Spinal Cord Injury The Role of Research

1. Spinal Cord Injury & The Role of Research Melvin S. Mejia, MD Physical Medicine and Rehabilitation MetroHealth Rehabilitation Institute of Ohio

2. History of treatment of SCI Accounts of spinal cord injuries and their treatment date back to ancient times, even though there was little chance of recovery from such a devastating injury. Earliest account found in an Egyptian papyrus roll manuscript (~1700 B.C.) = 2 spinal cord injuries involving fracture or dislocation of the neck accompanied by paralysis.* The description of each was "an ailment not to be treated.� Greek physician Hippocrates (460-377 B.C.) = no treatment options for spinal cord injuries, but rudimentary forms of traction has been used to treat spinal fractures without paralysis. (Hippocratic Ladder and the Hippocratic board as traction devices). Hindu, Arab, and Chinese physicians also developed basic forms of traction to correct spinal deformities, these same principles of traction are still applied today.

3. In ~ 200 A.D. = Roman physician Galen introduced the concept of the central nervous system when he proposed that the spinal cord was an extension of the brain that carried sensation to the limbs and back. 7th century A.D. = Paulus of Aegina recommended surgery for spine fracture to remove the bone fragments that he was convinced caused paralysis. 1543 = Renaissance physician and teacher Vesalius described and illustrated the spinal cord in all its parts. The illustrations in his books gave physicians a way to understand the basic structure of the spine and spinal cord and mechanics of injury. The words we use today to identify segments of the spine - cervical, thoracic, lumbar, sacral, and coccygeal - come directly from Vesalius. 19th century = through advances in sterilization, spinal surgery could finally be done with a much lower risk of infection. 1920s = Xrays gave surgeons a way to precisely locate the injury and also made diagnosis and prediction of outcome more accurate. Mid 20th century = standard method of treating spinal cord injuries was established - reposition the spine, fix it in place, and rehabilitate disabilities with exercise. 1990s = the discovery that the steroid drug methylprednisolone could reduce damage to nerve cells if given early enough after injury gave doctors an additional treatment option.

4. How Does the Spinal Cord Work?

5. Spine & Spinal cord Anatomy The spinal column is made up of 33 bones called vertebrae, each with a circular opening encasing the spinal cord. The vertebrae can be organized into sections, and are named and numbered from top to bottom according to their location along the backbone: Cervical vertebrae (1-7) located in the neck Thoracic vertebrae (1-12) in the upper back (attached to the ribcage) Lumbar vertebrae (1-5) in the lower back Sacral vertebrae (1-5) in the hip area Coccygeal vertebrae (1-4 fused) in the tailbone The circumference of the spinal cord varies depending on its location: larger in the cervical and lumbar areas because these areas supply the nerves to the arms and upper body and the legs and lower body, which require the most intense muscular control and receive the most sensory signals.

6. The spinal cord is organized into segments and named and numbered from top to bottom: Each segment marks where spinal nerves emerge from the cord to connect to specific regions of the body. L Locations of spinal cord segments do not correspond exactly to vertebral locations, but they are roughly equivalent. Cervical spinal nerves (C1 to C8) control signals to the back of the head, the neck and shoulders, the arms and hands, and the diaphragm. Thoracic spinal nerves (T1 to T12) control signals to the chest muscles, some muscles of the back, and parts of the abdomen. Lumbar spinal nerves (L1 to L5) control signals to the lower parts of the abdomen and the back, the buttocks, some parts of the external genital organs, and parts of the leg. Sacral spinal nerves (S1 to S5) control signals to the thighs and lower parts of the legs, the feet, most of the external genital organs, and the area around the anus. The single coccygeal nerve carries sensory information from the skin of the lower back. In additional to nerves coming into and out of the spinal cord at different segments, the spinal cord also conveys information between the brain and the periphery via large bundles of nerves, called tracts or columns.

7. Descending and Ascending Tracts

8. Spinal cord organization The organization of the spinal cord is elegant. In cross-section, it looks like a butterfly on an oval background. butterfly shape = gray matter, contains nerve cell bodies Oval background = white matter, has the axons, extensions from nerve cells that carry messages. In unstained tissue, the white matter appears white because axons are wrapped with an fatty insulating substance called myelin.

9. Cells : Neurons The spinal cord contains nerve cells, surrounded by long tracts of nerve fibers consisting of axons. The H-shaped grey matter of the spinal cord contains motor neurons that control movement, smaller interneurons that handle communication within and between the segments of the spinal cord, and cells that receive sensory signals and then send information up to centers in the brain. Surrounding the grey matter of neurons is white matter. Most axons are covered with an insulating substance called myelin, which allows electrical signals to flow freely and quickly. Myelin has a whitish appearance, which is why this outer section of the spinal cord is called "white matter."

10. Axons carry signals downward from the brain (along descending pathways) and upward toward the brain (along ascending pathways) within specific tracts. Axons branch at their ends and can make connections with many other nerve cells simultaneously. Some axons extend along the entire length of the spinal cord.

11. Descending and Ascending Tracts

12. Glial cells Only 10% of brain and spinal cord cells are neurons. The remaining 90% are support cells called glia (Latin for glue, as these cells bind the nervous system together) Many neuroscientists thought that glia were passive cells that did little except provide support for neurons. Because of this and a lack of good imaging techniques, glia have been all but ignored until recently. In the last few years, new technology for staining and imaging glia have been developed that allow scientists to better understand what these cells do. Glial cells include astrocytes, oligodendrocytes and Schwann cells.

13. Astrocyte Astrocytes make chemicals, or neurotrophic factors, that are like vitamins for neurons for nourishment and for energy. They are thought to play an important role in nerve cell communication (control messages sent). Neurons communicate by releasing chemical molecules called neurotransmitters into the tiny gap between nerve cells. Astrocytes mop up and break down extra neurotransmitter, as the extra can be toxic to surrounding cells. An excess of the neurotransmitter glutamate is particularly dangerous and is thought to be a major culprit in the secondary cell death after spinal trauma. Certain types of astrocytes are also responsible for building the scar around an injury site. The scar is a physical barrier to regeneration.

14. Oligodendrocyte Oligodendrocytes are cells that coat axons in the cetral nervous system with their cell membrane forming a specialized membrane called myelin, producing the so-called myelin sheath. myelin sheath provides insulation to the axon that allows electrical signals to propagate more efficiently. Normal myelin is formed by approximately 30 wraps round an axon, although remyelination studies have shown that messages can be sent with as few as 3-10 wraps. When oligodendrocytes are damaged and myelin in disrupted, the neurons cannot communicate effectively

15. Myelin after a spinal cord injury, myelin releases chemicals that stop neurons from regenerating. ** Thus myelin, while essential for normal communication in the nervous system, also inhibits regeneration after injury.

16. Schwann Cell Produces myelin in the peripheral nervous system. Both schwann cell and oligo-dendrocyte provide the necessary insulation that allows nerve cells to send electrical signals They both support nerve cells and their axons by releasing beneficial chemicals and molecules. One minor difference between the two cell types is that one Schwann cell myelinates only one axon, while oligodendrocytes myelinate many axons.

17. The major difference between the two myelin makers = Schwann cells do not inhibit regeneration. In fact, Schwann cells support axon regrowth. They also clear cellular debris that allows for regrowth of PNS neurons. In the peripheral nervous system, Schwann cells act as a guide for regenerating axons by creating a tunnel system that the nerve sprout can grow through. Regenerating axons that contact a Schwann cell tube will grow 3-4 mm a day, while sprouts that don't contact tubes die off. Research has shown that Schwann cells may be beneficial in the central nervous system, even though this is not their natural home. 

18. Macrophages Macrophages are one of the body's most talented cell types. These cells, which are born in bone marrow and circulate in the blood until needed, clean up cellular garbage, marshal the body's response to injury or disease, attack invading bacteria and pathogens, promote the formation of scar tissue and are able to produce over 100 different substances. Macrophages modulate the inflammatory response and stimulate the immune system. They are a critical part of the body's response to injury. However, there is controversy about the role of macrophages in central nervous system injury. The brain and spinal cord are immunologically privileged sites, that is in the healthy human there is very little immune function in the central nervous system. When the brain or spinal cord are injured, the blood-brain barrier is broken and macrophages run into the injury site. In the periphery, this is a good thing. In the central nervous system, however, macrophages may cause more damage than good. A primary function for macrophages is to clean up cellular debris. After central nervous system injury, they may consume and destroy cells that have been damaged but could recover, leading to an increase in secondary damage. 

19. ProCord - Spinal Cord Injury treatment ProCord is an autologous activated macrophage therapy, for the treatment of patients with acute complete spinal cord injury. Following injury, a type of white blood cell, called a macrophage, is quickly mobilized, and starts to remove cell debris. These macrophages then start to secrete growth factors that promote a controlled inflammatory reaction, the initial phase of the wound healing process. While this process normally occurs in most tissues, including peripheral nerves, it does not occur in the central nervous system (CNS), including the spinal cord. Preclinical studies led by Prof. Michal Schwartz of the Weizmann Institute of Science have shown that specially-treated macrophages promote recovery from spinal cord injury (SCI). Based on these findings, Proneuron is developing ProCord as a clinical product to treat spinal cord injury patients. ProCord consists of macrophages isolated from the patient's own blood, co-incubated with the patient's skin in a proprietary process and then injected directly into the patient's injured spinal cord.

20. Mechanics of a spinal cord injury? Vertebrae can still be broken or dislocated in a variety of ways and cause traumatic injury to the spinal cord. The segment of the cord that is injured, and the severity of the injury, will determine which body functions are compromised or lost. Thus, a spinal cord injury can have significant physiological consequences.

21. Most injuries to the spinal cord don't completely sever it. An injury is more likely to cause fractures and compression of the vertebrae, which then crush and destroy few or many axons. Some injuries will allow almost complete recovery. Others will result in complete paralysis. Improved emergency care for people with spinal cord injuries and aggressive treatment and rehabilitation can minimize damage to the nervous system and even restore limited abilities. Advances in research are giving doctors and patients hope that all spinal cord injuries will eventually be repairable.

22. A spinal cord injury usually begins with a sudden, traumatic blow to the spine that fractures or dislocates vertebrae. The damage begins at the moment of injury when displaced bone fragments, disc material, or ligaments bruise or tear into spinal cord tissue. Axons are cut off or damaged beyond repair, and neural cell membranes are broken. Blood vessels may rupture and cause heavy bleeding in the central grey matter, which can spread to other areas of the spinal cord over the next few hours. Within minutes, the spinal cord swells to fill the entire cavity of the spinal canal at the injury level. This swelling cuts off blood flow, which also cuts off oxygen to spinal cord tissue. Blood pressure drops, sometimes dramatically, as the body loses its ability to self-regulate. As blood pressure lowers even further, it interferes with the electrical activity of neurons and axons. All these changes can cause a condition known as spinal shock that can last from several hours to several days. Although there is some controversy among neurologists about the extent and impact of spinal shock, and even its definition in terms of physiological characteristics, it appears to occur in approximately half the cases of spinal cord injury, and it is usually directly related to the size and severity of the injury. During spinal shock, even undamaged portions of the spinal cord become temporarily disabled and can't communicate normally with the brain. Complete paralysis may develop, with loss of reflexes and sensation in the limbs. The crushing and tearing of axons is just the beginning of the devastation that occurs in the injured spinal cord and continues for days. The initial physical trauma sets off a cascade of biochemical and cellular events that kills neurons, strips axons of their myelin insulation, and triggers an inflammatory immune system response. Days or sometimes even weeks later, after this second wave of damage has passed, the area of destruction has increased - sometimes to several segments above and below the original injury - and so has the extent of disability.

23. Facts and Figures January 2008* Annual incidence of SCI (not including those who die at the accident = 40 cases per million in the US or an estimated 12,000 new cases each year. cord injuries every year in the United States. Age at injury = from 1973 � 1979: 28.7, most injuries occurred between the ages of 16-30 since 2005: average age of injury is 39.5. since 2000: % older than 60 yrs of age at injury increased from 4.7% to 11.5% Gender = since 2000: 77.8% men Ethnic representation = from 1973 � 1979 : 76.8% Cauc, 14.2% African American, 6% Hispanic, 3% other since 2000: 63.0% Cauc, 22.7% African American, 11.8% Hisp, 2.4% other Causes of SCI = since 2005: 42% motor vehicle accidents 27.1% falls 15.3% violence (gun shot wounds primarily) 7.4% sports 8.1% other / unknown Neurologic level and extent of lesion = since 2000: 34.1% incomplete tetraplegia 23.0% complete paraplegia 18.3% complete tetraplegia 14.6% (18.5%) incomplete paraplegia Level of injury = most frequent neurologic level of injury : C5, followed by C4, C6, T12, and L1. Overall about half are cervical injuries and half are either thoracic, lumbar, or sacral injuries. Causes of death = pneumonia, pulmonary embolism, septicemia *Source: Facts and Figures at a Glance, January 2008. National Spinal Cord Injury Statistical Center.

24. Effects of SCI

25. Multiorgan system effects of SCI A. Cardiovascular effects 1. blood pressure changes, changes in heart beat 2. blood clots 3. autonomic dysreflexia B. Respiratory changes 1. changes in breathing 2. increased risk for pneumonia 3. blood clots in lungs C. Bowel and bladder changes D. Changes in Reproduction E. Pressure ulcers F. Pain G. Spasticity H. Hormonal changes 1. diabetes 2. obesity 3. changes in fat metabolism 4. vitamin deficiencies 5. osteoporosis and increased risk for fractures

26. Cellular Mechanisms of Damage in SCI Changes in blood flow cause ongoing damage Major reduction in blood flow Cord blood vessels become leaky and swollen Net effect: decreased Oxygen delivery and nutrients to nerve cells, causing many of them to die As reduction of blood flow progresses ? self regulation begins to turn off ? BP and HR drop

27. Excitotoxicity Excessive release of neurotransmitters (Glutamate) lead to excitotoxicity Normally, glutamate released by nerve cells is kept in check because astrocytes remove the excess glutamate via a transporter pump Injured neurons produce reactive Oxygen that damages the transporter, thus glutamate accumulates further Calcium buildup ? blocks transmission of messages ? kills neurons and supporting cells (glial cells) As more nerve cells die, more glutamate is released, creating a cycle of destruction Surviving glial cells may malfunction, letting the excitotoxicity run its course

28. Inflammation An invasion of immune system cells creates inflammation ? fluid accumulation and the influx of immune cells - neutrophils, T-cells, macrophages, and monocytes; cytokines recruit T cells into the injury site after spinal cord injury, many damaged but surviving neuronal and glial cells of the spinal cord are 'tagged' for removal even though it is possible that these cells could recover and function again. Research suggests that up to 70% of the damage seen after a spinal cord injury may be due to the body's own immune system response. Whether or not the immune response is protective or destructive is controversial among researchers. Some speculate that certain types of injury might evoke a protective immune response that actually reduces the loss of neurons.

29. Nerve cells destruct Destruction of cells from the direct insult ? cells burst ? release of toxic substances ? cause nearby cells to burst as well ? secondary cell death that can be more damaging than the original insult Recent findings have revealed that cells in the injured spinal cord also die from a kind of programmed cell death called apoptosis, often described as cellular suicide, that happens days or weeks after the injury. Apoptosis strips myelin from intact axons in adjacent ascending and descending pathways, which further impairs the spinal cord's ability to communicate with the brain.

30. Secondary damage takes a toll All of these mechanisms of secondary damage - restricted blood flow, excitotoxicity, inflammation, free radical release, and apoptosis - increase the area of damage in the injured spinal cord. Loss of myelin - Damaged axons become dysfunctional, either because they are stripped of their myelin or because they are disconnected from the brain. Scar formation (Astrogliosis) - Glial cells cluster to form a scar, which creates a barrier to any axons that could potentially regenerate and reconnect. A few whole axons may remain, but not enough to convey any meaningful information to the brain. The scar gives off chemical stop signs that inhibit axonal regeneration. R Recent research has shown that the scar is not limited to immediately around the cavity that forms at the impact site. Cavity or cyst formation � fills with fluid and becomes a barrier for axons trying to regrow into the injury site. Scientists working on cavitation are exploring ways to decrease the amount of excitotoxicity and secondary cell death, as well as ways to create a bridge through the cyst so that axons can grow through the injury site.

31. There is ongoing research studying the mechanisms of this wave of secondary damage because finding ways to stop it could save axons and reduce disabilities. This could make a big difference in the potential for recovery.

32. History of Research in SCI 1830 : scientist Theodor Schwann reported that damaged nerve cells in rabbits showed signs of regrowth or regeneration. 1890 : Santiago Ramon Cajal described how damaged nerves in mammals try to regenerate but they lacked the ability to make proper connections. He also knew that nerves in the peripheral nervous system (PNS) did regrow and that if implanted into the damaged area of the spinal cord, they could make the injured nerves re-grow. Early 1900�s : scientist J.F. Tello showed nerves can regenerate but need nourishment.

33. Human SCI research did not make any major progress until after World War II with the advent of antibiotics and improved surgical techniques, helping more individuals survive their initial SCI. Researchers then turned their focus to explore the spinal cord, its cells and how the nerves work. But since the results were initially unsuccessful, some adopted the credo of "do no harm and do no surgery." During the Korean War a more aggressive surgical paradigm was established.

34. 1960s : Drs. Robert White and Maurice Albin experimented with cooling of the injured spinal cord in an animal model showing efficacy of induced hypothermia directly to the spinal cord. The results of cooling and myelotomies, however, could not be replicated in humans. During the 1960�s : Rita Levi-Montalcini and Viktor Hamburger discovered a substance that nourished nerve cells to help them grow = nerve growth factor (NGF). 1969: Raisman in 1969 showed that nerves can make new connections and that the central nervous system has the capacity to reorganize. 1980�s: scientists had success using peripheral nerve grafts in rats to show that axons can regrow. However, Martin Schwab showed that blockers or inhibitors found in the CNS stopped this growth. Researchers� next focus was to find ways to prevent these blockers from stopping nerve fibers� growth.

35. At the same time, Goodkin's research using cats documented the sequential changes that occur in the spinal cord at specific intervals from 2 minutes to weeks after injury. These studies showed that there is a critical period - between 3 and 8 hours after injury - in which treatment must occur in order to be effective. This research dovetailed nicely with experiments using steroids in the late 1960s. At the time, steroids were used successfully to treat brain tumors. While similar doses were not effective in reversing the neurological deficit from spinal cord disorders, massive doses - four times the amounts given to brain tumor patients - were found to improve neurological deficit in these patients. "Now it's the standard to give massive doses of steroids within the first eight hours after injury," Goodkin said.

36. The progress of SCI research often seems frustrating and slow (Goodkin) . "So far humans do not appear to follow what works in other animals in the case of spinal cord injury." Furthermore, the researcher is able to control the injury in animal studies, whereas in humans, each injury is unique.

37. Neurosurgeons today have a better understanding of when to operate - and when not to operate - to stabilize the spine or decompress the spinal cord than they did 20 years ago. Yet in spite of huge advances in neurological and orthopedic spine surgery, a surgical cure for the permanently spinal cord injured patient is still a dream. Claims of such cures periodically surface in the public media, but none of these claims so far has survived close scrutiny. *Sygen Consumers need to examine carefully when they a claim for cure surfaces in the popular media. Currently, there are several avenues of SCI research that show some promise, Goodkin said. Based on the theory that scarring from injury adversely affects recovery, drug treatments that prevent scarring are being investigated. Fetal cell transplants to treat syringomyelia (a secondary complication of spinal cord injury that can cause increased weakness and pain) are in the pilot phase now and may enter phase II soon. "Everything looks good in phase 1," Goodkin cautioned. "First results are sometimes the best."

38. Increased funding during the past 15 years has provided for more research in the area of spinal cord injury. The ultimate goal is for an individual to regain full function. However, �cure research� technically involves all phases of care, beginning with the effective handling of the patients at the time of injury, during acute care and through rehabilitation.

39. The Role of Scientific Research Can an injured spinal cord be rebuilt? investigators try to understand the underlying biological mechanisms that either inhibit or promote new growth in the spinal cord why nerve cells fail to regenerate after injury in the adult CNS? Need to understand cellular and molecular mechanisms involved in both the working and the damaged spinal cord that could point the way to therapies that might prevent secondary damage, encourage axons to grow past injured areas, and reconnect vital neural circuits within the spinal cord and CNS. Research into embryonic and adult stem cell biology has furthered knowledge about how cells communicate with each other.

40. Basic Research Basic research has helped describe the mechanisms involved in the mysterious process of apoptosis, in which large groups of seemingly healthy cells self-destruct. New rehabilitation therapies that retrain neural circuits through forced motion and electrical stimulation of muscle groups are helping injured patients regain lost function. Researchers are focused on advancing our understanding of the four key principles of spinal cord repair: 1. protecting surviving nerve cells from further damage 2. Replacing damaged nerve cells 3. Stimulating the regrowth of axons and targeting their connections appropriately 4. Retraining neural circuits to restore body functions Because the molecular and cellular environment of the spinal cord is constantly changing from the moment of injury until several weeks or even months later, combination therapies will have to be designed to address specific types of damage at different points in time.

41. Neuroprotection How can the damaged nerve cells at the site of the injury be protected and kept alive? there is a risk for further (secondary) damage after an SCI Researchers have been studying ways to medically stabilize the patient, relieve pressure on the spinal cord and prevent scar and cyst formation. They are also looking at using multiple treatments to prevent secondary damage and late cell death.

42. Research in the area of neuroprotection includes the following: Methylprednisolone: anti-inflammatory steroid; first drug shown to reduce spinal cord damage by preventing swelling and inflammation at the injury site. Methylprednisolone is now the American "standard of care." It is given to most individuals within 8 hours after their spinal cord injury; however, its true benefits are still being debated. Interleukin-10Interleukin-10 (IL-10) is a potent anti-inflammatory substance. Researchers at the Miami Project use IL-10 in their research with rats: recovered significant use of their hind limbs during the weeks following injury. Further study is needed before this drug can be tested on humans. Findings with animals show that more is not better as two doses of this highly effective drug can reverse its protective benefits. GM-1 Ganglioside (Sygen)The drug Sygen (GM-1 ganglioside) showed it enhanced nerve growth and regeneration in injured cats. It also counteracted some of the secondary damage. The news of these results had individuals requesting immediate access to this potential �cure� for spinal cord injury rather than waiting for further research studies. A human clinical trial on the use of Sygen was undertaken. But, the results were disappointing. The company has now taken the drug off the American market.

43. Glutamate Receptor Blockers Large amounts of glutamate can kill nerve cells by causing them to fire excessively. Animal studies have shown that Glutamate receptor blockers decrease this harmful activity and further damage to the spinal cord. Human clinical trials are being performed in stroke patients. Clinical trials with spinal cord injury patients could begin within a few years. 4-Aminopyridine The drug Fampridine-SR (also known as 4-aminopyridine or 4-AP) does not have neuroprotective effects. However, research does show it improves function in surviving spinal cord nerve cells long after the injury. 4-AP allows de-myelinated axons to send signals.

44. Other Neuroprotective TreatmentsResearch continues on other treatments to prevent or lessen the secondary damage caused by an SCI. These include preventing scar formation, developing improved surgical techniques to stabilize and decompress the spinal cord, and designing a more effective system to get drugs to the spinal cord. Some possible treatments under investigation include: Cyclohexamide, hypothermia (reducing body temperature to decrease metabolism and excitotoxicity) and opioid antagonists (i.e. Naloxone).

45. Regeneration & Transplantation Is it possible to get nerves to grow and regenerate? Are there factors preventing spinal nerve regrowth? What can be done to promote correct �connections� on both sides of the injury? What can be done to make it easier for nerves to grow? Researchers are investigating many different areas for answers to these questions on spinal cord regeneration.

46. Promoting regeneration Researchers are experimenting with cell grafts transplanted into the injured spinal cord that act as bridges across injured areas to reconnect cut axons. Several types of cells have been studied for their potential to promote regeneration and repair, including Schwann cells, olfactory ensheathing glia, fetal spinal cord cells, and embryonic stem cells

47. Olfactory ensheathing glia (OEGs) Olfactory neurons allow mammals to sense smells They are one of the very few central nervous system (CNS) nerves that regenerate normally. This regeneration is aided by cells called olfactory ensheathing glia or OEGs. Several studies have found that OEGs can help regeneration after spinal cord injury when used as a combination therapy. improved locomotor abilities with the combination of the Schwann cells + OEGs; holds great promise and may eventually become part of new clinical treatments for spinal cord injury.

48. Scientists are excited about olfactory tissue because, unlike spinal cord tissue, it contains so many cells with regenerative potential, including a source of renewable neurons, progenitor stem cells, and remyelinating OECs. Olfactory cells readily replicate and regenerate, turning over every 60 days throughout life (cells in different stages of neurogenesis) As neurons mature, they migrate from the base to the surface of the tissue and replace mature neurons, which die through apoptosis, a form of programmed cell death. The source of these new cells / neurons is a pool of progenitor stem cells that reside at the tissue base. Due to their potential to differentiate into cells that can treat neurological disorders, stems cells have been the focus of much research and also controversy because they have often been isolated from fetal tissue, a stigma olfactory-derived stem cells avoid. Olfactory Ensheathing Cells: (OECs/ OEGs) Enhance the axonal regenerative potential of damaged axons in the spinal cord: 1). produce insulating myelin sheaths around both growing and damaged axons in the spinal cord, 2) secrete various growth-enhancing neurotrophic agents, and 3) produce structural and matrix macromolecules that lay the tracks for axonal elongation. OECs promote axonal regrowth when implanted in areas that normally do not readily regenerate, such as the spinal cord. OEC-remyelinated spinal cord axons have been shown to penetrate the scar at the injury site, and then to migrate to their correct targets, restoring function. the implanted OECs provide an insulating armor that enables the struggling axon to fend off the inhibitory molecular clubs, pass through the gauntlet, and travel back home in a more receptive environment. OECs provide new conduction-restoring myelin insulation in the majority of the intact nerve cells that lack myelin Because only a small amount of functional neurons (10-15%) are needed to regain significant function, olfactory-tissues regeneration-fostering properties cumulatively portend much promise for SCI.

49. Animal Studies: Many animal studies have documented olfactory tissue�s potential to restore function after SCI. key 1994 study: Drs. Ramon-Cueto and Nieto-Sampedro (Madrid) severed rat dorsal nerve roots, the location where sensory nerves connect to the spinal cord. After reconnecting these nerves, they implanted OECs, which promoted axonal growth back into the cord, a process that normally does not happen 1998: Dr. Imaizumi and colleagues (PVA/EPVA Center for Neuroscience and Regeneration Research, Yale U.), and Dr. Li et al., (London): demonstrated that OECs could remyelinate the experimentally injured rat spinal cord. 2000: Dr. Ramon-Cueto et al: OECs injected into the transected rat spinal cord could promote axonal regrowth across the scar and functional improvement, including locomotion, weight bearing, and sensory perception. Dr. Lu et al. (Australia): OECs promote regeneration and locomotion in the rat spinal cord when implanted four weeks (i.e., a animal model for chronic injury) after cord transection. Currently, Dr. Lima studies: rats with severe, chronic injuries received transplants of their own olfactory tissue that includes not only OECs but also regenerating neurons and stem cells. These studies are essential for U.S. FDA clinical trial approval to replicate the ongoing Portuguese clinical trial by Dr. Lima�s team.

50. Human Transplantation: If the patient is the source of transplantation material, immunosuppressive drugs will not be needed to minimize tissue rejection Procedure involves a simple biopsy nostril, which will not affect long-term olfactory capability Scientists have transplanted both OECs and olfactory tissue into patients with SCI Portugal�s Dr. Carlos Lima implanted olfactory tissue back into the spinal cords of seven patients. Lima believes that more than one cell type is needed to maximize regeneration in the injured cord, including, in addition to OECs, neurons in different developmental stages, and precursor stem cells In Australia Dr. Alan MacKay-Sim�s team has implanted OECs previously isolated and cultured from the patient back into the cord. In China: Dr. Hongyuan Huang offers a third approach. He transplanted OECs isolated from fetal tissue into more than 150 patients. Because of fetal tissue�s undifferentiated nature, immunosuppression drugs have not been required so far. Although these preliminary efforts are promising, much still needs to be learned before a definitive judgment can be made on the therapys true potential. Conclusion: Growing evidence indicates that olfactory tissue and ensheathing cells have considerable potential to repair the traumatically injured spinal cord.

52. Lima experiments: Patients: Tests: Patients were subjected to various neurological, neurophysiological (i.e., neuronal conduction), magnetic resonance imaging (MRI), bladder-functioning, and psychological assessments before and after treatment. ASIA testing / scoring: Patients were excluded if they had psychological disturbances, multiple spinal cord lesions, confounding medical conditions, arm or leg denervation, or severe spinal cord atrophy. From July 2001 to the beginning of 2003, Lima�s team has operated on four female and three male patients. Three were quadriplegics and four paraplegics. Six of the seven had ASIA-classified complete injuries. Age: ranged from 11-32 (averaging 22) Time between injury and surgery varied from � - 6 � years Length of spinal cord lesions: ranged from 1-6 cm (1 cm = .39 inches) in length, although Lima now believes that the lesion optimally should be less than 2-3 cm Most injuries were contusion injuries, similar to those sustained in car accidents. Surgery: The surgery consists of harvesting olfactory tissue from the patient�s nasal cavity, preparing it, and implanting it back into his or her spinal cord injury site. The procedure takes 4-6 hours depending upon injury level and extent of injury, presence of fixation plates or screws, etc. The patient is discharged from the hospital after 4-7 days. The neurosurgeon exposes the cord�s injury site with a laminectomy and then myelotomy (cutting open the cord�s membrane coverings). Scar tissue is removed / holes are made through the scar. As the cavity is being prepared, Lima dissects the isolated olfactory tissue into 20-30 pieces while it is immersed in a small amount of the patient�s cerebrospinal fluid. The pieces are then implanted into the cavity. Lima estimates that a 1 cm2 cavity filled by this tissue will contain approximately 400,000 stem cells and 4 million each of mature neurons, immature neurons, and other supporting cells.

53. Outcomes: Although preliminary results are promising, Lima emphasizes that much follow-up work is needed to document long-term benefits and any delayed side effects. Using the ASIA standards, six of the seven patients regained some sensation and muscle control within a month of surgery. Because the seventh patient had a second undetected lesion, he did not improve. Lima suggests that this initial recovery may be due to bridging and remyelination of available axons and also perhaps due to some post-surgical cord decompression. Improvement should gradually continue with time as neurons or their axons further regenerate and grow (~ 0.1 cm/day), remyelinate, and make new connections. Overall, MRIs indicate substantial filling of and continuity in the lesions by the grafts, and electrophysiological assessments document voluntary muscle control. Lima�s patients have had access to only modest post-surgical rehabilitation. He believes maximal restored function will require much more aggressive rehabilitation.

54. Fetal spinal cord tissue implants have also yielded success in animal trials, giving rise to new neurons. Animals treated in these trials have regained some function in their limbs. Results in pts with long-term spinal cord injuries have been inconclusive. In animal models, these transplants appear to be more effective in the immature spinal cord than in the adult spinal cord. Stem cells are capable of dividing and yielding almost all the cell types of the body, including those of the spinal cord. Their potential to treat spinal cord injury is being investigated eagerly, but there are many things about stem cells that researchers still need to understand.

55. Challenge: Need to find chemical signals from the internal and external cellular to encourage proper growth and differentiation of the stem cell. Because of the complexities involved in stem cell treatment, researchers expect these kinds of therapies to be possible only after much more research is done.

56. Stimulating regrowth of axons Research on many fronts reveals that getting axons to grow after injury is a complicated task. CNS neurons have the capacity to regenerate, but the environment in the adult spinal cord does not encourage growth. For axon regeneration to be successful, the environment has to be changed to turn off the inhibitors and turn on the promoters. Investigators are looking for ways to take advantage of the chemicals that drive or halt axon growth: growth-promoting and growth-inhibiting substances, neurotrophic factors, and guidance molecules. Martin Schwab�s group in Zurich: The environment of the adult CNS is hostile to axon growth, primarily because growth-inhibiting proteins are embedded in myelin (Nogo), the insulating material around axons. These proteins appear to preserve neural circuits in the healthy spinal cord and keep intact axons from growing inappropriately. But when the spinal cord is injured, these proteins prevent regeneration. Research are underway directed at blocking the expression of Nogo or removing this protein entirely.

57. Rho Rho also prevents regeneration after injury Rho has also been implicated in increased death of neurons and other central nervous system cells. Research by Dr. Lisa McKerracher, McGill University in Montreal Canada: blocking Rho improves regeneration and cell survival in animal models. BioAxone has begun a Phase I/IIa clinical trail using Cethrin � 37 pts The BioAxone clinical trial involves the application of single dose of Cethrin � to the spinal cord during the surgery that often follows a spinal injury.

58. Increase Growth Factor ProductionDamaged nerves must first grow for regeneration to occur. The neurotrophic proteins function as �growth factors. These help prevent cell death. They also work like a "nerve fertilizer" to help neurons survive and nerves regenerate, allowing messages to flow up and down the spinal cord again.

59. Promote correct connections on both sides of injury Researchers are working with different substances to guide nerve growth so nerves grow past the injury site and reconnect with the proper nerve. Netrins: proteins produced in the brainstem, that encourage nerve cells to migrate to and grow branches toward a "target." Dr. Mark Tessier-Lavigne of Stanford University has identified netrins in several animal models and is evaluating their use with spinal cord injury. Neural Glues: can fuse together the ends of damaged nerve axons. Scientists at the Center for Paralysis Research, Purdue University, used polyethylene glycol (PEG) in guinea pigs: helps to partially restore nerve function immediately following spinal cord compression injury. It is thought that this helps restore nerve cell membranes disrupted by the spinal cord injury. Fibroblasts: act as a "bridge" across a spinal cord lesion. Scientists genetically engineer these fibroblast cells to produce neurotrophin-3. The cells can then stimulate regrowth. Rats showed improved leg function following implantation of these fibroblasts in research done by Dr. Marion Murray at MCP Hahneman University.

60. Electrical stimulation Researchers at Purdue University�s Center for Paralysis Research and Indiana University School of Medicine are using low-level electrical stimulation on paralyzed dogs. They implant a small battery pack, known as an extraspinal oscillating field stimulator (OFS), near the dog�s spine. It sends a weak electrical signal (thousandths of a volt) to the site of injury. This helps regenerate cells and guide growth in the damaged nerves. In about a third of the cases, the dogs improved significantly. The first human clinical trial of this new treatment is now underway. Patients being entered in the study must be within 18 days from the time of their injury.

61. Activated Macrophages  Based on work from Michal Schwartz, Ph.D., at the Weizmann Institute in Israel Proneuron has launched the ProCord trial, an international, multi-center, randomized-controlled, Phase II clinical trial for complete SCI. In this study, macrophages are taken from the blood of patients, activated in the laboratory and then injected into the injury site to increase the number of macrophages available for cellular clean up. Proneuron believes that these macrophages will help heal and support regeneration, ultimately leading to improved function after spinal cord injury. On the other hand, several Reeve-Irvine Research Center researchers showed that blocking macrophages and killer T cells decreased secondary damage. Which approach for dealing with macrophages in the spinal cord is the right one? It may be that different treatment techniques result in different immune responses or different molecule profiles for the cells that move into the injury site. There are also time course differences. There are conflicting views and quite a bit of data that seems contradictory. It's a story that will unfold with continued research.

62. Clinical Research 1. Restoring function through neural prostheses and computer interfaces 2. Retraining central pattern generators 3. Relieving pressure through surgery 4. Treating pain and controlling spasticity 5. Improving bladder control 6. understanding changes in sexual and reproductive function 7. Improving assistive devices 8. Promoting collaborative studies  

63. Restoring function through neural prostheses and computer interfaces Bioengineers are working to restore functional connections via advanced computer modeling systems and neural prostheses. Functional electrical stimulation (FES) system is one example of this kind of innovative research = devices that could mobilize paralyzed muscles via the interface between technology and neurobiology. Electrodes are taped to the skin over nerves or surgically implanted and then controlled by a computer system under the command of the user. For example, to assist reaching, electrodes can be placed in the shoulder and upper arm and controlled by movements of the opposite shoulder. Through a computer interface, the spinal cord injured person can then trigger hand and arm movements in one arm by shrugging the opposite shoulder.

64. Retraining central pattern generators Using a technique called sensory patterned feedback, researchers are attempting to retrain Central pattern generators in spinal cord injured patients with special programs that break down walking movements into their component patterns and force paralyzed limbs to repeat them over and over again. In one of these programs, the patient is partially supported by a harness above a moving treadmill while a therapist moves the patient's legs in a stepping motion. Other researchers are experimenting with combining body weight support and electrical stimulation with actual walking rather than treadmill training. Another technique uses an FES bicycle in which electrodes are attached to hamstrings, quadriceps, and gluteal muscles to stimulate the pedaling motion. Several studies have shown that these exercises can improve gait and balance, and increase walking speed. NINDS is currently funding a clinical trial with paraplegic and quadriplegic subjects to test the benefits of partial weight-supported walking. 

65. Relieving pressure through surgery The timing of surgical decompression (alleviating pressure on the spinal cord from fractured or dislocated vertebrae or disks) is a controversial topic. Animal studies have shown that early decompression can reduce secondary damage, but similar results haven't been reliably reproduced in human trials. Other studies have shown neurological improvement without decompression surgery, which has led some to believe that either avoiding or delaying surgery, and using pharmacologic interventions instead, is a reasonable (and non-invasive) treatment for spinal cord injuries. Additional research is needed to determine if early surgical intervention is sufficiently beneficial to offset the risk of major surgery in acute trauma.

66. Treating pain Two thirds of people with spinal cord injury report pain and a third of those rate their pain as severe. Nonetheless, both diagnosis and treatment of post-injury pain still remain a clinical challenge. There is no universally recognized scheme for classifying pain from spinal cord injury, nor is there a uniformly successful medical or surgical treatment to prevent or reduce it. Mainstays of neuropathic pain = antidepressants and anticonvulsants, even though they are not uniformly effective. Investigators are currently testing neuroprotective and anti-inflammatory strategies to calm overexcited neurons. Other studies are also looking at pharmacological options, including sodium channel blockers (such as lidocaine and mexiletine), opioids (such as alfentanil and ketamine), and a combination of morphine and clonidine. Drugs that interfere with neurotransmitters involved in pain syndromes, such as glutamate, are also being investigated. Other researchers are exploring the use of genetically engineered cells to deliver pain-relieving neurotransmitters. These treatments appear to alleviate pain in animal models and in preliminary clinical studies with terminally ill cancer patients. 

67. Controlling spasticity The mechanisms of muscle spasticity after spinal cord injury are not well understood. Loss of particular descending axonal pathways most likely results in the decreased activity of inhibitory interneurons, which causes the overreaction of motor neurons to excitatory stimuli. Medical and surgical treatments for spasticity are established and highly successful. 1. oral medications : act within the central nervous system (baclofen and diazepam) and one that acts directly on skeletal muscle (dantrolene). 2. implanting pump systems that continuously supply antispasmodic drugs such as baclofen. 3. rhizotomy or myelotomy is sometimes performed to sever reflex pathways. Investigators are currently exploring neuromodulation procedures based on preliminary results showing that electrical spinal cord stimulation below the injury can modulate spasms. 

68. Improving bladder control Use of electrical stimulation and neuromodulation to achieve bladder control. The current treatment for reflex incontinence includes a surgical procedure that cuts the sacral sensory nerve roots from S2 to S4. (Brindley procecure / Vocare system). Limited participation due to loss of erectile function. Researchers hope that by combining neuromodulation for reflex incontinence with neurostimulation for bladder emptying, the bladder could be completely controlled without having to cut any sacral sensory nerves.

69. Understanding changes in sexual and reproductive function Sperm count in men may or may not change due to spinal cord injury, but sperm motility often does. Researchers are investigating whether or not spinal cord injury causes changes in the chemical composition of semen that make it hostile to sperm viability. Preliminary studies show that the semen of men with spinal cord injury contains abnormally high levels of immunologically active leukocytes, which appear to have a negative impact on sperm motility. Recent animal studies have revealed what appears to be a neural circuit within the spinal cord that is critical for triggering ejaculation in animal models and may play the same role in humans. Triggering ejaculation by stimulating these cells might be a better option than some of the current, more invasive methods, such as electroejaculation.

70. The Spinal Cord Injury Model Systems of Care & MetroHealth Rehabilitation Institute of Ohio

71. NIDRR Model SCI Systems To qualify and receive funding from NIDRR: rehabilitation programs must utilize and evaluate a prototype of SCI treatment based on providing care through the development of 5 key areas within the system: 1. EMS 2. expertise in treating trauma 3. comprehensive rehabilitation programs 4. vocational and psychological counseling services 5. community reintegration services Model systems must conduct research of interest to NIDRR and collect data on SCI Designated systems are expected to provide care to a significant volume of people with SCI

72. MetroHealth SCI Model System Staff: Gregory Nemunaitis, MD � Principal Investigator Mary Jo Roach, PhD � Project Coordinator Ron Triolo, PhD � Site Specific Project Director Jennifer Nagy, MPT � Project Manager Jeanne Marlow, RN � Research Nurse Amy Winslow, MPT Erna Savage � Database Manager

73. MetroHealth Rehabilitation Institute of Ohio SCI Model System Projects 1. National SCI Database: direct contribution to the National Spinal Cord Injury Statistical Center (Information & Statistics about SCI) web: www.spinalcord.uab.edu/ 2. Wheelchair Research Study: in collaboration with Univ of Pittsburgh

74. 3. Identifying the Best Measure of Participation: in collaboration with Craig Hospital 4. Dynamic cushion study 5. Evacuation Readiness 6. Individuals with disabilities in emergency preparedness 7. Trunk Muscle Functional electrical Stimulation 8. Preferences for Neural Prosthesis for Bladder management (survey)

75. 9. Bladder Stimulation Study 10. Vitamin D Deficiency and Osteoporosis 11. Impact of Leg Elevation with Seated Interface Pressures 12. Medical complications of SCI 13. The United States multi-center study to Assess the validity and reliability of the Spinal Cord Independence Measure (SCIM III)

76. Rehabilitation Rehabilitation is expected to be a crucial part of any cure treatment strategy. The physical therapy routines and other health care practices taught during their initial rehabilitation can help them remain healthy and maintain their flexibility and muscle strength. Researchers must continue to explore rehabilitation methods that can help in recovery after injury.

77. The Future of Research Future studies: A Multidisciplinary Approach It is more likely individuals will need a combination of therapies to return maximum function. What will be the best combination of cell based therapies to restore function after spinal injury? Surgical and rehabilitative efforts? By closely looking at and incorporating each component, it is hoped that an ideal strategy can be found.

78. *If you are participating in a trial� Why are clinical trials necessary? Why should you think carefully before enlisting in a clinical trial? How are clinical trials structured? -- phases and design of clinical trials -- how would participation affect you? -- what if you get assigned to a control group� -- what should you expect after a clinical trial? You have been invited to a clinical trial, how do you decide? Where can you get advice?

79. The following web links offer more detailed information on the research discussed in this paper. For additonal information on Research and Research for the Cure, visit the SpinalCord Injury Information Network web pages at www.spinalcord.uab.edu/show.asp?durki=21783 or www.spinalcord.uab.edu/show.asp?durki=21781 Prolonged treatment with methylprednisolone improves recovery in spinal cord injured patients www.ninds.nih.gov/news_and_events/pressrelease_methylprednisolone_052797.htm Interleukin-10 protects the spinal cord by reducing inflammation www.miamiproject.miami.edu/miami-project/Library/nl9912/nl991223.htm Fampridine (4-AP) study at UW http://depts.washington.edu/rehab/sci/forum-research4AP0400.shtml Fampridine-SR (Product page) www.acorda.com/pfam.htm Martin Schwab�s research groupwww.neurozh.ch/e/groups/schwab00.htm Mechanisms of axon guidance in vertegrates www.hhmi.org/research/investigators/tessierlavigne.html Neuron fusion and repair using polyethylene glycol (PEG) www.vet.purdue.edu/cpr/research.html#PEG%20repair Axonal regeneration, synaptic plasticity, recovery of function http://neurobio.mcphu.edu/MurrayWeb/murray.html Applied voltages and electrical stimulation www.vet.purdue.edu/cpr/research.html#Electrical%20Stimulation Human trial for spinal injury treatment launched by IU, Purdue www.medicine.indiana.edu/news_releases/archive_00/spinalcord_00.html Spinal cord study may offer hope for paralysis patients www.cnn.com/2000/HEALTH/12/11/spinal.cord.research.ap/index.html Swedish researchers combine treatments to repair severed rat spinal cords http://science-education.nih.gov/nihHTML/ose/snapshots/multimedia/ritn/spinal/swedish.html In a triumph of microsurgery http://whyfiles.org/023spinal_cord/karolinska.html Porcine spinal cord cells for spinal cord injury www.diacrin.com/newpage1.htm Albany med physicians first to use pig cells in spinal cord surgery www.diacrin.com/SCI%20Albany%20Surg.htm The stem cell: another promising tool www.miamiproject.miami.edu/miami-project/Library/nl0111/nl011123.htm Proneuron biotechnologies www.proneuron.com/index2.html Macrophage therapy www.proneuron.com/MacrophageTherapy.html CNS regeneration www.proneuron.com/Regeneration.html Melissa�s story www.cbsnews.com/now/story/0,1597,296665-412,00.shtml Do the locomotion... training the spinal cord to improve gaitwww.miamiproject.miami.edu/miami-project/Library/nl0004/nl000423.htm The Parastep� I System www.sigmedics.com/AboutUs/Parastep%20Technology/parastep%20Technology.htm

80. Information also is available from the following organizations: Christopher and Dana Reeve Foundation636 Morris TurnpikeSuite 3AShort Hills, NJ � 07078info@christopherreeve.orghttp://www.christopherreeve.orgTel: 973-379-2690 800-225-0292Fax: 973-912-9433The Christopher Reeve Foundation raises money to help fund spinal cord injury research and operates the Christopher and Dana Reeve Paralysis Resource Center, located in Short Hills, New Jersey and online at www.paralysis.org.National Rehabilitation Information Center (NARIC)4200 Forbes BoulevardSuite 202Lanham, MD � 20706-4829naricinfo@heitechservices.comhttp://www.naric.comTel: 301-459-5900/301-459-5984 (TTY) 800-346-2742Fax: 301-562-2401 Miami Project to Cure Paralysis/ Buoniconti FundP.O. Box 016960R-48Miami, FL � 33101-6960mpinfo@miamiproject.med.miami.eduhttp://www.themiamiproject.orgTel: 305-243-6001 800-STANDUP (782-6387)Fax: 305-243-6017Supports and conducts research and related programs in the area of spinal cord injury. National Institute on Disability and Rehabilitation Research (NIDRR)U.S. Department of Education Office of Special Education and Rehabilitative Services400 Maryland Ave., S.W.Washington, DC � 20202-7100http://www.ed.gov/about/offices/list/osers/nidrrTel: 202-245-7460 202-245-7316 (TTY)

81. National Spinal Cord Injury Association1 Church Street#600Rockville, MD � 20850info@spinalcord.orghttp://www.spinalcord.orgTel: 800-962-9629Fax: 301-963-1265Works to help those suffering from the catastrophic results of spinal cord injury and disease. Offers educational materials and also sponsors programs to empower survivors of spinal cord injury and disease through a toll-free help-line and a network of chapters and support groups.Paralyzed Veterans of America (PVA)801 18th Street, NWWashington, DC � 20006-3517info@pva.orghttp://www.pva.orgTel: 202-USA-1300 (872-1300) 800-424-8200Fax: 202-785-4452Non-profit organization dedicated to serving the needs of its members�more than 19,000 veterans paralyzed by spinal cord injury or disease, as well as caregivers and others affected by these disabilities�through advocacy, education, and research programs. Spinal Cord Society19051 County Highway 1Fergus Falls, MN � 56537http://members.aol.com/scswebTel: 218-739-5252 or 218-739-5261Fax: 218-739-5262International advocacy organization that supports research, publishes a newsletter, and sponsors an international network of chapters.Clearinghouse on Disability InformationSpecial Education & Rehabilitative Services Communications & Customer Service Team550 12th Street, SW, Rm. 5133Washington, DC � 20202-2550http://www.ed.gov/about/offices/list/osersTel: 202-245-7307 202-205-5637 (TTD)Fax: 292024507636

82. STAY TUNED!