Wise Young

A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: Results of the second national acute spinal cord injury study

In 1990, the Second National Acute Spinal Cord Injury Study reported that high-dosage methylprednisolone improves neurologic recovery in spinal-injured humans. The study showed that patients who received the drug within 8 hr after injury improved, whereas those who received the drug later did not. The drug significantly increased recovery even in severely injured patients who were admitted with no motor or sensory function below the lesion, contradicting a long-held dogma that such patients would not recover. Some researchers, however, have questioned the stratification of the patient population, the use of summed neurologic change scores, and the absence of functional assessments. The stratification by injury severity and treatment time was planned a priori and based on objective criteria. Detailed analyses revealed no differences between groups attributable to stratification or randomization. While multivariate analyses of the summed neurologic scores were used, the conclusions were corroborated by other analytical approaches that did not rely on summed scores. For example, treatment with methylprednisolone more than doubled the probability that patients would convert from quadriplegia or paraplegia to quadriparesis or paraparesis, analgesia to hypalgesia, and anesthesia to hypesthesia. The treatment also significantly improved neurologic scores in lumbosacral segments, indicating that beneficial effects were not limited to segments close to the lesion site. The treatment did not significantly affect mortality or morbidity. The study strongly suggests that methylprednisolone has significant beneficial effects in human spinal cord injury, that these effects occur only when the drug is given within 8 hr, and that it helps even in patients with severe spinal cord injuries. These conclusions have important implications for spinal cord injury care and research.

International standards for neurological and functional classification of spinal cord injury

International Standards for Neurological and Functional Classification of Spinal Cord Injury

A Randomized, Controlled Trial of Methylprednisolone or Naloxone in the Treatment of Acute Spinal-Cord Injury

Abstract Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurologic examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eigh...

H2 clearance measurement of blood flow: a review of technique and polarographic principles.

H2 clearance is a powerful method for monitoring blood flow. Simple and inexpensive to implement, the method allows multiple in situ determinations of blood flow from any tissue in which a small electrode can be implanted. There is, however, evidence to suggest that H2 clearance is neither as accurate nor as local a measure of blood flow as generally supposed. Both in theory and practice, it probably cannot accurately determine blood flow rates greater than 100 ml/100 gm/min or localize blood flow to tissue volumes of less than 5 ml. Moreover, its experimental application is complicated by many technical problems hitherto largely ignored by workers in the field. Some of these problems arise from the limitations of the steady state polarographic technique used to measure tissue H2 concentrations. Other problems stem from the failure to consider possible sources of error in H2 clearance monitoring; these include interference with the H2 signal by spurious electrode and tissue currents, and contributions from tissue ascorbate and O2. Nevertheless, with the appropriate safeguards and qualifications, H2 clearance is a valid and important approach to measuring blood flow.

Extracellular calcium ionic activity in experimental spinal cord contusion.

Abstract Entry of calcium ions (Ca2+) into axons has been hypothesized by several investigators to play a major role in myelopathy of spinal trauma. Although some evidence supports this hypothesis, a rapid and large influx of Ca2+ into cells prior to development of necrotic changes has not been demonstrated in spinal injury. Because large influxes of Ca2+ into cells are manifested by decreases in extracellular Ca2+, we measured extracellular Ca2+ activity in contused cat spinal cords, using ion-selective microelectrodes and relating the Ca2+ changes to local blood flow and evoked potentials. Within 5 min of 400 g·cm contusion, we found decreases of spinal extracellular Ca2+ from normal pre-injury levels (1.0–1.3 mM) to The initial extracellular Ca2+ fall preceded the onset of significant blood flow changes in spinal cord white matter. Thus, the Ca2+ change was related to the trauma and not to subsequent blood flow alterations. Evoked potentials often recovered transiently at 1–2 h after injury, suggesting that some axons were not immediately destroyed by the contusion and their subsequent survival or function was influenced by factors other than the initial Ca2+ derangement. Neither blood flow changes nor action potential conduction recovery depended on specific levels of extracellular Ca2+. In conclusion, our data support the hypothesis of Ca2+-mediated injury of spinal tracts but additional work is required to define the role of Ca2+ in the later phases of spinal injury.

Central axons in injured cat spinal cord recover electrophysiological function following remyelination by Schwann cells

Axonal morphometry of the lesion site was studied at 3 months after standardized weight-drop contusion injury of the thoracic spinal cord in adult cats. From a sample of 25 injured animals, 12 examples were found in which all surviving axons in the dorsal column were remyelinated by Schwann cells, at the level of the lesion. The dorsolateral tracts were also peripherally myelinated in 6 of these cases, and there was no central myelination in complete transverse sections through the lesion in four animals. In these cases, Schwann cell myelination was prevalent for several millimeters on either side of the lesion center. The extent of Schwann cell invasion correlated with the intensity of injury, measured by overall axon loss. Cortical somatosensory evoked potentials (CSEP) were recorded from all animals before and at intervals for 12 weeks after injury. CSEP to hindlimb (tibial nerve) stimulation were lost immediately at injury but some recovery took place during the first month. The extent of CSEP recovery correlated negatively but weakly with overall axon loss. Clear SEP were recorded at 3 months post-injury in 3 of the animals in which the dorsal columns were remyelinated by Schwann cells; in one of these, the dorsolateral funiculi were also peripherally myelinated. In another, oligodendrocyte myelination was absent from the entire transverse section of the lesion site. Thus, abnormal remyelination by cells of the peripheral nervous system, which is known to occur in a variety of central demyelinating conditions, is capable of restoring effective action potential conduction in mammalian spinal cord sensory tracts.

The Recovery of 5-HT Immunoreactivity in Lumbosacral Spinal Cord and Locomotor Function after Thoracic Hemisection

To determine the role of serotonin (5-HT) in recovery from spinal cord injury, we examined spinal cord 5-HT immunohistologically and assessed locomotor recovery after thoracic (T8) spinal cord hemisection in 68 rats. Forty eight rats had laminectomy and hemisection, while the remaining 20 rats received laminectomy only. All rats were evaluated every other day for 4 weeks, using a 0-14 point scale open field test. Hemisection markedly reduced mean hindlimbs scores from 14 to 1.5 +/- 0.32 and 5.6 +/- 0.31 (mean +/- standard error of mean) in the ipsilateral and contralateral side, respectively. The rats all recovered apparently normal walking by 4 weeks. The 5-HT immunohistological study revealed a marked reduction of 5-HT-containing terminals in the ipsilateral but not the contralateral lumbosacral cord by 1 week after hemisection. By 4 weeks after hemisection, 5-HT immunoreactive fibers and terminals returned to the ipsilateral lumbosacral cord, with many 5-HT fibers crossing over the central canal at thoracic level. We estimated the recovery of 5-HT neural elements in lumbosacral ventral horn by ranking 5-HT staining intensity and counting 5-HT terminals. The return of 5-HT immunoreactivity of the lumbosacral ventral horn correlated with locomotor recovery. Locomotory recovery invariably occurred when the density of 5-HT terminals approached 20% of control values. These results indicate that return of 5-HT fibers and terminals predict the time course and extent of locomotory recovery after thoracic spinal cord hemisection.

21-Aminosteroid reduces ion shifts and edema in the rat middle cerebral artery occlusion model of regional ischemia.

U74006F is a member of a new family of steroid drugs called 21-aminosteroids, which are potent inhibitors of lipid peroxidation with little or no glucocorticoid or mineralocorticoid activity. We investigated the effects of U74006F on the early ionic edema produced by middle cerebral artery occlusion in rats. Intravenous doses of 3 mg/kg U74006F were given 10 minutes and 3 hours after occlusion. Tissue concentrations of Na+, K+, and water at and around the infarct site were measured by atomic absorption spectroscopy and by wet-dry weight measurements 24 hours after occlusion. Compared with vehicle treatment, U74006F treatment reduced brain water entry, Na+ accumulation, K+ loss, and net ion shift by 25-50% in most brain areas sampled in the frontal and parietal cortex. However, reductions of ionic edema were most prominent and reached significance (p less than 0.005, unpaired two-tailed t test) mostly in the frontoparietal and parietal cortex areas adjacent to the infarct site. Our findings suggest that a steroid drug without glucocorticoid or mineralocorticoid activity can reduce edema in cerebral ischemia but that the effects are largely limited to tissues in which collateral blood flow may be present.

Experimental spinal cord injury: treatment with naloxone.

We studied the effect of the opiate antagonist naloxone on the recovery of cats injured with a 400-g-cm impact injury to T-9. The animals were evaluated by recording somatosensory evoked potentials and performing weekly neurological examinations. Several dose schedules were followed. Six of eight cats that received an intravenous or intraperitoneal bolus of naloxone (10 mg/kg) 45 minutes after injury regained the ability to walk. Recovery occurred in only one of five animals that were treated with an infusion of naloxone, 10 mg/kg/hour, and in none of five animals given 1 mg/kg as a bolus. Because these results are not related to any observed change in blood pressure, we believe that naloxone may be achieving its effect through the preservation of spinal cord blood flow, as well as other mechanisms that have yet to be defined.

Regulation of Trk Receptors Following Contusion of the Rat Spinal Cord

Neurotrophins function through high-affinity tyrosine kinase (Trk) receptors to promote growth and survival of cells in the injured nervous system. To investigate the role of Trk receptors in the adult nervous system, we examined TrkA, TrkB, and TrkC mRNA expression in spinal cord and brain after spinal contusion. At 1 day postinjury, all Trk receptor transcripts were down regulated at and around the site of injury, a situation that persisted through the first week. By 42 days, Trk expression was absent only within the cavity. In addition, truncated TrkB expression was substantially increased in ependymal cells and astrocytes surrounding the lesion cavity of chronically injured spinal cords. Rostral and caudal to the injury site, TrkA, TrkB, and TrkC mRNA expression did not differ from that of uninjured control spinal cords. Furthermore, no changes were observed in TrkB or TrkC expression in the axotomized corticospinal and rubrospinal neurons. These studies suggest that loss of Trk receptors at the injury site may contribute to the early progressive cellular loss in injured spinal cords, while increased presence of truncated TrkB receptors in the chronic injured spinal cord may sequester and restrict BDNF availability to support axonal regeneration and neuronal survival. The persistence of Trk receptors on supraspinal neurons suggests that neurotrophin application can support growth and survival in the acute and chronic injury states.