[Editor's note: This article is from 2007. Some newer treatments and current statistics are not included here. See further information on BrainWeb]
sections include: diagnosis and treatment, recovery after spinal cord injury, the science of spinal cord recovery, future therapies for recovery of movement, the outlook for regeneration
An injury to the spinal cord disconnects the body below the injury site from the brain. Thus, an injury to the cervical spinal cord, at the level of the neck, produces quadriplegia, or loss of function in all four limbs, while an injury to the thoracic spinal cord, at chest level, causes paraplegia, or loss of function in the legs. Spinal cord injury, however, does much more than cause loss of sensation to, and paralysis of, the arms and legs. The spinal cord also carries autonomic signals for the bowel, bladder, lungs, and other organs to and from the brain.
Spinal cord injury interrupts brain control and sensation of these organs. An injury to the upper part of the neck will stop breathing, and the person must be artificially respirated. Most spinal cord injuries affect the bowel and bladder.
The part of the spinal cord that is separated from the brain by the injury usually becomes hyperexcitable. The paralyzed parts of the body often show increased reflexes or spasticity and can even produce spasms violent enough to throw the person out of a wheelchair. Likewise, bladder and bowel become spastic. Bladder spasticity is a particular problem, since it can cause urine reflux and kidney damage. The autonomic system becomes similarly hyperexcitable and can produce life threatening increases of blood pressure.
Most people with spinal cord injury suffer from abnormal sensations and pain below the injury site. Closely akin to “phantom limb” pain that people suffer after amputations, the abnormal sensations are often “burning” or “freezing,” and are localized to areas below the injury site. Called neurogenic pain because these sensations originate from the spinal cord, this kind of pain is typically unresponsive to conventional painkilling drugs.
Paralyzed muscles shrink and become atrophied. If the injury damages the spinal cord where the motoneurons—the neurons that send movement commands to, or innervate, the muscles—are situated, the person will develop severe atrophy of the muscles innervated by the motoneurons. This will result in flaccid limbs, incompetent bowel and bladder sphincters, and dysfunctional sexual organs. These consequences of spinal cord injury can be devastating, particularly for young men, who are the most frequent victims of spinal cord injury.
For much of human history, spinal cord injury was considered to be an incurable condition. The standard clinical approach emphasized prevention of further injury, acceptance of the condition, and learning to use remaining function, rather than restoring function. Several recent developments, however, provide hope that curative therapies of spinal cord injury are not only possible but also imminent.
Diagnosis and Treatment
Diagnosis of spinal cord injury is relatively straightforward. Because the injury causes a loss of motor and sensory function below the injury site, a careful neurological examination suffices to identify and characterize the level and severity of injury. The American Spinal Injury Association has developed a spinal cord injury classification system and a neurological outcome scale that are internationally accepted. The spinal cord and spinal column can be readily studied by magnetic resonance imaging (MRI) and computed tomography (CT) scans, which show soft tissue and bone and their impingement on the spinal cord.
Medical treatment of spinal cord injury is also straightforward. In 1990 the National Acute Spinal Cord Injury Study (NASCIS) reported that highdose methylprednisolone, a potent synthetic steroid, improves neurologic recovery by about 20 percent in people when it is administered within eight hours after injury. This was the first therapy that improved recovery of function in people when given after spinal cord injury. This discovery opened the doors to the concept of secondary tissue damage in the spinal cord and brain, leading to the new field of neuroprotective therapies. Although several recent studies have criticized several aspects of the NASCIS trial, methylprednisolone is now routinely given to all patients with acute spinal cord injury in the United States and around the world.
Surgical treatment of spinal cord injury, however, is split between two camps. The first, and more conservative group, holds that if the patient has no function below the injury site and therefore has a “complete” injury, surgical decompression of the cord will not restore function. Therefore, a common practice is to delay the surgery for a week or more after injury, so that the surgery can be carried out electively. The second group comprises surgeons who will decompress the spinal cord immediately, believing that there is a small window of opportunity. Most surgeons will now stabilize the spinal column with titanium plates or rods that allow immediate immobilization of the fracture and more rapid rehabilitation of patients, in contrast to years past when patients had to remain in traction or external devices that required prolonged bed rest and limitations of activity for many months.
Rehabilitative therapy focuses on teaching patients, families, and caretakers techniques to manage the most serious consequences of spinal cord injury: impaired bladder function and infections, skin care, spasticity, neuropathic pain, paralysis, and sensory loss. Although the goal of rehabilitation remains constant—making the most of residual function—the techniques for achieving this goal have shifted dramatically. In addition to standard physical therapy, urological and skin care, and help dealing with social and environmental barriers, many rehabilitation centers are now emphasizing novel exercise and pharmacological and electrical stimulation.
Perhaps the most important research advance in spinal cord injury care was the recent discovery that many people who have never walked after injury can recover independent locomotion through intensive supported ambulation training. This has led to a popular theory that neuronal circuits in the spinal cord may turn off if they are not used for a period of time. The good news, however, is that intensive forced-use exercise and training can restore function, sometimes many years or even decades after injury.
Recovery After Spinal Cord Injury
Contrary to popular belief, recovery is the rule and not the exception in spinal cord injury. If a person has even a trace of voluntary movement or touch sensation below the injury site shortly after injury, that person has a good prognosis for substantial recovery. In the United States about 10,000 people every year have traumatic spinal cord injuries of sufficient severity to require hospitalization. More than 60 percent of people who are admitted to hospitals with the diagnosis of spinal cord injury have “incomplete” injuries. A much larger number of people suffer a milder form of spinal cord injury called whiplash, which causes temporary loss of arm or leg function. An estimated 4 out of 1,000 people, or about a million a year, are treated for whiplash. Thus, many people walk away from spinal cord injury. On the other hand, about 250,000 people in the United States have had severe traumatic spinal cord injury from which they did not recover.
The Science of Spinal Cord Recovery
A majority of people recover to some extent after injury. Many recover substantially more than expected by their doctors. How is it possible that some people recover so well from spinal cord injury while others do not? Two factors may influence recovery. First, the spinal cord has redundant pathways for achieving the same function. Both humans and animals can recover locomotor function even after injuries that damage as much as 90 percent of the pathways. The spinal cord is quite plastic and can continue to function with relatively few connections with the brain. Second, while the spinal cord turns off neuronal circuits that are not used for a period of time, intensive forced-use therapy may be able to restore them.
The Spinal “Brain”
The spinal cord is capable of remarkably complex motor behavior on its own. It not only contains the neuronal circuitry and reflexes necessary for complex motor activities and sensory processing, but also can adjust its circuitry to perform in a wide variety of environments and situations. It does this with little or no input from the brain. For example, locomotion is controlled by, a neural center in the lower spinal cord called a central pattern generator (CPG). To walk, the brain sends a signal to the CPG to initiate walking. Once the program starts, the brain just manages the movements. Relatively few connections are required.
Animals and people with no voluntary motor control can be trained to stand, walk, and even perform complex behaviors such as walking on a treadmill. Several studies have reported that the isolated spinal cord is capable of learning complex behaviors. For example, researchers recently reported that cats and rats with completely cut spinal cords not only can learn to walk on a treadmill but can adjust their walking behavior in response to sensory cues. While the animals do not have voluntary control over the muscles and do not have sensory feedback to the brain, training can produce remarkably coordinated locomotion that outlasts the training period. The ability of the spinal cord to function with relatively little input from the brain probably accounts for the remarkable recovery of many people who have so-called incomplete spinal cord injuries.
However, recovery of control and sensation in the limbs and organs affected takes months, or even years, after spinal cord injury. During that period, several developments may limit recovery. Muscles undergo atrophy when they are not used. Such atrophy can be partly reversed with electrical stimulation; and spasticity, even though it is troubling to the patient and family, can help maintain muscle bulk. Thus, it is important that antispasticity drugs not be overused during the recovery phase of spinal cord injury. Several recent studies have suggested a novel approach to preventing atrophy and perhaps restoring muscles: researchers showed that implantation of embryonic neurons into muscles can prevent the atrophy that occurs in denervated muscles.
Atrophy may also occur in the central nervous system. In the 1970s researchers showed that monkeys would stop using a hand when the sensory nerve to the hand was cut. Over time, the unused hand became effectively paralyzed, even though motor nerve connections were still intact. In other words, failure to use a limb due to sensory loss may lead to paralysis of the limb. Called learned nonuse, this phenomenon may account for much of the lack of recovery after stroke, traumatic brain injury, and spinal cord injury. For many years, clinicians considered this condition to be irreversible, and few attempts were made to restore function. Patients have been told not to even try to use their paralyzed limbs, and the loss of function was attributed to loss of neural connections. Most clinicians and scientists believed that regeneration would be necessary to overcome the paralysis.
Recent studies, however, indicate that learned nonuse can be reversed, even after many years of paralysis. Researchers have reported that forceduse training programs can reverse learned nonuse in people even many years after stroke. In the mid-1990s several groups in Germany reported that they were able to use intensive supported treadmill walking to restore locomotion in as many as 50 percent of people five years or more after their spinal cord injuries. Several preliminary trials in the United States have confirmed these results. The National Institutes of Health is funding a clinical trial to assess supported ambulation training, and preliminary data suggest that such training can restore locomotion in chronic spinal cord injury.
The discovery that locomotor function can be restored even after years of functional loss has profound implications for the biology of functional recovery. First, it means that central neural circuits can remain silent for years, even decades, and can then be reactivated. Most clinicians have hitherto assumed that absent function means absent circuits. Second, activity is important for maintaining and restoring function. The old maxim “Use it or lose it” may apply to both muscle and neurons. These findings have important implications for clinical care and trials of therapies. Clinical trials must take the post-treatment rehabilitation seriously. Without programs to reverse learned nonuse, regenerative and remyelinative therapies may well fail.
Training programs to reverse learned nonuse are laborious and expensive. Several groups are developing computerized robots to substitute for the manual labor required for such training. Much research is required to validate, improve, and define the most effective timing, duration, and intensity of forced-use training. However, if these techniques do restore function, such training will be well worth the expense. People who survive spinal cord injury live an average of 40 years, at the cost of more than $22,000 a year. Current care costs for spinal cord injury exceed $10 billion a year. Restoring function will yield recurrent lifetime savings, saving government and society many billions of dollars.
From Bench to Bedside
A majority of scientists and clinicians believe that regenerative therapies are both possible and imminent. Many promising spinal cord injury therapies have been discovered in animals, and a few have entered clinical trial. Reliable animal models of spinal cord injury have been established and well-standardized outcome measures are available for both animal and clinical trials. These advances made it possible for spinal cord injury research to show methylprednisolone to be the first effective neuroprotective therapy for the central nervous system. Likewise, the first studies showing functional regeneration were done in spinal cord injury models. For these reasons, the first regenerative therapies will probably be demonstrated in human spinal cord injury.
Future Therapies for Recovery of Movement
Scientists and clinicians have long known that the survival of only a remarkably few spinal axons (nerve fibers) is necessary for a person to recover most functions. Nearly 50 years ago, studies in cats showed that only 10 percent of spinal axons are necessary and sufficient to support substantial motor and sensory recovery, including locomotion. Rats are able to walk with only 10 percent of their spinal axons. Much clinical experience suggests that people with as much as 90 percent damage of the spinal cord will walk out of the hospital. Thus, therapies do not have to restore or regenerate many axons to restore function.
Spinal cord injury not only disconnects axons but also damages the cells that myelinate spinal axons. Myelin, the white fiber coating around axons, helps them conduct electrical signals efficiently, and thus the loss of myelin through crushing or bruising of the cord causes further neurological deficits in spinal cord injury. Implantation of myelinating cells, such as Schwann cells, cells that contribute to the formation of myelin (called oligodendroglial precursors), and neural stem cells can remyelinate spinal axons. A drug called 4-aminopyridine (4-AP) increases the ability of myelin-damaged axons to conduct and was in clinical trial as of 2001. Another drug, called M1, with similar action, was being readied for clinical trial as this book went to press.
The Outlook for Regeneration
Early studies indicated that damaged spinal axons will engage in short-distance sprouting, but long-distance regrowth of axons did not occur. Thus, most scientists believed that the spinal cord could not regenerate. However, studies in the 1990s decisively overturned this dogma, such that a majority of scientists now believe that the spinal cord can regenerate.
Healing with the Immune System
Recent studies suggest several novel approaches to regenerating the spinal cord. Some of the most provocative involve the immune system: scientists have reported that vaccinating mice with parts of the spinal cord can induce antibodies that promote spinal cord regeneration. Other researchers have found that macrophages or lymphocytes activated by exposure to certain proteins can protect the spinal cord and improve recovery. The former are currently being tested in clinical trial. These findings suggest that the immune system may play an important role in the recovery of the spinal cord.
Scientists have long suspected that electrical current can enhance regeneration. Several groups of researchers have reported that electrical currents produced spinal cord regeneration in rabbits and dogs. A study in 2001 revealed that electrical currents increase an intracellular messenger molecule, called cAMP (cyclic adenosine monophosphate), that stimulates growth of axons. Although studies over many years have shown that electrical currents stimulate axonal growth, the mechanism was not well understood until this discovery. A clinical trial has started testing the effects of implanted devices that deliver alternating electrical currents to the spinal cord.
Cell transplant therapy for spinal cord injury began with fetal cells. Researchers showed that transplanted fetal cells survive and integrate into injured spinal cords, altering the behavior of rats after injury. In addition, a clinical trial of fetal cell transplants has shown the safety and feasibility of these transplants in human spinal cord injury. Fetal cells, however, may soon be supplanted by embryonic stem cells, cells that can produce many cell types. Scientists recently discovered that embryonic stem cells will remyelinate the spinal cord and improve function recovery in rats.
Until recently, scientists believed that certain cells in the brain and spinal cord could not be replaced. For example, the neurons that we die with were believed to be the same neurons that we were born with. However recent studies have shown that the human brain and spinal cord contain stem cells that can produce additional neurons and glial cells. In other words, the brain and spinal cord appear to be capable of producing new neurons to replace those that have been lost due to injury, disease, or aging. Furthermore, implantation of stem cells into an injured brain and spinal cord may restore function.
Animal stem cells taken from bone marrow can also myelinate the human spinal cord. Neural stem cells from pigs are now being implanted into people with chronic spinal cord injury in a clinical trial. Animal studies have shown that other cell transplants can stimulate regeneration and improve recovery. For example, olfactory ensheathing glia (OEG) are special cells that reside in the olfactory nerve and bulb, the nerve inside the nose and the related brain structure that mediate our sense of smell. The OEG cells are believed to be responsible for the mammalian olfactory nerve’s unusual ability to regenerate continuously throughout adult life. OEG transplants into rat spinal cords have stimulated functional regeneration. Several groups are considering implanting OEG cells into patients, and trials have already begun in Russia.
Recent studies in animals have suggested that it may not even be necessary to breach the spinal cord in order to implant cells to prompt regeneration. For example, several research teams showed that bone marrow stem cells injected into a vein or into the space around the gut migrate to the brain and produce neurons. Similarly, another team found that embryonic stem cells injected into the cerebrospinal fluid surrounding the spinal cord migrated into the spinal cord and replaced neurons that had degenerated in a mouse model of amyotrophic lateral sclerosis. Thus, future clinical trials of cell transplants may not require surgery to place the cells in the spinal cord.
A dazzling array of promising therapies are or will soon be available for experimental clinical studies. Initial clinical trials have already shown the safety and feasibility of some of these therapies. These are the first generation of therapies for spinal cord injury that may help restore some function to some people. In a few years, a second generation of optimized first-generation therapies should begin, which should restore more function to more people. Third-generation “curative” therapies should be available by the year 2010.
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