could provide extremely selective stimulation within the CNS, allowing the patient much more refined muscle control and a greater range of function. Future clinical development may allow easier, faster, and more natural movements; improve the longevity and reliability of components; and eliminate external cabling systems and external mounting of sensors.

Further research to improve components and increase understanding of brain circuits may yield prostheses that can provide sensory information to the brain. This will improve both the safety of the devices and the patient’s performance of tasks. Devices now being developed may eventually enable people with spinal cord injury to stand unassisted and to use signals from the brain, instead of muscles, to control movement. Other types of neural prostheses currently being developed around the world aim to improve respiratory functions, bladder control, and fecal continence. Ultimately, researchers may be able to harness reflexes or the innate pattern-generating abilities of the spinal cord’s central pattern generators to help people with spinal cord injuries walk.

Rehabilitation

Rehabilitation techniques can greatly improve patients’ health and quality of life by helping them learn to use their remaining abilities. Studies of problems that spinal cord injury patients experience, such as Spasticity, muscle weakness, and impaired motor coordination, are leading to new strategies that may overcome these challenges. As they gain a better understanding of what causes these problems, physicians are learning how to treat them, sometimes using drugs already available for other health problems.

Spasticity, in which abnormal stretch reflexes intensify muscle resistance to passive movements, often develops after spinal cord injury. Several factors may contribute to spasticity. Changes in the strength of connections between neurons or in the neurons themselves may alter the threshold of the stretch Reflex. Spinal cord injury also may release one type of interneurons from control by a class of neurotransmitters that includes serotonin and norepinephrine. This change in the balance of neurotransmitters may increase these neurons’ excitability and enhance stretch reflexes. Drugs that mimic serotonin can partially restore reflexes, a finding that supports this Neurotransmitter theory. Another possible cause of spasticity is that the reactions of pressure receptors in the skin may become stronger, causing muscle spasms that may grow stronger with time. Interneurons activated by NMDA receptors also may contribute to spasticity. NMDA receptors probably help adjust the strength of connections in the brain during learning. Researchers have found that a class of drugs that blocks NMDA receptors can restore stretch reflexes to almost normal strength.

The muscle weakness that frequently occurs after spinal cord injury may result from a loss of excitatory signals from the descending tracts. Abnormal patterns of motor activation in muscles may also contribute by making muscles less efficient so that they tire more easily. Loss of serotonin and related neurotransmitters may disrupt the process that controls how much each nerve cell’s activity increases with increasingly strong stimuli. Restoring normal neurotransmitter signals with drugs may partially relieve these problems. Some muscle weakness may also result from abnormal patterns of muscle usage or from changes in muscle properties, including muscular Atrophy and growth of connective tissue.

Scientists believe another common motor problem, muscle incoordination, may result in part from the substantial brain reorganization that occurs after injury to the CNS. With a better understanding of how the spinal cord changes following injury, researchers may be able to use drugs or Physical Therapy to promote reorganization when it is useful and block it when it is harmful.

Rehabilitation strategies will continue to play an important role in the management of spinal cord injury, and they will increase in importance as the ultimate goal of Functional spinal cord Regeneration is realized. Studies in animals with spinal cord injuries have shown that recovery of movement is linked to the type of training the animals receive. Physical therapy and other rehabilitation strategies also are crucial for maintaining flexibility and muscle strength and for reorganizing the nervous system. These factors will be vital to recovering movement following regeneration as well as maximizing the use of undamaged nerve fibers.

Conclusion

Therapies for spinal cord injury have improved substantially in the last few years. Drugs for treatment of acute injury, neural prostheses, and advanced rehabilitation strategies are improving the survival and quality of life for many patients. However, there are still many opportunities for improvement. These include finding ways to build on CNS reorganization and comparing the usefulness of different rehabilitation strategies. Investigators must also develop improved animal models for spinal cord injury to allow testing of new or improved therapies.