Spinal Cord Injury

Spring 1998
Volume 9, Number 1

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Over the past several decades, progress in basic research has yielded a more complete understanding of the pathophysiology of acute and chronic spinal cord injury (SCI). This has led to clinical trials in a number of acute treatments and the widespread application of one such treatment, methylprednisolone, for human SCI. Research in chronic restorative therapies is progressing and will hopefully yield beneficial treatments in the future. Rehabilitation should progress to facilitate patient education and enable incorporation of emerging therapies as they achieve clinical applicability.

Introduction. In the past, it was commonly believed that spinal cord injury (SCI) was a condition not amenable to therapy intended to improve neurologic function. Over the past several decades, however, progress in basic research has yielded a more elaborate understanding of the underlying mechanisms of tissue damage, healing processes, and the pathophysiology of neurologic impairment after SCI. Progress in SCI research can be divided into several broad categories based on the chronologic evolution of spinal cord pathology. Acute therapies are directed at interrupting or interfering with various steps of complex biochemical cascade that is set in motion by traumatic contusion of the spinal cord. Chronic therapies are more directed at stimulating repair or regrowth of chronically damaged neural elements.

Medical Treatment of Acute SCI. Over the past several decades, animal experimentation in acute SCI has yielded a more thorough understanding of the complex biochemical processes that follow trauma to the spinal cord. While paralysis is typically immediate in onset following injury, it is now known that a significant proportion of long-term tissue damage is the result of secondary processes that evolve hours after the injury. Contusion injury to the spinal cord leads to progressive vascular and neuronal degeneration characterized by loss of auto regulation, the intracellular accumulation of calcium ions, the accumulation of vasoactive eicosanoids, excitotoxicity, oxygen free radical accumulation, and lipid peroxidation of neuronal cell membranes. A better understanding of these processes has led to the concept of a “window of opportunity” wherein pharmacologic treatment aimed at one or more of these pathophysiologic steps might limit the amount of tissue damage and thus improve the chances for neurologic recovery.

Methylprednisolone is a glucocorticoid that has been used in the acute treatment of SCI for decades. Based on the observation that the use of this drug could produce improved function in individuals suffering from brain edema, neurosurgeons had used methylprednisolone on an empiric basis in an attempt to treat edema following spinal cord trauma. The first National Acute Spinal Cord Injury Study (NASCIS I) studied doses commonly used in the late 1970’s (100 to 1,000 mg/day) and found no evidence of treatment effect when comparing the lower with the higher dose groups.1

Furthermore, it was thought that treatment for 10 days in the higher dose group caused an increase in morbidity. At the time of the publication of NASCIS I, it had also become apparent through further animal research that the neuroprotective effect of methylprednisolone was achieved through a more complex biochemical mechanism resulting in the inhibition of lipid peroxidation through the “scavenging” of oxygen-free radicals. To achieve this effect, much higher doses of methylprednisolone would be required, leading to the NASCIS II, which was mounted in the late 1980’s and published in 1990.2 This important study was the first randomized placebo-controlled large-scale trial of acute SCI treatment to yield positive results. Patients whose methylprednisolone therapy was initiated within 8 hours of injury showed improvements in motor and sensory scores when compared with placebo counterparts at 6 weeks, 6 months, and 1 year after injury. Since the publication of NASCIS II, the use of high-dose methylprednisolone has become widespread in the United States for the treatment of acute SCI.

Laboratory research had also suggested that a different class of chemicals, gangliosides, could have beneficial effect in acute SCI by inhibiting the cellular influx of calcium ions, reducing excitotoxicity, and potentiating endogenous growth factors. A pilot study testing the efficacy of the ganglioside GM-1 showed a promising effect when studied on a small group of human subjects with acute SCI.3 The results of this study, which were published in 1991, have led to a randomized, placebo-controlled, national collaborative trial of high-dose methylprednisolone followed by 2 months of once daily dosing of GM-1 or placebo.

Tirilazad mesylate is a 21-aminosteroid that possesses antioxidant properties similar to methylprednisolone, but without the potential for glucocorticoid side effects.4 A randomized placebo-controlled trial of this medication following administration of high-dose methylprednisolone has also been undertaken with the results yet to be released.

A number of other drugs have shown promise in animal SCI models including opiate antagonists, inhibitors of excitotoxicity, antioxidants, and calcium channel blockers.5 As animal research yields more information regarding the effects of these drugs on SCI, we will hopefully see more therapies advance to successful human trials.

Decades of basic and clinical research have finally come to fruition with the 1990 publication of NASCIS II, which, for the first time, showed that medical treatment of acute SCI could improve neurologic outcome. Several other medications have shown promise and are in clinical trials yet to be published. The success of this research has led to renewed hope for recovery in the person with acute SCI.

Experimental Treatments of Chronic SCI. In contrast to the treatment dilemma in acute SCI where therapy is directed at interrupting or inhibiting progressive damage, the approach to chronic SCI is more concerned with altering a chronic steady state, wherein the repair process has not produced adequate recovery of function. The neurologic impairment caused by the progressive damage of acute SCI results from the death of neurons, interruption of axons, or failure of impulse conduction, typically due to demyelinization. The pathology of chronic SCI is now understood to include not only cavitation necrosis and the formation of glial scar, but also significant demyelinization at the periphery of the traumatic myelopathy.7 Inadequate recovery of function in the chronic state is, therefore, likely due to inadequate repair of neural structures. This is most commonly ascribed to the inability of neurons in the adult mammalian central nervous system (CNS) to regenerate and to inadequate remyelinization of demyelinated axons. In addition, since neurons do not reproduce after the fetal state of development, replacement of dead neurons cannot occur naturally. While a number of experimental therapies have shown promise in animal models of chronic SCI, none have yet reached the stage of development to enable widespread clinical application.

Perhaps the most widely studied potential chronic therapy involves tissue implantation into the injured spinal cord.7 Peripheral nerve implants have been proposed to provide a favorable environment for central neuron regeneration. While initial animal experiments showed only histologic evidence of central neuron regenerative growth, more recent studies have also begun to show recovery of physiologic function and the formation of functional synapses.8, 9 Schwann cells, the cellular component of peripheral nerve felt to promote neuronal regeneration, have been implanted into experimentally injured animal spinal cords. Cultured Schwann cells placed in a semipermeable tube have been inserted into transected adult rat spinal cords and were shown to promote significant axonal regeneration into the graft. The regenerating axons were ensheathed and myelinated by Schwann cells in the graft, but showed little capability to grow into host spinal cord at the other side of the lesion and form functional synapses.10

Because of their growth properties, their lack of immunoreactivity, and their limited promotion of glial scar, fetal neuronal cell implants have also generated much scientific interest. Fetal grafts implanted into the CNS not only survive, but also promote connections with the host, both sending axons into the host and promoting the growth of host axons into the graft.11 The abundance of such interconnections would appear to be influenced by the maturity of the host, with grafts placed into newborn animals producing the most extensive interconnections of neurons while implants into more mature adult animals result in relatively less elaborate connectivity.12 There is also evidence that fetal implants into newborn animals are more likely to promote extensive regeneration of host axons through the graft, thus acting not only as a neurologic “relay,” but also as a “bridge.” Grafts into adult animals would appear to predominantly act as “relays.”12 With recent studies for the first time showing improvements in ambulatory behavior in mammals with incomplete SCI after fetal cell grafting, the era of human trials in tissue implantation may be approaching.13 Indeed, basic researchers have begun the dialogue with clinicians to explore the possible extension of this concept to human application.14 Some fetal transplants have been performed into humans with SCI in Russia with very limited benefit reported over a few spinal segments.14 While it is unclear how much benefit may derive from such implants in humans, fetal grafts in Parkinsonism indicate that such procedures can be relatively safe.15

Progress is also being made in further understanding the roles of trophic factors and their counterpart inhibitory factors in recovery after SCI. The combined application of specific nerve growth and antibodies to inhibitory factors has been shown to produce long-distance regeneration of corticospinal tract neurons in adult rats with SCI.16 More recently, young adult rats with a partial interruption of the spinal cord showed recovery of specific reflex and locomotor functions when treated with application of antibodies to inhibitory factors.17

The potential benefit of combinations of these therapies was documented in a recently reported study which included both the implantation of peripheral nerve grafts and the use of a growth factor in adult rats with experimental SCI.18 In this experiment, which was the first to document behavioral improvement in an adult mammalian species with a completely transected spinal cord, peripheral nerve bridges were carefully routed from white matter to “permissive” grey matter and stabilized in place with a fibrin glue containing acidic fibroblastic growth factor. Animals which received both grafts and growth factor not only exhibited histologic evidence of corticospinal tract regeneration, but also regained functional posture, partial weight bearing, and stepping of the hind limbs over a 6 month period.

In addition to animal studies of tissue implantation and growth-inhibitory factors, the realm of chronic treatment has also seen new developments in drug therapy and innovative rehabilitation research. 4-Aminopyridine is a potassium channel blocker that has been found to produce a transient, modest improvement in neurologic function in persons with spinal cord demyelinization due to multiple sclerosis. With some of the neurologic impairment in SCI due to focal demyelinization at the site of myelopathy, application of this treatment is worthy of investigation. To date, several small pilot studies on the effects of 4-Aminopyridine in chronic SCI have shown temporary neurologic improvement in some individuals with incomplete SCI, but no effect in more severely impaired individuals with motor complete lesions.19 These preliminary reports have prompted interest in a more extensive national collaborative trial to determine efficacy and safety.

Research in neurophysiology has also resulted in a greater understanding of the nature of SCI neurologic impairment. Recent studies have, for the first time, documented the presence of a central rhythm generator for locomotion in man.20 Other workers have investigated the ability of the incompletely injured spinal cord to modulate locomotor activity with peripheral sensory inputs using treadmill training with partial body weight support.21 With only an estimated 5% to 10% of descending axons required to produce functional ambulation, this new appreciation of the spinal cord’s functional capability will hopefully lead to innovative therapeutic approaches to maximize the benefit of regenerative therapies.

Conclusion. While not yet ready for widespread clinical application, restorative and regenerative therapies are beginning to show significant promise in animal models of chronic SCI. The treatments under investigation are not “cures” in the simple sense of the term, but rather biologic treatments for chronic paralysis that will require growth and the elaboration of neuronal interconnections to lay the foundation for functional recovery. Neurologic improvement will manifest gradually over a period of time and will likely benefit from rehabilitation to focus and maximize functional gains. It is reasonable to hope the results of these endeavors will provide improved quality of life for persons with SCI. Rehabilitation clinicians should incorporate information about chronic SCI research in patient education programs and look forward to incorporating innovative treatments to promote functional recovery as they become available.
  

Reprinted with permission from Topics in Spinal Cord Injury Rehabilitation, “Recovery of neurologic function in spinal cord injury: A review of new and experimental therapies,” Daniel P Lammertse, MD, 1997;2(3):95-100.

Address comments and questions to:

Daniel P Lammertse, MD
3425 South Clarkson Street
Englewood, CO 80113

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