Elsevier

Experimental Neurology

Volume 182, Issue 2, August 2003, Pages 247-260
Experimental Neurology

Review
Repair of chronic spinal cord injury

https://doi.org/10.1016/S0014-4886(03)00029-3Get rights and content

Abstract

Advances in medical and rehabilitative care now allow the 10–12,000 individuals who suffer spinal cord injuries each year in the United States to lead productive lives of nearly normal life expectancy, so that the numbers of those with chronic injuries will approximate 300,000 at the end of the next decade. This signals an urgent need for new treatments that will improve repair and recovery after longstanding injuries. In the present report we consider the characteristics of the chronically injured spinal cord that make it an even more challenging setting in which to elicit regeneration than the acutely injured spinal cord and review the treatments that have been designed to enhance axon growth. When applied in the first 2 weeks after experimental spinal cord injury, transplants, usually in combination with supplementary neurotrophic factors, and possibly modifications of the inhibitory central nervous system environment, have produced limited long-distance axon regeneration and behavioral recovery. When applied to injuries older than 4 weeks, the same treatments have almost invariably failed to overcome the obstacles posed by the neurons’ diminished capacity for regeneration and by the increasing hostility to growth of the terrain at and beyond the injury site. Novel treatments that have stimulated regeneration after acute injuries have not yet been applied to chronic injuries. A therapeutic strategy that combines rehabilitation training and pharmacological modulation of neurotransmitters appears to be a particularly promising approach to increasing recovery after longstanding injury. Identifying patients with no hope of useful recovery in the early days after injury will allow these treatments to be administered as early as possible.

Introduction

During the First World War soldiers with complete spinal cord injuries did not survive; 80 percent of British soldiers with traumatic paraplegia are estimated to have died within 3 years of injury. Survivors were chronically ill and dependent, and, because their prospects were so dismal, programs of aggressive rehabilitation were not established. Even through the early years of World War II most soldiers and civilians with spinal cord injuries died within 2–3 years from sepsis due to infections of the bladder and kidneys and infected pressure sores, which were considered to be inevitable consequences of their injuries (reviewed by Guttmann, 1976). Now, however, nearly 94 percent of patients with spinal cord injuries survive the first year after their injury and, of those that survive their initial hospitalization in specialized units, 93 percent are sufficiently independent to be discharged back into the community (DeVivo, 2002). The life expectancy of the estimated 11,000 annual victims of traumatic spinal cord injuries in the United States has improved in recent years, and this improved survival is projected to increase the prevalence rate in the United States to nearly 280,000 by 2014 (DeVivo, 2002). Many of these individuals remain healthy and productive thanks to programs designed to prevent the debilitating long-term effects of their injuries.

While these advances in care are dramatic, there remains a pressing need for treatments that will improve repair processes and recovery in individuals with longstanding spinal cord injuries. Christopher Reeve has described the daily exertions required for severely injured people to maintain physical and psychological well-being (Reeve, 1998). These individuals remain eager, even desperate, for treatments that will improve autonomic function, diminish neuropathic pain, and restore walking. Particularly for those who were injured recently, progress in treating injuries in the laboratory has made treatments in the clinic seem tantalizingly close. Patients with chronic injuries are also of research interest because they provide a potentially attractive population for the initial clinical application of experimental therapies. Because deficits of chronic patients are stable, treatments will not interfere with spontaneous recovery and spontaneous recovery will not confound the results of treatments.

Section snippets

Acutely injured central axons can regenerate

Prior to 1980 the prevailing view was that damage to the mature central nervous system (CNS) was permanent, without the possibility of repair. At best there would be local sprouting from adjacent, uninjured axons but sprouting was thought to be as likely to cause maladaptive responses, such as spasticity, autonomic dysrreflexia, and pain, as to contribute to recovery. Failure of injured axons to achieve long distance regrowth was blamed on the inability of adult CNS neurons to maintain a

What is a chronic injury?

There appears to be no generally agreed upon definition of what constitutes a chronic injury of the mammalian spinal cord. “Chronic” implies a stable injury that is undergoing little additional change, but the time at which an injury stabilizes differs depending on whether it is based on pathological or behavioral criteria. Contusion injuries in the rat continue to show development of pathology until 14 weeks (Hill et al., 2001), whereas recovery based on an open field rating score (BBB score)

Lessons from chronic peripheral nerve injuries

The prognosis is good for most peripheral nerve injuries in which the endoneurial tubes remain intact. The damaged neurons increase their expression of growth-associated molecules and the region of the injury is filled by an influx of growth-promoting Schwann cells, macrophages, and fibroblasts. The distal nerve stump provides a favorable environment for axon regrowth due to the rapid phagocytosis of degenerating myelin and increased synthesis of neurotrophic factors and substrate molecules by

The chronically injured spinal cord presents additional challenges

The chronic lesion challenges efforts to enhance regeneration in ways that acute injuries do not, in part because an increasingly inhospitable environment develops at the injury site and beyond (overview in Fig. 1). In the most common pattern of closed spinal cord injury, swelling and hemorrhagic necrosis appear within hours of the contusion in the gray matter and adjacent white matter of the injury site. Neurons, astrocytes, and oligodendrocytes die as the lesion expands over several spinal

Retrograde degeneration: death, atrophy, and metabolic failure

Strategies designed to promote regeneration after longstanding injuries assume that neurons survive and remain responsive to treatment. Axotomized rubrospinal tract neurons undergo severe atrophy that makes them difficult to recognize in Nissl-stained material, but many survive cervical spinal cord injury and remain responsive to exogenous neurotrophic factors (Kwon et al., 2002a). Supraphysiological amounts of BDNF delivered through a cannula placed in the midbrain adjacent to their perikarya

Strategies for promoting recovery from chronic injuries

The encouraging results found with acute transplantation of fetal spinal cord (FSC) tissue led to investigations to determine whether these transplants would survive in a chronic lesion site and whether neurons that had been injured for several weeks to months retained the ability to regenerate their axons, if provided an appropriate substratum. The initial studies compared survival, differentiation, and integration of FSC tissue grafted into a lumbar hemisection cavity 2 or 7 weeks after the

Neuronal response to a second injury

Studies designed to enhance chronically injured axon regeneration emphasize the importance of removing glial scar tissue to optimize integration of host and graft tissues Grill et al 1997, Houle 1991. Because sectioned supraspinal axons remain relatively close to the lesion (see above), removal of scar tissue will subject many of them to a second injury. The observation that the regenerative response of some supraspinal neurons diminishes with an increased interval between initial injury and

Changes in the lumbar cord may facilitate recovery

Cervical and thoracic spinal cord injuries spare most caudal ventral horn neurons Kaelan et al 1988, Bjugn et al 1997 and produce alterations in lumbar segments that may contribute to spontaneous recovery and be exploited therapeutically to enhance recovery after chronic injuries. One alteration that may serve as a therapeutic target is upregulation of receptors for neurotransmitters that initiate or modulate locomotion. When given to spinalized cats that have already recovered the ability to

Concluding remarks

With one exception (Coumans et al., 2001), the current experimental treatments of chronic spinal cord injury have not produced lengthy regeneration of adult CNS axons into host spinal cord when treatment has been delayed for 4 weeks or longer. Even then, regeneration depended upon a treatment paradigm that included supraphysiological exogenous neurotrophic factor support. Supraphysiological quantities of BDNF have also allowed bulbospinal neurons to regenerate into delayed grafts of peripheral

Acknowledgements

We appreciate the helpful comments of Drs. Marion Murray and Felix Eckenstein in review of the manuscript. Research in the author’s laboratories is supported by NIH NS26380, NIH NS 40008, NIH NS24707, The Veteran’s Administration, The Eastern Paralyzed Veteran’s Administration, and The International Spinal Research Trust.

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