New Horizons in the Treatment of Spinal Cord Injury

Richard B. Borgens, Ph.D.
Director, Center for Paralysis Research

Introduction

Prior to the end of the second world war, if a person survived a severe spinal cord injury (SCI), the injury still usually resulted in their early death. This was due to the numerous complications that can accompany this type of injury such as infections of the lungs and kidneys. Though the development and widespread use of new antibiotics (and other innovations) has greatly improved the life expectancy for injured persons since that time, medical science has still not been able to restore their bodies to more normal functioning. In the last few years however, this situation is finally beginning to change. Many promising new treatments for SCI are now in the experimental stage, and a few have already moved into human clinical testing. This signals a new era in the history of this awful and devastating injury. Here I will describe some of the approaches pioneered at Purdue University, in the Center for Paralysis Research. This Center has a unique approach to the development of treatments. As do other excel lent spinal research centers, we have a vigorous laboratory based program of spinal injury research. Since we are part of the School of Veterinary Medicine, we have also built a program of experimental clinical treatment where promising laboratory techniques are moved to the stage of hospital based (or clinical) testing. Our clinical trials involve a partnershipCPR Dog between the owners of naturally injured paraplegic dogs and a clinical team of veterinary medical specialists. We provide state of the art neurosurgical management of these dogs combined with our experimental treatments. We teach owners how to care for their pet - even providing them a specially designed wheeled cart for the animal (the equivalent of a wheelchair for humans) and pay all medical costs. Ordinarily, severely injured paraplegic dogs would be put to sleep. Dogs, like people, remain paralyzed after an injury for life, and Veterinary Medicine, like Human medicine, is unable to cure this problem. As I will describe below, this approach to the development of treatments has led to very rapid progress.

Spinal Cord Injury in Man

To be able to understand how new treatments for SCI might work, I should explain a little about what happens to the spinal cord when it is injured and why this has such catastrophic medical consequences. First, it would be both instructive and convenient to view our spinal cord as sort of a superhighway between our brain and our body. There are two major lanes of "traffic" (nerve impulses) running North and South, and there are many "on ramps" and "off ramps" at regular intervals. The northbound lanes are many millions of single nerve fibers coming in from the body carrying traffic to our brain. Most of this nerve impulse "traffic" is sensory information, coming from our many sense organs that sample the world around or inside of us. The south bound lane is from the brain to the body and this nerve impulse traffic is largely "motor" information going to our muscles and organs. These lanes of millions of nerve fibers project the conscious or unconscious will of our brain to all parts of our body. The "on ramps" and "off ramps" are where nerve fibers enter the superhighway from the body - or get off of it heading to the body. These ramps are actually thousands of nerve fibers arranged in bundles entering or leaving the spinal cord on the left and the right side of each bony vertebral segment surrounding the spinal cord from the "tail bone" (sacrum) to the highest neck (cervical) bone.

When the vertebral column (spine) is crushed or bent in an extreme accident, the spinal cord inside is severely bruised and compressed, causing localized injury and death to many of the nerve cells and their fibers. There is bleeding in this local area of injury, and a slow healing process begins where a type of scar is formed, along with fluid-filled cysts and cavities where there was once healthy tissue. It is rare for a cord to be actually cut in two, though as we shall see, the functional consequences are the same.

Some of the injured nerve fibers survive intact but loose their electrical insulation (a fatty substance called myelin) over the very short distance of the injury zone. Nerve impulse traffic is blocked at this point. Therefore sensory or motor information never reaches the target tissue just as if these nerve fibers were cut in two. Many nerve fibers are so damaged at this local region that they actually go on to separate into two pieces. That part of the fiber separated from its nerve cell body (where the cell's nucleus is) always dies in about 48 - 72 hours and is lost forever. The remaining portion of the fiber does not begin to regrow at its tip to make new connections in mammals. The result is that major portions of the north and south bound lanes actually disappear, and these millions of fibers do not regenerate to restore nerve impulse traffic. There are two important lessons to be learned from this admittedly oversimplified description that are still worthwhile:
1.) The point along this superhighway where the damage occurs determines the level of functioning left to an injured person. If the damage occurs in the lower back, than incoming sensory information from the lower body and legs stops at the injury, and motor information to the legs is lost. Thus the individual is "paraplegic". What remains functional is the upper torso and arms. If the injury is at the neck, then control even of the arms and legs is lost, and there is no normal sensing of any portion of the body. This injury results in "quadriplegia". Since the nerves that control breathing at the diaphragm leave the spinal cord high in the neck, an injury to this region can even result in the loss of respiratory ability, and breathing has to be driven by artificial means.
2.) To restore spinal cord functioning, an experimental strategy might try to a.) produce regeneration of the remaining segment of a nerve fiber to make new connections on the other side of the injury, b.) prevent, or rescue, the damaged nerve fiber from proceeding on to separation, or perhaps even functionally reuniting the two segments so that both portions of the fiber survive, c.) facilitate nerve impulse traffic to cross the region of injury in intact fibers where they have lost their electrical insulation, and d.) to limit the delayed and slow degeneration of spinal cord tissue and the formation of nonfunctional scar (that is believed to be a barrier to nerve regeneration). Where nervous tissue is killed by the injury, medical science would like to find a replacement "graft" of nervous tissue to repopulate this region. While these scenarios may seem fanciful, in fact, these are the types of experimental treatments that are becoming a medical reality.

Spinal Cord Regeneration

This is indeed a growth area in spinal research, no pun intended. Neuroscientists have identified and produced a battery of natural chemical substances (growth factors) that have been shown to induce regeneration of spinal cord nerve fibers in animals. One interesting technique is to genetically engineer cells grown outside the body to produce specific growth factors like miniature factories, and then to implant these into the damaged area of the spinal cord or brain. Another approach is to chemically deactivate specific, natural, inhibitory chemicals that are found in the mammalian spinal cord - thus permitting the nerve fibers to begin regeneration. These techniques are still restricted to the realm of laboratory animal experimentation, but they are inventive and potentially useful.

At Purdue we induce spinal nerve fiber regeneration, and to some extent guide it, through the use of an applied electrical field. Very weak electrical fields are a natural part of embryonic development, particularly the nervous system, and a natural control of wound healing in animals. Though once considered controversial, it is now clearly established that artificially-applied, weak electrical fields can direct the growth of normal, or injured, nerve fibers. We use a very weak electrical field (thousandths of one volt) to induce and guide nerve regeneration in the two laned traffic of the spinal cord. We have proven this occurs in the adult guinea pig, and have developed a clinical treatment around this fact. In an experimental treatment for paraplegia in dogs, we reverse the polarity (positive pole/ negative pole) of the applied field imposed over the region of injury every 15 minutes using an implantable electronic circuit. This is done to facilitate nerve regeneration in both directions along this nervous tissue "superhighway". What neurosurgeons like about this technique is that the electrical leads do not have to touch the spinal cord tissue, being secured to the outside of the vertebral column. Oscillating Field Stimulation (OFS) has already been proven to be very useful in clinical trials using paraplegic dogs, (the results were first published in 1993). The treatment group was significantly more improved than the sham treated (placebo) group, if we could make the OFS implantation at the time of initial surgery, or within 7 - 12 days following the injury. We have no evidence that OFS can be useful weeks, months, or years following the injury. Our Clinical faculty, headed by Dr. Jim Toombs has just completed a second clinical trial of this technique in spinal injured dogs using a new OFS stimulator designed in part for eventual human use. This trial was successful as well (J. Neurotrauma 16(7): 639-657, 1999). It is also clearly established by both clinical trials that this technique is completely safe. It is our desire to now move this technique into human clinical testing.

The adjacent figure is a radiograph of an OFS unit implanted within a spinal injured dog. The arrows point to the location of electrical leads, the spinal cord injury was located between them.

Taking a Pill for Paraplegia

Another means to restore nerve impulse traffic in both directions through the injured spinal cord is to allow these impulses to cross the regions on the nerve fibers that have been denuded of their insulation, myelin. The electrical conduction of nerve impulses are blocked at these regions, and though the fiber may be intact, it is still "silent" as discussed above. If nerve impulses do not decay in this damaged region, but are conducted to the other side, than they are carried throughout the rest of the nervous system in a normal fashion. The drug 4 aminopyridine (4 AP) can indeed allow this to happen. Former Center researcher Dr. Andrew Blight (now at the University of North Carolina) first explored this technique in laboratory animals, and later moved the research to clinical cases of paraplegic dogs with Dr. Toombs and his colleagues at our Center. The drug was administered by injection, and behavioral improvements could be observed sometimes within 15 minutes. This breakthrough was subsequently moved to limited human testing in two Canadian medical centers with colleagues Dr. Keith Hayes and Dr. Robert Hansebout. Their results extended the utility of 4 AP in human quadriplegic and paraplegics. As an observer to the first human trials of the drug, I particularly remember one man, 5 years after his injury, who began to breath again more normally within 1/2 hour of the administration of the drug. Now several more clinical trials of the drug in spinal cord injury have been completed in the US and Canada, organized by the drug company Acorda Therapeutics. Some of these have employed oral administration of the drug to patients. It is still to soon to forecast when this new clinical tool will be deemed both safe and acceptable to be provided as a treatment to spinal injured people by subscription under doctor's supervision. I also want to point out that this is not a "cure", and that the drug does not produce beneficial results in all patients. However, it is an important first step towards a treatment for persons who have been injured for a long time, perhaps offering them recoveries of function that can improve the quality of their life. For quadriplegics who cannot feed themselves, to be able to move their arms enough to do this is a big step towards independence.

Like any powerful drug there is a limit to how much of it can be dissolved into the body's circulation. Therefore, there are some persons who might benefit from 4 AP application, but simply cannot tolerate a high enough concentration of the drug to be helpful. Purdue researcher's have continued to investigate another interesting way to deliver the drug to circumvent this problem. We can now deliver 4 AP directly to the spinal injury through a implanted tube so that the local concentration of the drug at the injury is very high, but eventually becomes very dilute in the blood to be nearly undetectable. The tube is connected to a completely implanted pump that can deliver the drug for months before being refilled through the skin by special techniques. The pumps are already used in humans to aid in drug delivery of various kinds, the technique being called "intrathecal" application. Several years ago we pioneered this intrathecal technique in dogs using 4 AP. This was accomplished by our team working with former Indiana University Neurosurgeon, Kimbal Pratt. Since the publication of those results others have investigated the intrathecal application of 4 AP in spinal injured humans. There is still much to do now that this general approach towards treatment of SCI has become feasible.

The adjacent drawing shows the round pump (approximately 2 1/2" in diameter) implanted within a paraplegic dog. An actual radiograph of one of these dogs is also provided.

Saving the spinal cord by using the gut and molecular bandaids for nerve repair.

What once used to be considered science fiction is now becoming science fact, and what used to be perceived as fanciful is now becoming practical. This is indeed the new age of neuroscience that we are living in. Who would have ever thought that a pill could recover some lost functions in paralyzed humans when swallowed years after their injury? We are very proud of our Center's achievements in developing the examples discussed above near to - or into - human clinical testing. This is our Center's mission as a division of Purdue University. However, there are still some amazing and inventive techniques that Center researchers are still creating, though they are yet restricted to laboratory animal testing in rat and guinea pig.

We have already discussed that it would be important to find a "replacement" graft of nervous tissue for damaged regions of the brain or spinal cord. This is the aim of so called "fetal nervous tissue" grafts, where nervous tissue from the fetus is surgically removed and re-implanted in damaged areas of the central nervous system. There is evidence that such grafts can thrive, if they are not rejected as "foreign" tissues, and may even cause some recovery of function. The drawbacks are that it would be very dangerous to suppress the immune system of spinal injured persons with special drugs allowing the graft to persist in its new location. In the United States, the use of fetal tissue is also a very controversial subject - leading to a presidential ban on any use of human-derived material. We have developed an alternative to this technique. Our source of nervous tissue is the gut, where nerves constantly renew themselves anyway. Moreover, the body will not reject a tissue graft if the donor and the host are the same individual. We have shown that nerve cells removed from the gut can be grafted to a spinal cord injury in the same animal and can survive indefinitely (over a year in a laboratory rat). We need to determine a means to increase the number of gut nerve cells that can be transplanted to the spinal cord, and finally determine if they actually function in their new location. This work is fascinating, but moving very slowly as it is not easily funded - preference always seems to be given to the better known fetal techniques.

Another interesting and potentially breakthrough technology involves the repair of individual nerve fibers using special chemicals that can both repair holes in nerve membranes - even fuse the two segments of a cut nerve fiber back together again. One can think of this technique as a molecular/chemical "bandaid" that prevents injured nerve fibers from proceeding on to separation and death. This has previously been accomplished using the giant nerves of earthworms. Dr. Riyi Shi of our Center has shown that immediate repair of nerve fibers is possible in severed and compressed adult guinea pig spinal cords. This offers the promise of rescuing substantial portions of damaged spinal cord at the time of initial surgery. We hope to move this technology called "PEG-mediated neural repair" into clinical testing of naturally-occurring paraplegic dogs soon.

These are just a few of the many avenues we are exploring to provide new treatments for spinal cord injury. Some of these techniques may have application to brain injury as well. For this and other reasons we are trying to increase faculty strength in experimental head injury, and to formalize our relationship with several Medical Centers such as Indiana University Medical Center and the University of Chicago Hospitals and Clinic. Through such partnerships we hope to speed the development of treatments from the "laboratory bench" to the "bedside".


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