Methylprednisolone sodium succinate (MPSS) has been proposed as a first-line treatment for acute spinal cord injury (SCI). Its clinical use remains, however, controversial because of the modest benefits and numerous side-effects. We investigated if MPSS could protect spinal neurons and glia using an in vitro model of the rat spinal cord that enables recording reflexes, fictive locomotion and morphological analysis of damage. With this model, a differential lesion affecting mainly either neurons or glia can be produced via kainate-evoked excitotoxicity or application of a pathological medium (lacking O2 and glucose), respectively. MPSS (6-10 μM) applied for 24 h after 1-h pathological medium protected astrocytes and oligodendrocytes especially in the ventrolateral white matter. This effect was accompanied by the return of slow, alternating oscillations (elicited by NMDA and 5-hydroxytryptamine (5-HT)) reminiscent of a sluggish fictive locomotor pattern. MPSS was, however, unable to reverse even a moderate neuronal loss and the concomitant suppression of fictive locomotion evoked by kainate (0.1 mM; 1 h). These results suggest that MPSS could, at least in part, contrast damage to spinal glia induced by a dysmetabolic state (associated to oxygen and glucose deprivation) and facilitate reactivation of spinal networks. Conversely, when even a minority of neurons was damaged by excitotoxicity, MPSS did not protect them nor did it restore network function in the current experimental model.

A need exists for the effective treatment of individuals suffering from spinal cord injury (SCI). Recent advances in the understanding of the pathophysiological mechanisms occurring in SCI have resulted in an expansion of new therapeutic targets. This review summarizes both preclinical and clinical findings investigating the mechanisms and cognate pharmacologic therapeutics targeted to modulate hypoxia, ischemia, excitotoxicity, inflammation, apoptosis, epigenetic alterations, myelin regeneration and scar remodeling. Successful modulation of these targets has been demonstrated in both preclinical and clinical studies with agents such as Oxycyte, Minocycline, Riluzole, Premarin, Cethrin, and ATI-355. The translation of these agents into clinical studies highlights the progress the field has made in the past decade. SCI proves to be a complex condition; the numerous pathophysiological mechanisms occurring at varying time points suggests that a single agent approach to the treatment of SCI may not be optimal. As the field continues to mature, the hope is that the knowledge gained from these studies will be applied to the development of an effective multi-pronged treatment strategy for SCI.

a literature review was made to investigate the role of nitric oxide (NO) in spinal cord injury, a pathological condition that leads to motor, sensory, and autonomic deficit. Besides, we were interested in potential therapeutic strategies interfering with NO mechanism of secondary damage.

A literature search using PubMed Medline database has been performed.

excessive NO production after spinal cord injury promotes oxidative damage perpetuating the injury causing neuronal loss at the injured site and in the surrounding area.

different therapeutic approaches for contrasting or avoiding NO secondary damage have been studied, these include nitric oxide synthase inhibitors, compounds that interfere with inducible NO synthase expression, and molecules working as antioxidant. Further studies are needed to explain the neuroprotective or cytotoxic role of the different isoforms of NO synthase and the other mediators that take part or influence the NO cascade. In this way, it would be possible to find new therapeutic targets and furthermore to extend the experimentation to humans.

Acute spinal cord injury is a devastating condition typically affecting young people, mostly males. Steroid treatment in the early hours after the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life.

To review randomized trials of steroids for human acute spinal cord injury.

We searched the Cochrane Injuries Group Specialised Register (searched 02 Aug 2011), The Cochrane Central Register of Controlled Trials 2011, issue 3 (The Cochrane Library), MEDLINE (Ovid) 1948 to July Week 3 2011, EMBASE (Ovid) 1974 to 2011 week 17, ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to Aug 2011, ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) 1990 to Aug 2011 and PubMed [www.ncbi.nlm.nih.gov/sites/entrez/] (searched 04 Aug 2011) for records added to PubMed in the last 90 days). Files of the National Acute Spinal Cord Injury Study (NASCIS) were reviewed (NASCIS was founded in 1977 and has tracked trials in this area since that date). We also searched the reference lists of relevant studies and previously published reviews.

All randomized controlled trials of steroid treatment for acute spinal cord injury in any language.

One review author extracted data from trial reports. Japanese and French studies were found through NASCIS and additional data (e.g. SDs) were obtained from the original study authors.

Eight trials are included in this review, seven used methylprednisolone. Methylprednisolone sodium succinate has been shown to improve neurologic outcome up to one year post-injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial results were replicated in a Japanese trial but not in the one from France. Data was obtained from the latter studies to permit appropriate meta-analysis of all three trials. This indicated significant recovery in motor function after methylprednisolone therapy, when administration commenced within eight hours of injury. A more recent trial indicates that, if methylprednisolone therapy is given for an additional 24 hours (a total of 48 hours), additional improvement in motor neurologic function and functional status are observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries. A modified regimen was found to improve recovery after surgery for lumbar disc disease. The risk of bias was low in the largest methyprednisolne trials. Overall, there was no evidence of significantly increased complications or mortality from the 23 or 48 hour therapy.

High-dose methylprednisolone steroid therapy is the only pharmacologic therapy shown to have efficacy in a phase three randomized trial when administered within eight hours of injury. One trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours, if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacologic therapy for acute spinal cord injury.

The multifactorial pathological progress of spinal cord injury (SCI) is probably the main reason behind the absence of efficient therapeutic approaches. Hence, very recent highlights suggest the use of new multidrug delivery systems capable of local controlled release of therapeutic agents. In this work, a biocompatible hydrogel-based system was developed as multiple drug delivery tool, specifically designed for SCI repair strategies. Multiple release profiles were achieved by loading gel with a combination of low and high steric hindrance molecules. In vitro, in vivo and ex vivo release studies showed an independent combination of fast diffusion-controlled kinetics for smaller molecules together with slow diffusion-controlled kinetics for bigger ones. A preserved functionality of loaded substances was always achieved, confirming the absence of any chemical stable interactions between gel matrix and loaded molecules. Moreover, the relevant effect of the cerebrospinal fluid flux dynamics on the drug diffusion in the spinal cord tissue was here revealed for the first time: an oriented delivery of the released molecules in the spinal cord tract caudally to the gel site is demonstrated, thus suggesting a more efficient gel positioning rostrally to the lesion.

The initial level of injury and severity of volitional motor and clinically detectable sensory impairment has been considered the most reliable for predicting neurologic recovery of function after spinal cord injury (SCI). This consensus implies a limited expectation for physical rehabilitation interventions as important in the facilitation of recovery of function. The development of pharmacologic and surgical interventions has always been pursued with the intent of altering the expected trajectory of recovery after SCI, but only recently physical rehabilitation strategies have been considered to improve recovery beyond the initial prognosis. This article reviews the recent literature reporting emerging activity-based therapies that target recovery of standing and walking based on activity-dependent neuroplasticity. A classification scheme for physical rehabilitation interventions is also discussed to aid clinical decision making.

Extracellular non-adenine based purines are neuroprotective. Preliminary studies indicate that administration of the synthetic purine 4-[[3-(1,6 dihydro-6-oxo-9-purine-9-yl)-1-oxypropyl] amino] benzoic acid (AIT-082, leteprinim potassium) to rats immediately after acute spinal cord injury (SCI), improves functional outcome. The effects of potential new agents are often compared to methylprednisolone (MPSS). We evaluated the effects of AIT-082 and MPSS, separately and in combination, on the functional and morphological outcome of acute SCI in adult rats. After standardized T11-12 spinal cord compression rats were given intraperitoneally one of the following: vehicle (saline); MPSS (30 mg/kg or 60 mg/kg body weight, first dose 15 min after crush); AIT-082 (60 mg/kg body weight daily, first dose 15 min after crush); or AIT-082 plus MPSS. After 1, 3, or 21 days, the rats were perfused for histological analysis. AIT-082 administrations significantly reduced locomotor impairment from 121 days post-operatively. At 1 and 3 days post injury, AIT-082-treatment reduced tissue swelling, tissue loss and astrogliosis at the injured cords but did not alter the extent of hemorrhage and the number of macrophages and/or microglia. MPSS reduced hemorrhage and the number of macrophages and/or microglia, but did not alter astrogliosis. At 21 days, either AIT-082 or MPSS administration improved function and morphology similarly (less tissue loss and astrogliosis). In contrast, administration of AIT-082 and MPSS together abolished the beneficial effects observed when either drug was given individually. These results suggest that MPSS and AIT-082 may exert their beneficial effects through different and potentially antagonistic pathways.

Acute spinal cord injury is a devastating condition typically affecting young people with a preponderance being male. Steroid treatment in the early hours of the injury is aimed at reducing the extent of permanent paralysis during the rest of the patient's life.

To review randomized trials of steroids for acute spinal cord injury.

The review draws on the search strategy developed by the Cochrane Injuries Group. In addition, files of the National Acute Spinal Cord Injury Study have been reviewed and a Medline search conducted.

All published or unpublished randomized controlled trials of steroid treatment for acute spinal cord injury in any language.

Data have been abstracted from original trial reports. For the NASCIS, Japanese and French trials, additional data (e.g. SDs) have been obtained from the original authors.

There are few trials in this area of medical care. Only one steroid has been extensively studied, methylprednisolone sodium succinate, which has been shown to improve neurologic outcome up to one year post injury if administered within eight hours of injury and in a dose regimen of: bolus 30mg/kg administered over 15 minutes with a maintenance infusion of 5.4 mg/kg per hour infused for 23 hours. The initial North American trial was replicated in a Japanese trial but not in the one from France. Data has been obtained from the latter studies to permit appropriate meta-analysis of all three trials. This analysis indicates significant recovery in motor function after methylprednisolone therapy when administration commences within eight hours of injury. A more recent trial indicates that if methylprednisolone therapy is given for an additional 24 hours (for a total of 48 hours), additional improvement in motor neurologic function and functional status is observed. This is particularly observed if treatment cannot be started until between three to eight hours after injury. The same methylprednisolone therapy has been found effective in whiplash injuries and a modified regimen found to improve recovery after surgery for lumbar disc disease.

High dose methylprednisolone steroid therapy is the only pharmacological therapy shown to have efficacy in a Phase Three randomized trial when it can be administered within eight hours of injury. A recent trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours if start of treatment must be delayed to between three and eight hours after injury. There is an urgent need for more randomized trials of pharmacological therapy for acute spinal cord injury.

Randomized, double-blind, sequential, multicenter clinical trial of two doses of Sygen versus placebo.

To determine efficacy and safety of Sygen in acute spinal cord injury.

An earlier, single-center trial in 28 patients showed an improvement (50.0% vs. 7.1%, P = 0.034) in marked recovery with Sygen.

Standard clinical trial techniques.

The prospectively planned analysis at the prespecified endpoint time for all patients was negative. There was a significant effect in all patients in the primary outcome variable (the percentage of marked recovery) at week 8, the end of the dosing period. There was a significant effect in all patients in the time at which marked recovery is first achieved. Restricted to severity Group B, which has small sample size, the primary efficacy analysis showed a trend but did not reach significance. There is a large, consistent and, at some time points, significant effect in the primary outcome variable in the nonoperated patients through week 26. The American Spinal Injury Association motor, light touch, and pinprick scores showed a consistent trend in favor of Sygen, as also did bowel function, bladder function, sacral sensation, and anal contraction. The less severely injured patients appeared to have a greater beneficial drug effect. Evidence against an effect of Sygen was minimal and scattered.

Although not proven in the primary efficacy analysis of this trial, Sygen appears to be beneficial in patients with severe spinal cord injury.

From the beginning, the reporting of the results of National Acute Spinal Cord Injury Studies (NASCIS) II and III has been incomplete, leaving clinicians in the spinal cord injury (SCI) community to use or avoid using methylprednisolone in acute SCI on the basis of faith rather than a publicly developed scientific consensus. NASCIS II was initially reported by National Institutes of Health announcements, National Institutes of Health facsimiles to emergency room physicians, and the news media. The subsequent report in the New England Journal of Medicine implied that there was a positive result in the primary efficacy analysis for the entire 487 patient sample. However, this analysis was in fact negative, and the positive result was found only in a secondary analysis of the subgroup of patients who received treatment within 8 hours. In addition, that subgroup apparently had only 62 patients taking methylprednisolone and 67 receiving placebo. The NASCIS II and III reports embody specific choices of statistical methods that have strongly shaped the reporting of results but have not been adequately challenged or or even explained. These studies show statistical artifacts that call their results into question. In NASCIS II, the placebo group treated before 8 hours did poorly, not only when compared with the methylprednisolone group treated before 8 hours but even when compared with the placebo group treated after 8 hours. Thus, the positive result may have been caused by a weakness in the control group rather than any strength of methylprednisolone. In NASCIS III, a randomization imbalance occurred that allocated a disproportionate number of patients with no motor deficit (and therefore no chance for recovery) to the lower dose control group. When this imbalance is controlled for, much of the superiority of the higher dose group seems to disappear. The NASCIS group's decision to admit persons with minor SCIs with minimal or no motor deficit not only enables statistical artifacts it complicates the interpretation of results from the population actually sampled. Perhaps one half of the NASCIS III sample may have had at most a minor deficit. Thus, we do not know whether the results of these studies reflect the severely injured population to which they have been applied. The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public. The reporting of the NASCIS studies has fallen far short of the guidelines of the ICH/FDA and of the Evidence-based Medicine Group. Despite the lucrative "off label" markets for methylprednisolone in SCI, no Food and Drug Association indication has been obtained. There has been no public process of validation. These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.

This article provides a substantive review and synthesis of major areas of emphasis in spinal cord injury (SCI) research. Comprehensive examination of the current status and future implications for SCI research includes consideration of investigations from the following arenas: epidemiology, functional classification and prediction, neurophysiologic testing, models of injury and recovery, psychosocial considerations, surgical strategies, animal laboratory research, economic implications, life expectancy, complication rates, gender differences, pharmacological management, and prevention. Synthesis of these research conclusions from a broad spectrum of laboratory, clinical, and scientific domains provides opportunity for improving SCI prevention, treatment, and adaptation.

The recently published research data on the possible pathophysiology of acute spinal cord injury provide the basis of a number of exciting possibilities for its treatment. The present article reviews these lines of investigation. It focusses on methylprednisolone, which is the only effective proven therapy to limit secondary spinal cord injury known to date. In addition, the initial evaluation of patients with possible spinal cord trauma and airway management in patients with cervical spine injury are also discussed. Finally, the anaesthetic regimen in patients with these injuries is reviewed, showing that no anaesthetic agent or technique is superior to other anaesthetic methods.

Two patients underwent thoracotomy for resection of pulmonary or esophageal carcinoma. Postoperatively, epidural catheters were inserted for pain management. Complaints of severe injection pain over the abdomen or lower extremities were made during one administration of pain medication. Progressive weakness and numbness developed over the lower trunk and lower extremities, with subsequent respiratory difficulties. Potassium chloride (KCl) was suspected to have been mistaken for normal saline as the diluent for morphine. In addition to endotracheal intubation and ventilatory support, steroids were administered both intravenously and epidurally to suppress spinal cord irritation. The two patients regain motor and sensory functions 14 and 18 hours later, respectively, without sequelae.

Methylprednisolone (MP) improves motor recovery in spinal cord-injured patients when administered in a 24 h intensive high dose regimen beginning within 8 h after spinal cord injury (SCI). The rationale for this regimen has been based upon the need for high doses (i.e., 30 mg/kg initial IV dose) to inhibit posttraumatic lipid peroxidation (LP) in the injured spinal segment. However, injury also triggers the immediate calcium-mediated activation of phospholipase A2 (PLA2), the release of arachidonic acid, and the enzymatic formation of potentially deleterious prostaglandins (PGE2 alpha, PGE2), thromboxane A2 (TXA2), and leukotrienes (LTs). Thus, in view of the glucocorticoid receptor-mediated inhibition of PLA2 that underlies much of MP's antiinflammatory actions, an additional neuroprotective mechanism may relate to an inhibition of eicosanoid formation. Using the cat spinal cord compression model (180g x 5 min at L3; Na pentobarbitol anesthesia), we examined whether 30 min postinjury dosing with MP (30 mg/kg IV) could attenuate spinal tissue eicosanoid levels measured by enzyme immunoassay at 1 h (Experiment 1). Pial blood flow was measured over the dorsal columns at the injury site using laser doppler flowmetry to monitor posttraumatic hyperperfusion as an index of the microvascular pathophysiology of acute SCI. In vehicle treated animals at 1 h postinjury, there was a significant increase in the tissue levels of PGF2 alpha (+290%), PGE2 (+260%), TXB2 (stable analog of TXA2, +126%), and LTB4 (+73%) in comparison to sham, uninjured animals. However, 6-keto-PGF1 alpha (stable analog of prostacyclin or PGI2) and LTC4 did not increase. Methylprednisolone did not reduce the increase in eicosanoid production. In the case of LTB4 and LTC4, MP actually increased the levels further. In addition, we examined the effects of a double dose MP regimen (30 mg/kg IV at 30 min plus 15 mg/kg IV at 2.5 h postinjury) on spinal cord eicosanoid levels at 4 h postinjury (Experiment 2). At 4 h postinjury, significant increases in PGF2 alpha, PGE2, TXB2, and 6-keto-PGF1 alpha were observed, and with the exception of PGE2, no MP attenuation of the increased eicosanoids was seen. These results fail to provide evidence that postinjury administration of high dose MP exerts a significant anti-PLA2 action. On the other hand, MP effectively inhibited secondary spinal cord pial hyperperfusion, which is believed to be largely mediated by free radical-lipid peroxidative mechanisms. Thus, it seems likely that the protective action of MP on the acute microvascular pathophysiology of SCI is mediated by its well-documented effects on posttraumatic LP.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies in animals and especially the NASCIS II study illustrated the neuroprotective effects of methylprednisolone, but they are disputed. At the University Clinic of Traumatology, Vienna, 31 patients with spinal cord injuries were given methylprednisolone as a bolus of 30 mg/kg body weight followed by a maintenance dose of 5.4 mg/kg body weight/h for another 23 hours. Twenty-seven patients were stabilised within 8 hours, 2 patients were not operated on, because of their low prognosis. Two patients could be treated conservatively, because the spinal fractures were supposed to be stabile. Then follow-up studies of these patients were between 1 and 3.2 years. All patients (100%) with incomplete neurologic deficits (n = 18) showed a significant recovery and even 3 patients (23.1%) with primarily a complete tetraplegia (n = 13) showed a nearly entire recovery. Compared to these results we look back at 113 patients with complete and incomplete neurologic deficits who were treated at the I. University Clinic of Traumatology, Vienna, and would have got methylprednisolone following our current management procedures.

Neural injury leads to tissue damage beyond that caused by the initial lesion, mainly as a result of a chain of autodestructive events triggered by the trauma. These events apparently include the activation of immune-derived cells and their products, as treatment with anti-inflammatory agents, such as corticosteroids, limits the damage and thus improves recovery. On the other hand, immune-derived substances, such as cytokines, are thought to play an important role in post-traumatic axonal regeneration. Thus, the need to reduce inflammation to limit the spread of damage appears to be in conflict with the need to permit inflammation to promote regeneration. Comprehension and resolution of this apparent conflict may lead to the development of treatment protocols aimed at rescuing axons spared by the initial injury, without hampering the potential regeneration of directly and indirectly injured axons. In this study, carried out on rats with crushed optic nerves, daily intraperitoneal injections of dexamethasone commencing prior to the injury significantly attenuated the injury-induced decrease in electrophysiological activity and reduced the area of tissue damage. On the other hand, dexamethasone treatment reduced the permissiveness of the injured nerves to neural adhesion and regrowth in vitro. This latter phenomenon was also observed in injured peripheral nerves. Results are discussed with respect to the possible establishment of an appropriate protocol for corticosteroid treatment of nerve injuries aimed at promoting neuronal rescue without compromising neuronal regeneration.

The possibility that prostaglandins influence edema formation, microvascular permeability increase and reduction of blood flow following spinal cord trauma was examined in a rat model. In addition, the influence of prostaglandins on serotonin metabolism of the traumatized spinal cord was evaluated. Trauma to spinal cord (2-mm-deep and 5-mm-long incision in the right dorsal horn of T10-11 segments) resulted in a profound increase of the water content 5 h after injury. At this time, the microvascular permeability to Evans Blue and [131I]sodium was increased by 457 and 394%, respectively. The blood flow was reduced by 30%. The serotonin (5-hydroxytryptamine) content of the spinal cord increased by 205%. The plasma serotonin level rose by 152% in the injured group of rats. Pretreatment with indomethacin (10 mg/kg, i.p.) 30 min before trauma significantly reduced the edema and microvascular permeability increase. The local spinal cord blood flow of traumatized animals was partially restored. The increases of serotonin levels of the spinal cord and plasma were significantly attenuated. These beneficial effects of indomethacin were not present in rats given a lower dose (5 mg/kg). Indomethacin in either dose did not influence these parameters of control rats without trauma to the cord. Since indomethacin is a potential inhibitor of prostaglandins synthesis our observations indicate: (i) that prostaglandins participate in many microvascular responses (permeability changes, edema, blood flow) occurring after a trauma to the spinal cord; (ii) that these effects of the drug seem to be dose dependent, and (iii) that the prostaglandins may influence the serotonin metabolism following trauma to the spinal cord.

The potential efficacy of indomethacin (a potent inhibitor of endogenous prostaglandin synthesis) on spinal cord-evoked potentials and edema formation occurring after a focal trauma to the spinal cord was examined in a rat model. The spinal cord evoked potentials were recorded in urethane-anesthetized male rats using monopolar electrodes placed epidurally over the T9 (rostral) and T12 (caudal) segments after stimulation of the ipsilateral right tibial and sural nerves. Reference electrodes were placed in the corresponding paravertebral muscles. The spinal cord evoked potential consisted of a small positive peak followed by a broad and high negative peak. Amplitudes and latencies of the maximal positive peak and the maximal negative peak were measured. The latencies and amplitudes 30 min before injury were used as references (100%). A complete loss was denoted as 0%. All the potentials were quite stable during 30 min of recording before injury. Infliction of trauma to the T10-T11 segments of the spinal cord with a sterile scalpel blade (about 5 mm longitudinal and 2 mm deep incision into the right dorsal horn extending to Rexed's laminae VII) in untreated animals resulted in an immediate depression of the rostral maximal negative peak amplitude (60-100%) which persisted during 5 h of recording. The latencies of the rostral as well as caudal maximal negative and positive peaks increased successively from 2 h post-trauma. In this group of animals, 5 h after injury the spinal cord water content in the traumatized segments was increased by more than 6% as compared with a group of uninjured animals. Pretreatment with indomethacin (10 mg/kg body weight i.p. 30 min before injury) markedly attenuated the immediate decrease in the maximal negative peak amplitude after injury, but did not influence the successive latency increase. However, the increase in the water content of the traumatized cord after 5 h was less pronounced compared with untreated injured rats. Our results show a beneficial effect of indomethacin on trauma-induced spinal cord evoked potential changes and edema formation. Prostaglandins may thus influence early bioelectrical changes occurring in traumatized spinal cord not reported earlier. The findings support the view that early recording of spinal cord evoked potential may be useful to predict the outcome in some forms of spinal cord injuries.