When spinal cord injury (SCI) occurs, one of the most difficult issues to deal with is that there is no “cure” at the present time. One would think that with the explosion in scientific knowledge we hear of every day someone would find a cure for people with SCI. If we can achieve the impossible in other areas like transplanting entire organs and organ systems from one person to another and isolating human genes, why can’t we figure out why the spinal cord does not repair itself and then do something to correct this biological problem? Compared to a lot of the scientific puzzles that have been solved, it shouldn’t be all that difficult.
Let’s look at these issues and put them into the context of what scientists have been doing about spinal cord injury over the past half century.
Before World War II, an injury to the spinal cord was considered to be a fatal condition. If one did not die as a direct result of the injury, he or she would probably dies within a few weeks or months from complications, such as kidney infection, respiratory problems, or badly infected Pressure Sore.
Fortunately, an improved understanding of SCI led to better patient management, enabling many people to survive their injuries and the initial period afterwards. In addition, the discovery of penicillin and sulfa drugs made common, but life-threatening complications manageable.
Because the spinal cord carries vital information between the brain, muscles and many organs, the fact that SCI is now a survivable injury is itself a miracle. However, this miracle leads to another pressing need – to find a way to reverse, or at least diminish the devastating physical effects of the injury.
The Search for a Cure
Recent years have been an exciting time for people interested in spinal cord injury repair and Regeneration. Both in terms of treatment techniques and general knowledge about nervous system function, the progress that has occurred is very encouraging.
The search for a cure involves one of the most complex parts of the human body. The spinal cord is an integral part of the body’s most specialized system, the Central Nervous System. The central nervous system consists primarily of the brain and spinal cord.
A major role of the spinal cord is to carry messages to and from all parts of the body and the brain. Some of these messages control sensation, such as knowing when your finger is touching a hot stove, while others regulate movement. The spinal cord also carries messages that regulate autonomic functions such as heart rate and breathing – over which we generally do not exert voluntary control.
The spinal cord carries these messages through a network of nerves, which link the cells of the spinal cord to target cells in all other systems of the body. An individual nerve cell is called a Neuron, each with receptive branching fibers called dendrites. The Axon, carrying an output signal, extends from the cell body, and is covered by protective fatty substance called a Myelin sheath, which helps the impulse travel efficiently.
A Nerve Impulse from one neuron is picked up by the Dendrite of the next nerve cell in the pathway at a specialized connection called a Synapse. An electrochemical reaction causes the impulse to “jump” across the synapse and the signal stimulates the second nerve cell and the impulse then travels down its axon. The message is picked up and transmitted by a series of neurons until the connection is complete.
There are millions of nerve cells within the spinal cord itself. Some of these Lower Motor Neurons receive Motor commands from the brain and send their signals directly to the muscles. Other spinal cord neurons form relay pathways for information travelling up or down the length of the spinal cord. Still other spinal cord neurons remain intact and form intricate circuits below the level of injury. Because cells below the injury are no longer under voluntary control, they cannot be utilized as effectively and may cause unintentional movements, such as spasms.
Most of the cells in the human body have the ability to repair themselves after an injury. If you cut your finger, often you have a visible laceration for a few days or weeks, followed by the formation of a scar. In time, you may not be able to tell that the cut had occurred. This indicates that the skin cells regenerate, just like cells in blood vessels, organs, and many other tissues. Peripheral nerves (nerve fibers outside the brain and spinal cord), such as those located in your fingertips, also regenerate, although this process is different from that in the skin and other organs.
For years, scientists have focused on the big mystery: “Why doesn’t the central nervous system regenerate?” This question is even more perplexing because we know that central nerves in the lower animal species can regenerate. There are no definite answers to this mystery yet, but scientists are exploring the questions in many ways.
Basic Cell Research
An important avenue of research is to look at normal cell function in the central nervous system of mammals. Scientists investigating this area of research are attempting to identify and describe cellular interactions in properly working system. In addition, they are working with SCI models in an attempt to identify and explain what occurs after an injury.Through cell research, scientists are trying to identify the following:
1. What substances are present in the central nervous system which “switch off” nerve growth in mammals?
It has been shown that regeneration occurs in lower animals, as well as in mammalian fetuses in the very early stages of development. At some point in development, the cells appear to lose the ability to regenerate. This loss may be related to the maturation of the nerve cells or to changes in other nervous system cells past which axons must regenerate.
What growth inhibiting factors present in the central nervous system of mammals prevent nerve cells from regenerating and reestablishing connections (synapses).
Scientists have identified some proteins in the myelin sheath surrounding spinal cord axons, which inhibit nerve cell growth. Additionally, other regeneration-inhibiting proteins have been identified on the surfaces of cells that form the nervous system equivalent of a scar. Some scientists believe that nerve cells can be encouraged to re-grow and reestablish Functional synapses by removing or altering this cellular scar. Antibodies generated against some of these proteins can neutralize the inhibitors and allow growth to occur. The ability of central nerves to regenerate in lower animals is thought to be due to the lack of inhibitors in their central nervous system.
Can growth-stimulating substances be introduced into the mammalian central nervous system to encourage nerve growth and synapse development?
Investigators are attempting to alter the Environment around the injury site to encourage nerve cell growth and repair. The peripheral nerves can regenerate; this is due to the presence of cell proteins that stimulate, rather than inhibit, nerve growth. When these cells or the factors they produce, such as growth factors that nourish nerve cells, are introduced into the central nervous system, central nerve re-growth can occur. Finding ways to effectively introduce these cells or substances to achieve functional recovery is a major goal of cure research today.
Development of New Therapeutic Approaches
Ongoing research using animal models to test possible new therapies is progressing more rapidly than ever before. This type of research takes several forms that can best be explained as they apply to solving certain types of damage that result from spinal cord injury. There are three major classes of damage to neural tissues that have been identified, each requiring a different therapeutic approach.
Death of nerve cells within the spinal cord. Because nerve cells lose the ability to undergo cell division as they mature into the highly specialized forms that make up our nervous systems, the death of nerve cells due to injury presents a difficult problem. No functional connections can be established if the nerves no longer exist. Therefore, replacement of nerve cells may be required.
Disruption of nerve pathways. When the long axons carrying signals up and down the spinal cord are cut or damaged to the point where they break down after an injury, the parent nerve cells and axons often survive up to the point where the injury occurred. In this case, regeneration of damaged axons to re-establish connections of the nerve circuits is a real possibility.
Demyelination, or the loss of the insulation around axons. Animal studies and recent studies of human specimens have established that in some types of SCI, the nerve cells and axons may not be lost or interrupted, but that the loss of function may be due to a loss of myelin sheaths. Myelin sheaths provide insulation so that electrochemical signals are carried efficiently down the long axons. This type of damage may be the most amenable to treatment because rewiring of complex circuits may not be needed and remyelination of axons is known to be possible.
Although specific human injuries may involve any or all types of damage just described, therapies developed to combat any one of them might restore important functions. The cure for spinal cord injury may take the form of multiple strategies, each in turn restoring functions that make important improvement in the quality of life for a spinal cord injured individual.
The approach to cure research then is to concentrate on techniques that hold the promise of repairing specific types of spinal cord damage. With the explosion of efforts and progress in the fields of neuroscience and molecular biology (sometimes called genetic engineering), the scope of possible new therapies is wider than ever before.
Replacement of Nerve Cells
Mature nerve cells cannot divide to heal a wound as skin cells can. Replacement of nerve cells requires transplantation of new nerve cells into the site of the injury with the hope that they will mature and integrate themselves into the host nervous system. One approach is to transplant healthy central nervous system cells from the same animal species. Researches have been unanimous in their agreement that transplantation of adult nerve tissues does not work, while embryonic or fetal transplantation can be quite successful. The embryonic tissues do grow and develop below the injury. Research to date has not supported the hope that host axons would use these grafts as “bridges” across the injury site. An important consideration is that if fetal tissue transplants prove successful in animal models, transferring this approach to human being will involve important ethical considerations regarding donor tissues and other important questions about immune rejection of cells transplanted from one individual to another.
Another approach that may avoid some of those problems is the use of genetic engineering to manufacture “cell lines” that would work as nerve cells after grafting. This approach involves inserting segments of DNA (genes) into fetal nerve cells that allow the cells to divide indefinitely, creating an ongoing supply of donor tissue. The use of purely neuronal cell lines diminishes the changes of immunological rejection of the grafts. Recently rodent cell lines have been developed that stop dividing after transplantation (so there is no risk of tumor formation), and that mature into very specialized nerve cells. Research has not yet shown that these cells can restore function after spinal cord injury.
Regeneration of Damaged Axons
Nerve cells in both the central and peripheral nervous systems are associated with helper cells called neuroglial cells. After injury, the central nervous system helper cells largely inhibit regeneration, while those of the peripheral nerves, the Schwann Cells, stimulate regeneration. Scientists are attempting to isolate these cells from peripheral nerves and transplant them into the spinal cord to induce regeneration by providing an altered, supportive environment. In this strategy, a spinal cord injured individual could act as their own donor, since Schwann cells can be obtained from biopsies of peripheral nerves in adults.
Schwann cells, nerve cells and some other cells make proteins known to nourish nerve cells called “growth factors.” By introducing these factors into injury sites alone or in combination with grafts, researchers hope to stimulate additional nerve regeneration and promote the health of nerve cells. This approach has been shown to stimulate central nervous system regeneration, including growth of axons from nerve cells within the spinal cord and those from the brain that send the long axons down the spinal cord. Significant restoration of function has not yet been achieved.
Another technique is to genetically alter cells so that they produce large amounts of growth factors and to introduce these into the injury site. While nerve fibers have been stimulated to grow by such grafts, this type of research is in its very early stages. Cells making many types of factors will have to be tested and functional recovery carefully demonstrated.
Remyelination of Axons
Schwann cells are also the cells in peripheral nerves that form myelin sheaths. They are not usually found in the brain or spinal cord where another neuroglial cell, the ogliodendrocyte is responsible for making myelin. Researches have shown that Schwann cells grafted into the brain can myelinate central axons. When the loss of myelin is an important part of injury, implanting Schwann cells could stimulate remyelination and thereby restore function.
Another approach involves a drug called 4-aminopyridine (4-AP) which may help demyelinated nerves conduct signals. Animal studies show that a very small percent of healthy, myelinated axons can be enough to carry on important functions in the spinal cord, even in the face of damage to surrounding nerve cells. Helping nerve fibers that have lost myelin to conduct impulses should improve functions after injuries that extensively damage myelin sheaths, but do not disrupt nerve connections. This research is also in its very early phases.
The problem of the central nervous system’s response to injury is incredibly complex. No one theory or approach will overcome all of the effects of spinal cord injury and many scientists now believe that the “cure” will not be found in a single approach, but rather in a combination of techniques. Consequently, it is important for all possible research areas to be addressed so the overall knowledge about how the system works may eventually lead to a cure for SCI.
What about the “imminent breakthroughs” you hear about regularly in the press? It must be remembered that there is a vast difference between a scientific breakthrough and a clinical breakthrough. While scientific discoveries occur quite frequently, clinical treatments do not. Public announcements of scientific progress help to keep the attention and funding focused on finding solutions to the problems caused by SCI, but new scientific breakthroughs generally do not lead to immediate treatment applications.
Regeneration of Damaged Axons
Drug Treatments for New Injuries
It is important to realize these drugs are not a cure for chronic (long-term) spinal cord injuries. It is heartening to note, however, that treatments finally are available to lessen the severity of some acute injuries.
Research has shown that all damage in SCI does not occur instantaneously. Mechanical disruption of nerves and nerve fibers occurs at the time of injury. Within 30 minutes, hemorrhaging is observed in the damaged area of the spinal cord and this may expand over the next few hours. By several hours, inflammatory cells enter the area of the spinal cord injury and their secretions cause chemical changes that can further damage nervous tissue. Cellular content of nerve cells killed by the injury contribute to this harmful chemical environment. This process may go on for days or even weeks.
Hope lies, therefore, in treatments that could prevent these stages of progressive damage. Drugs that protect nerve cells following injury are now available to lessen the severity of some injuries. Other drugs and combinations of drugs are currently being tested in both animal and clinical trials.
Few treatment approaches have raised as much hope as the announcement by the National Institute of Health that the steroid methylprednisolone reduces the degree of paralysis if administered shortly after a spinal cord injury.
In clinical trials, an extremely high dosage of methylprednisolone was used in a double-blind study (neither patients nor doctors knew who was getting the experimental drug). The improvement in some patients was so remarkable that the National Institute of Health felt it was important to “break the code” (determine who was getting the drug and who was not) so more patients could potentially be helped. Overall, the trial showed that while the methylprednisolone-treated group retained significantly more function than the placebo group, subjects in both groups experienced chronic loss of function due to their injuries.
Methylprednisolone is effective only if used in high doses within eight hours of acute injury. It is hypothesized that this drug reduces damage caused by the inflammation of the injured spinal cord and the bursting open of the damaged cells. The contents of the damaged cells are believed to adversely affect adjacent cells. High does of methylprednisolone can lead to side effects, such as suppression of the immune system, but no serious problems have been reported when it is used over a short term, as in the study.
Because the success of the methylprednisolone trial had changed the standard of care in the United State, subsequent drug trials are now testing the effectiveness of other drugs in combination with methylprednisolone administration. Thus, to demonstrate significant effectiveness, new treatments will have to surpass the functional sparing effects seen with methylprednisolone alone. Simultaneously, researchers are cooperating to conduct a large, multi-center animal study to test the effect of other drugs with or without methylprednisolone.
Similar positive results to those of methylprednisolone have been achieved in animal studies using another steroid, tirilizde mesylate (Freedox®). This drug, which acts like methylprednisolone, also appears to be effective only if administered within a few hours after injury. From initial studies, it appears that this drug may cause fewer side effects than methylprednisolone. Clinical trials are ongoing. A large clinical trial with humans is currently underway, comparing 48-hour treatment of methylprednisolone, with or without added tirilizade. Analysis of the data is ongoing at this point.
In a small study, the experimental drug Sygen®, or GM-1 Ganglioside, was given within 72 hours of injury and then continued for up to 32 days. Neurological assessments were conducted up to one year after the treatment.The following summary was prepared by Fidia Pharmaceutical Corporation based on a presentation by Fred H. Geisler, M.D., Ph.D., of the Chicago Institute of Neurosurgery and Neuroresearch on October 8, 1998.
“The Sygen® Acute Spinal Cord Injury Study presented at the Congress of Neurological Surgeons in Seattle on October 8, 1998 is the largest prospective study ever completed on treatment of spinal cord injuries. Over a five-year period, 28 North American neuro-trauma center enrolled 797 patients with injuries ranging from the most severe to relatively mild. Patients were treated for eight weeks with either Sygen® or placebo after methylprednisolone therapy. Analyses completed to date show that while the difference in recovery rates six months after injury was not statistically significant, there was a clear pattern of enhanced recovery among Sygen®-treated patients. Because of the magnitude and complexity of the study, analysis of the full database of information – containing approximately eight million entries – is still underway. Additional results will be released after completion of the remaining analyses. On the basis of the evidence available to date, the company is currently pursuing the registration of Sygen® in the United States and Canada.
There are two theories about how GM-1 Ganglioside may act on spinal cord tissue. The first is that it performs some type of damage control by reducing the toxicity of amino acids released after spinal cord tissue is injured. The “excitatory” amino acids cause cells to die and increase the damage caused by the initial injury. The second theory suggests there may be a neurotrophic effect, somehow encouraging the growth of injured neurons. Neither of these theories has been scientifically proven yet. The FDA has not yet approved Sygen® for clinical use.
Clinical studies are being conducted by surgeons to determine the optimum time for surgery to relieve pressure on the spinal cord after spinal cord injury. Additionally, the use of delayed decompressive surgery is being investigated in cases of chronic SCI.
Preventing New Injuries During Spinal Surgery
Intraoperative monitoring techniques have been developed to protect healthy nerve roots during spinal stabilization procedures. Scientists tested, first on animals then on humans, a technique that assists surgeons in the placement of metallic hardware for stabilizations of the spine. The technique, which utilizes nerve stimulation and muscle responses, has been shown to effectively predict and allow the prevention of nerve damage during surgery in the lumbosacral spinal column.
Treatments for Chronic Spinal Cord Injury and its Complications
Functional Electrical Stimulation
Functional Electrical Stimulation (FES) uses implanted electrodes to stimulate paralyzed nerves so that arms and legs can be used for improved function. Primary applications for FES include the following: FES for exercise, FES for upper extremity (hand/arm) function, and FES for lower extremity (leg function) and FES for bowel and bladder control. FES is discussed in detail in the fact sheet entitled “Functional Electrical Stimulation: Clinical Applications.”
One controversial treatment for SCI is Omentum Transposition. The omentum is a band of tissue in the abdomen of mammals, which provides circulation to the intestines. A surgical procedure is used to partially detach the omentum, tunnel it under the skin and suture it in place at the injury site. The omentum tissue, which is rich in blood vessels, may supply the damaged nerve cells with vital oxygen. It is believed that the omentum tissue may also secrete chemicals that stimulate nerve growth, as well as have the ability to soak up fluids to reduce pressure which can damage nerve cells.
Initial animal trials seem to show some functional improvement if the operation is completed within three hours of injury. Little or no improvement is shown when the procedure is done six to eight hours post injury. This research, however, has never been scientifically documented. The on-going clinical trial for people who have had a SCI for months or years has been canceled, since the results of earlier research have not been sufficiently documented.
Scientists in the field of biomedical engineering developed mechanical devices that use today’s computer technology to assist individuals in activities of daily life. Examples of the types of devices under research and development are environmental control devices, electronic handgrip devices and walking devices.
Spasticity and Pain
The complications of spasticity and pain are common in spinal cord injury. Spasticity that is severe enough to cause problems with mobility and self-care, that contributes to Skin Breakdown, and that causes pain is reported in a number of cases of SCI.
Studies in the treatment of spasticity are investigating pharmacological agents, Intrathecal Baclofen, and spinal cord stimulation. In addition to drugs that have been available for some time (baclofen, valium and dantrium), the use of trizanidine is being explored.
The problem of pain occurs in approximately 50% of all cases of SCI. Five to thirty percent characterize the pain as disabling. Pharmacologic agents, as well as surgical interventions such as the DREZ (Dorsal Root entry zone) procedure, cordotomy and cordectomy, are under investigation for the treatment of severe causes of pain from SCI.
In most SCI men, the ability to have an ejaculation and to father a child naturally is diminished. In fact, ten years ago, doctors were telling newly injured SCI men that they would not be able to father their own children. With advances made in procedures to assist men in obtaining an ejaculation as well as advances in assistive reproduction technology, SCI men now have the potential to become biological fathers. Vibratory stimulation and electroejaculation are procedures that have been investigated and are currently available to assist men in obtaining ejaculations.
Obtaining the ejaculation is only part of the fertility problem in SCI men, however, the semen from SCI men most often contains a lower than normal percent of motile sperm. Questions that researchers hope to be able to answer with investigations on the quality of sperm of SCI men are: what happens to semen quality following SCI and, how successful is artificial insemination and other reproductive technology using semen from SCI men.
Technology and research are making it possible for spinal cord injured men to consider options regarding their fertility and is providing a more encouraging answer to the question “Will I be able to have children?”
Various controversial treatments for SCI have come and gone over the years, but none have proved to be effective in reversing the damage to the spinal cord that occurs in spinal cord injury. Often alternative therapies are very difficult to evaluate because of the unscientific nature in which the treatments are introduced to the human population. Many alternative therapies have no documented scientific evidence to substantiate their effectiveness. Currently, examples of treatments that fall into this category are the use of Sygen® (GM-1) in chronic injuries and omentum transposition.
Over the last several years there has been progress in the treatment of acute SCI to limit damage and preserve function. Treatment of chronic SCI presents a greater challenge, as damage that has already occurred must be corrected and then reversed.
It is entirely possible that, given appropriate financial support, many of the complex problems of SCI one-day will be solved. Until that day arrives, it is important to urge the federal government to provide broad-based support for basic science research so the fundamental questions about how and why the CNS acts the way it does can be answered. A cure or new treatments are possible only if scientists receive the support necessary to continue their work in this important area.
For further information on Freedox® clinical trials, contact: Upjohn Company,
929 Lawrence Court, N. Bellmore, NY 11710, 516-486-5276.
For further information on Sygen® clinical trials, contact: Fidia Pharmaceutical Corp., 1401 I Street, NW, #900, Washington, DC 20005, (202) 371-9898 x334.
For further information about FES applications, contact: F.E.S. Information Center, 25100 Euclid Avenue, Suite 105, Cleveland, Oh 44117, (800) 666-2353.
For further information about The Miami Project, contact: The Miami Project, 1600 Northwest 10th Avenue, R-48, Miami, FL 33136, (800) STAND-UP.