Neuroprotection and acute spinal cord injury: A reappraisal

It has long been recognized that much of the post-traumatic degeneration of the spinal cord following injury is caused by a multi-factorial secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygen-induced lipid peroxidation (LP). In 1990 the results of the Second National Acute Spinal Cord Injury Study (NASCIS II) were published, which showed that the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP), which had been previously shown to inhibit post-traumatic LP in animal models of SCI, could improve neurological recovery in spinal-cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI since the drug was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the non-glucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy was obtained in a third NASCIS trial (NASCIS III). In recent years, the use of high-dose MP in acute SCI has become controversial largely on the basis of the risk of serious adverse effectsversus what is perceived to be on average a modest neurological benefit. The opiate receptor antagonist naloxone was also tested in NASCIS II based upon the demonstration of its beneficial effects in SCI models. Although it did not a significant overall effect, some evidence of efficacy was seen in incomplete (i.e., paretic) patients. The monosialoganglioside GM1 has also been examined in a recently completed clinical trial in which the patients first received high-dose MP treatment. However, GM1 failed to show any evidence of a significant enhancement in the extent of neurological recovery over the level afforded by MP therapy alone. The present paper reviews the past development of MP, naloxone, tirilazad, and GM1 for acute SCI, the ongoing MP-SCI controversy, identifies the regulatory complications involved in future SCI drug development, and suggests some promising neuroprotective approaches that could either replace or be used in combination with high-dose MP.     

Pharmacological treatment of acute spinal cord injury: current status and future prospects.

The history and results of the National Acute Spinal Cord Injury Studies (NASCIS) are briefly reviewed. The current status of pharmacological therapy for acute spinal cord injury and future prospects are also summarized.     

Neurogenic bladder model for spinal cord injury: spinal cord microdialysis and chronic urodynamics

We describe an animal model to study neurotransmitter changes in parallel with urodynamic testing following Spinal Cord Injury (SCI). Urodynamic access was achieved using a subcutaneously placed 7 French dual lumen portacatheter. Spinal cord injury was induced by weight drop technique onto exposed dura at T8. The L6-S1 detrusor nuclei were localized stereotactically and microdialysis probe placement was confirmed through histologic methods. Chronic urodynamics revealed detrusor hyperreflexia (DH) 14 days following SCI. In vivo microdialysis of spinal cord amino acids was performed using CMA 11 (240 uM) probes in halothane-anesthetized rats at baseline and intervals of 20-30 min following spinal cord injury. Significant increases in the excitatory amino acid glutamate, and the inhibitory amino acids, glycine and taurine, were seen following spinal cord injury. Amino acid levels peaked at approximately 40 min following contusion injury with glycine demonstrating the highest levels of all amino acids measured. This neurogenic rat model provides a useful means of examining the effects of spinal cord injury on bladder function. By utilizing spinal cord microdialysis, one could intervene at the level of the detrusor nuclei to modulate bladder function.     

Head and spinal cord injury: diagnosis and management

This article reviews aspects of management of traumatic brain and spinal cord injury. A discussion of management of intracranial pressure after traumatic brain injury is followed by a discourse on cerebrovascular trauma and pediatric injuries. Specific management methods are discussed, including medical and surgical management in intracranial hypertension. A special attempt is made to include the current recommendations for management of brain and spinal cord injuries. Spinal cord injuries are discussed in the final section. With an increasing number of patients surviving after devastating spinal cord injuries, the special issues in their management are evaluated.     

A re-assessment of erythropoietin as a neuroprotective agent following rat spinal cord compression or contusion injury

This study was initiated due to an NIH “Facilities of Research — Spinal Cord Injury” contract to support independent replication of published studies that appear promising for eventual clinical testing. We repeated a study reporting the beneficial effects of recombinant human erythropoietin (rhEPO) treatment after spinal cord injury (SCI). Moderate thoracic SCI was produced by two methods: 1) compression due to placement of a modified aneurysm clip (20 g, 10 s) at the T3 spinal segment (n=45) [followed by administration of rhEPO 1000 IU/kg/IP in 1 or 3 doses (treatment groups)] and 2) contusion by means of the MASCIS impactor (n = 42) at spinal T9 (height 12.5 cm, weight 10 g) [followed by the administration of rhEPO 5000 IU/kg/IP for 7d or single dose (treatment groups)]. The use of rhEPO following moderate compressive or contusive injury of the thoracic spinal cord did not improve the locomotor behavior (BBB rating scale). Also, secondary changes (i.e. necrotic changes followed by cavitation) were not significantly improved with rhEPO therapy. With these results, although we cannot conclude that there will be no beneficial effect in different SCI models, we caution researchers that the use of rhEPO requires further investigation before implementing clinical trials.     

Methylprednisolone fails to improve functional and histological outcome following spinal cord injury in rats

Currently, methylprednisolone sodium succinate (MPSS) is the standard treatment following acute spinal cord injury (SCI) as a consequence of the results obtained from the National Acute Spinal Cord Injury Studies. However, many have questioned the efficacy of MPSS because of its marginal effects. Additionally there has been criticism of both study design and statistical interpretation. The functional consequences of experimental SCI have been assessed in many ways. The purpose of this investigation was to determine the effects of MPSS vs. saline solution (SS) following moderate T10 contusion injury in rat. Functional recovery was evaluated using the 21-point Basso, Beattie and Bresnahan (BBB) locomotor recovery scale, the inclined plane, the beam walk, footprint analysis and the horizontal ladder. To optimize the precision and accuracy of functional results we examined the locomotion on a treadmill using three-dimensional (3D) analysis. Stereology was used to estimate the amount of damaged tissue. The results of the traditional functional methods showed that administration of the NASCIS dosage of MPSS following acute spinal cord contusion did not lead to any significant differences in the functional recovery of MPSS- vs. SS-treated animals. More importantly, the results of the 3D kinematic showed that the MPSS administration did not affect the flexion/extension of the hip, knee and ankle joints during the step cycle. Finally, stereological results revealed no statistically significant differences between the two experimental groups. Altogether, our results support data previously reported by several authors, suggesting that MPSS does not lead to improved functional outcome following experimental acute SCI.     

Seven-year survival following spinal cord injury

This retrospective study of 5131 persons who sustained a spinal cord injury between 1973 and 1980 sought to determine the overall seven-year survival rate and the effect of several prognostic factors on survival. All study subjects had been treated at one of seven federally designated Model Regional Spinal Cord Injury Care Systems and each had survived at least 24 hours after injury. The cumulative seven-year survival was 86.7%. Advancing age at time of injury and being rendered a neurologically complete quadriplegic were significant prognostic factors. The cumulative seven-year survival among neurologically complete quadriplegics who were at least 50 years of age when injured, was only 22.7%. Spinal cord injury mortality rates ranged from 3.26 to 20.78 times higher than corresponding rates for nonspinal injured persons. Although mortality rates for spinal cord injury patients have declined dramatically since World War II, life expectancies for these patients are still substantially below normal.     

Spinal cord seizures: a possible cause of isolated myoclonic activity in traumatic spinal cord injury: case report.

Spinal cord seizures are infrequently reported. They have been associated with intravenous dye placement, transverse myelitis and multiple sclerosis, but never with traumatic spinal cord injury (SCI). We report the case of a 48-year-old SCI male with complete C6 quadriplegia, and apparent spinal cord seizures. These seizures were characterised by myoclonus simplex activity involving the upper extremities only. The lower extremities were spared. The patient was conscious throughout the myoclonic activity and an electroencephalogram of the brain obtained during an event revealed no cortical epiliptiform activity. The seizures lasted approximately 30 seconds to a few minutes, and an acute increase in blood pressure and a decrease in pulse generally occurred 30 to 60 seconds prior to the event. Previously reported spinal cord seizures in multiple sclerosis were frequently treated with carbamazepine. In this case successful treatment was with diazepam. Spinal cord seizures may present in those with traumatic SCI. Benzodiazepines may be useful in the treatment of spinal cord seizures.     

Cortical processing of residual ano-rectal sensation in patients with spinal cord injury: an fMRI study

Abstract  Eleven paraplegic patients with complete traumatic spinal cord injuries (SCI) [according to American Spinal Injury Association (ASIA) criteria] at different levels (Th3–L3) were investigated during non-painful stimulation of the distal rectum and anal canal, using event related functional magnetic resonance imaging. Although a complete lesion was clinically diagnosed in all, four of them experienced reproducible sensations during anal and/or rectal stimulation. In six patients, individual data analysis revealed significant activation in the right secondary somatosensory cortex SII, the posterior cingular gyrus, the prefrontal cortex, and the left posterior cerebellar lobe during either anal or rectal stimulation or both. A Region of interest analysis using a data mask from healthy controls confirmed that SCI patients demonstrate cortical activation in areas similar to those activated in healthy volunteers, but to a less extensive degree. This supports the notion that the diagnosis of complete spinal cord transsection by ASIA criteria alone may be insufficient for assessment of 'completeness' of cord lesions, and that visceral sensitivity testing may be required in addition.     

Community reintegration and quality of life following spinal cord injury.

This report contains a brief overview of issues related to community reintegration and quality of life for persons with spinal cord injuries. Current data from the National Spinal Cord Injury Statistical Center are provided on place of residence, employment, education and marital status after rehabilitation discharge. The health policy implications of these data are discussed along with prospects for continued improvement of long term social outcomes and directions for future research.     

Topiramate as a neuroprotective agent in a rat model of spinal cord injury

Topiramate(TPM) is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury(SCI). After rat models of thoracic contusive SCI were established by free weight-drop method, TPM(40 mg/kg) was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.     

Sensory perception in complete spinal cord injury

OBJECTIVES: To describe sensations evoked by painful or repetitive stimulation below injury level in patients with a clinically complete (American Spinal Injury Association, ASIA Grade A) spinal cord injury (SCI). MATERIAL AND METHODS: Twenty-four patients (11 with central neuropathic pain and 13 without pain) with a traumatic SCI above the tenth thoracic vertebra were examined using quantitative sensory testing, MR imaging, and somatosensory evoked potentials (SEP). RESULTS: Painful (pressure, pinch, heat or cold) or repetitive (pinprick) stimuli elicited vague localized sensations in 12 patients (50%). Pain, spasticity, and spasms were equally seen in SCI patients with or without localized sensations. SEP and MRI did not differentiate between these two groups. CONCLUSION: The present study suggests retained sensory communication across the injury in complete SCI, i.e. 'sensory discomplete' SCI.     

Evidence that local non-NMDA receptors contribute to functional deficits in contusive spinal cord injury

To investigate the role of (non-NMDA) types of excitatory amino acid (EAA) receptors in traumatic spinal cord injury, we administered 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX), a potent and specific antagonist of non-NMDA receptors, to rats with a standardized contusive spinal cord injury. Focal infusion of NBQX into the injury site significantly reduced long-term hindlimb functional deficits as well as decreasing the time required for the rats to establish a reflex bladder. The results suggest that non-NMDA receptors at or near the injury site are involved in producing a portion of the functional deficits that result from contusive spinal cord injury.     

Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury

The natural history of post-traumatic demyelination and myelin repair in the human spinal cord is largely unknown and has remained a matter of speculation. A wealth of experimental studies indicate that mild to moderate contusive injuries to the mammalian spinal cord evolve into a cavity with a preserved rim of white matter in which a population of segmentally demyelinated axons persists. It is believed that such injured axons have abnormal conduction properties. Theoretically, such axons might show improved function if myelin repair occurred. Schwann cells can remyelinate axons affected by multiple sclerosis, but little evidence exists that such repair can occur spontaneously following traumatic human SCI. Therefore, it is important to determine if chronic demyelination is present following human spinal cord injury. There are no previous reports that have conclusively demonstrated demyelination in the human spinal cord following traumatic spinal cord injury using immunohistochemical techniques. Immunohistochemical methods were used to study the distribution of peripheral and central myelin proteins as well as axonal neurofilament at the injury epicenter in 13 postmortem chronically injured human spinal cords 1-22 years following injury. Of these seven could be assessed by our methods. We found that some axonal demyelination can be detected even a decade following human SCI and indirect evidence that invading Schwann cells contributed to restoration of myelin sheaths around some spinal axons.     

丹酚酸B促进大鼠急性脊髓损伤修复及量效关系探讨

目的 研究腹腔注射丹酚酸B(Sal B)对大鼠急性脊髓损伤(SCI)模型的神经保护作用和促功能恢复作用,探讨Sal B在急性SCI治疗的应用价值,并探讨其量效关系. 方法参照Allen法制作SD大鼠T9脊髓节段急性损伤模型,腹腔注射Sal B或PBS液,按照注射液的不同分为4组:Sal B高剂量组(20 mg/kg组),Sal B中剂量组(10 mg/kg组),Sal B低剂量组(2 mg/kg组)和对照组(注射PBS液),每组12只.用比色法检测髓过氧化物酶活性;用免疫组织化学染色法检测损伤脊髓节段MMP-1、c-Fos抗体表达情况,用干湿重法评价的水肿程度,并采用后肢功能评分(BBB)评分评价10 d内大鼠的运动功能恢复情况. 结果损伤后4 h Sal B治疗组髓过氧化物酶活性下降,损伤后1 dHE染色切片显示SalB组治疗后局部组织损伤减轻,炎性细胞浸润数量减少,损伤后1d免疫组化染色结果显示,Sal B治疗组比对照组MMP-1表达减少,c-Fos表达下调;Sal B治疗组水肿程度轻于对照组,从SCI后第7天起,SalB组高剂量组(20 mg/kg组)和对照组之间的BBB评分有显著性差异(P<0.05).各指标改善情况与Sal B剂量呈正相关性. 结论 Sal B可减轻大鼠SCI后的组织损伤,下调损伤相关因子MMP-1和c-Fos的表达,降低损伤局部髓过氧化物酶活性,减轻组织水肿,并能促进损伤大鼠的功能恢复.     

Endogenous opioid immunoreactivity in rat spinal cord following traumatic injury

It has been postulated that endogenous opioids play a pathophysiological role in spinal cord injury, based on the therapeutic effects of the opiate receptor antagonist naloxone in certain experimental models. The high doses of naloxone required to exert a therapeutic action suggest that naloxone's effects may be mediated by non-mu opiate receptors, such as the kappa receptor. This notion is supported by recent pharmacological studies demonstrating that an opiate antagonist more active at kappa sites is effective and far more potent than naloxone in improving outcome after spinal cord injury. Moreover, dynorphin--postulated to be the endogenous ligand for the kappa receptor--is unique among opioids in producing hindlimb paralysis following intrathecal administration in the rat. In the present studies we have examined changes in endogenous opioid immunoreactivity following traumatic spinal cord injury in the rat. Dynorphin A was found to increase progressively with graded injury; changes were restricted to the injury segment and adjacent areas and were time dependent. Dynorphin A-(1-8) showed no marked changes. Methionine and leucine enkephalin were either unaltered or reduced at the injury site; changes were not well localized and were not clearly related to the injury variables. These findings provide further support for a potential pathophysiological role of prodynorphin-derived peptides in spinal cord injury.     

Comprehensive locomotor outcomes correlate to hyperacute diffusion tensor measures after spinal cord injury in the adult rat

In adult rats, locomotor deficits following a contusive thoracic spinal cord injury (SCI) are caused primarily by white matter loss/dysfunction at the epicenter. This loss/dysfunction decreases descending input from the brain and cervical spinal cord, and decreases ascending signals in long propriospinal, spinocerebellar and somatosensory pathways, among many others. Predicting the long-term functional consequences of a contusive injury acutely, without knowledge of the injury severity is difficult due to the temporary flaccid paralysis and loss of reflexes that accompany spinal shock. It is now well known that recovery of high quality hindlimb stepping requires only 12-15% spared white matter at the epicenter, but that forelimb-hindlimb coordination and precision stepping (grid or horizontal ladder) require substantially more trans-contusion communication. In order to translate our understanding of the neural substrates for functional recovery in the rat to the clinical arena, common outcome measures and imaging modalities are required. In the current study we furthered the exploration of one of these approaches, diffusion tensor magnetic resonance imaging (DTI), a technique now used commonly to image the brain in clinical research but rarely used diagnostically or prognostically for spinal cord injury. In the adult rat model of SCI, we found that hyperacute (<3h post-injury) DTI of the lateral and ventral white matter at the injury epicenter was predictive of both electrophysiological and behavioral (locomotor) recovery at 4 weeks post-injury, despite the presence of flaccid paralysis/spinal shock. Regions of white matter with a minimum axial diffusivity of 1.5 μm(2)/ms at 3h were able to conduct action potentials at 4 weeks, and axial diffusivity within the lateral funiculus was highly predictive of locomotor function at 4 weeks. These observations suggest that acute DTI should be useful to provide functional predictions for spared white matter following contusive spinal cord injuries clinically.     

Standardized assessment of walking capacity after spinal cord injury: the European network approach

OBJECTIVES: After a spinal cord injury (SCI), walking function is an important outcome measure for rehabilitation and new treatment interventions. The current status of four walking capacity tests that are applied to SCI subjects is presented: the revised walking index for spinal cord injury (WISCI II), the 6 minute walk test (6MinWT), 10 meter walk test (10MWT) and the timed up and go (TUG) test. Then, we investigated which categories of the WISCI II apply to SCI subjects who participated in the European Multicenter Study of Human Spinal Cord Injury (EM-SCI), and the relationship between the 10MWT and the TUG. METHODS: In the EM-SCI, the walking tests were applied 2 weeks and 1, 3, 6 and 12 months after SCI. We identified the WISCI II categories that applied to the EM-SCI subjects at each time point and quantified the relationship between the 10MWT and the TUG using Spearman's correlation coefficients (rho) and linear regression. RESULTS: Five WISCI II categories applied to 71% of the EM-SCI subjects with walking ability, while 11 items applied to 11% of the subjects. The 10MWT correlated excellently with the TUG at each time point (rho>0.80). However, this relationship changed over time. One year after SCI, the time needed to accomplish the TUG was 1.25 times greater than the 10MWT time. DISCUSSION: Some categories of the WISCI II appear to be redundant, while some discriminate to an insufficient degree. In addition, there appear to be ceiling effects, which limit its usefulness. The relationship between the 10MWT and TUG is high, but changes over time. We suggest that, at present, the 10MWT appears to be the best tool to assess walking capacity in SCI subjects. Additional valuable information is provided by assessing the needs for walking aids or personal assistance. To ensure comparability of study results, proposals for standardized instructions are presented.     

Dynamic correlation of diffusion tensor imaging and neurological function scores in beagles with spinal cord injury

Exploring the relationship between different structure of the spinal cord and functional assessment after spinal cord injury is important. Quantitative diffusion tensor imaging can provide information about the microstructure of nerve tissue and can quantify the pathological damage of spinal cord white matter and gray matter. In this study, a custom-designed spinal cord contusion-impactor was used to damage the T_(10) spinal cord of beagles. Diffusion tensor imaging was used to observe changes in the whole spinal cord, white matter, and gray matter, and the Texas Spinal Cord Injury Score was used to assess changes in neurological function at 3 hours, 24 hours, 6 weeks, and 12 weeks after injury. With time, fractional anisotropy values after spinal cord injury showed a downward trend, and the apparent diffusion coefficient, mean diffusivity, and radial diffusivity first decreased and then increased. The apparent diffusion-coefficient value was highly associated with the Texas Spinal Cord Injury Score for the whole spinal cord(R = 0.919, P = 0.027), white matter(R = 0.932, P = 0.021), and gray matter(R = 0.882, P = 0.048). Additionally, the other parameters had almost no correlation with the score(P 0.05). In conclusion, the highest and most significant correlation between diffusion parameters and neurological function was the apparent diffusion-coefficient value for white matter, indicating that it could be used to predict the recovery of neurological function accurately after spinal cord injury.     

丹酚酸B促进大鼠急性脊髓损伤修复及量效关系探讨

目的 研究腹腔注射丹酚酸B(Sal B)对大鼠急性脊髓损伤(SCI)模型的神经保护作用和促功能恢复作用,探讨Sal B在急性SCI治疗的应用价值,并探讨其量效关系. 方法参照Allen法制作SD大鼠T9脊髓节段急性损伤模型,腹腔注射Sal B或PBS液,按照注射液的不同分为4组:Sal B高剂量组(20 mg/kg组),Sal B中剂量组(10 mg/kg组),Sal B低剂量组(2 mg/kg组)和对照组(注射PBS液),每组12只.用比色法检测髓过氧化物酶活性;用免疫组织化学染色法检测损伤脊髓节段MMP-1、c-Fos抗体表达情况,用干湿重法评价的水肿程度,并采用后肢功能评分(BBB)评分评价10 d内大鼠的运动功能恢复情况. 结果损伤后4 h Sal B治疗组髓过氧化物酶活性下降,损伤后1 dHE染色切片显示SalB组治疗后局部组织损伤减轻,炎性细胞浸润数量减少,损伤后1d免疫组化染色结果显示,Sal B治疗组比对照组MMP-1表达减少,c-Fos表达下调;Sal B治疗组水肿程度轻于对照组,从SCI后第7天起,SalB组高剂量组(20 mg/kg组)和对照组之间的BBB评分有显著性差异(P<0.05).各指标改善情况与Sal B剂量呈正相关性. 结论 Sal B可减轻大鼠SCI后的组织损伤,下调损伤相关因子MMP-1和c-Fos的表达,降低损伤局部髓过氧化物酶活性,减轻组织水肿,并能促进损伤大鼠的功能恢复.