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A case of reflex sympathetic dystrophy (complex regional pain syndrome, type I) resolved by cerebral contusion.

We present a case of refractory reflex sympathetic dystrophy (RSD) (complex regional pain syndrome, type I) whose symptoms (ongoing pain, allodynia, hyperhydrosis and temperature abnormalities) were resolved after the patient suffered a traumatic cerebral contusion in the left temporal lobe, which caused no neurological deficit. This case suggests that symptoms of some RSD patients may largely sustained by a complex network involving the brain.

Brain Concussion↗

Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury.

Pain and allodynia following spinal cord injury are poorly understood and difficult to treat. Since there is evidence that supraspinal mechanisms are important in such pain, we have studied the role of the thalamus in an experimental model of spinal injury. Extracellular recordings were obtained from neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats and those which had sustained a contusive spinal cord injury to the thoraco-lumbar junction 7 days previously. Behavioural testing with von Frey hairs established that 11 spinally injured rats showed exaggerated vocal responses to normally innocuous mechanical stimulation (allodynia) whereas eight were non-allodynic. Thalamic VPL neurones in spinally injured rats (both allodynic and non-allodynic) exhibited a dysrhythmia in that a significantly higher proportion fired spontaneously in an oscillatory mode when compared with neurones in uninjured rats. Thus this dysrhythmia was linked to spinal injury, not to allodynia. The evoked responses of VPL thalamic neurones to brushing the skin, however, were significantly elevated in allodynic rats when compared with those in uninjured rats and neuronal afterdischarges to these stimuli (which were absent in uninjured rats) were more common in allodynic than in non-allodynic rats. We have previously reported that a proportion of spinal neurones in allodynic spinally injured rats show increased evoked responses and afterdischarges following brushing the skin and hence the enhanced thalamic responses may reflect a greater spinal input. In view of the increasing evidence that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive brain functions, we propose that pain following brushing the skin results from an exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both spinal and thalamic mechanisms may be important in the genesis of pain and allodynia following spinal cord injury.

Action Potentials↗

Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury.

Spinal cord injury leads to acute local ischemia, which may contribute to secondary degeneration. Hypoxia stimulates angiogenesis through a cascade of events, involving angiogenesis stimulatory substances, such as vascular endothelial growth factor (VEGF). To test the importance of angiogenesis for functional outcome and wound healing in spinal cord injury VEGF165 (proangiogenic), Ringer's (control) or angiostatin (antiangiogenic) were delivered locally immediately after a contusion injury produced using the NYU impactor and a 25 mm weight-drop. Rats treated with VEGF showed significantly improved behavior up to 6 weeks after injury compared with control animals, while angiostatin treatment lead to no statistically significant changes in behavior outcome. Furthermore, VEGF-treated animals had an increased amount of spared tissue in the lesion center and a higher blood vessel density in parts of the wound area compared with controls. These effects were unlikely to be due to increased cell proliferation as determined by bromo-deoxy-uridine-labeling. Moreover, VEGF treatment led to decreased levels of apoptosis, as revealed by TUNEL assays. In situ hybridization demonstrated presence of mRNA for VEGF receptors Flt-1, fetal liver kinase-1, neuropilin-1 and -2 in several important cellular compartments of the spinal cord. The different experiments indicate that beneficial effects seen by acute VEGF delivery was attributable to protection/repair of blood vessels, decreased apoptosis and possibly also by other additional effects on glial cells or certain neuron populations.

Analysis of Variance↗

Cognitive dysfunction and histological findings in rats with chronic-stage contusion and diffuse axonal injury.

The Morris water maze (MWM) technique is well known as a prominent method of evaluating learning acquisition and memory retention impairments in rats. We previously reported on a modified fluid percussion device that is able to consistently produce experimental cortical contusion (CC) and diffuse axonal injury (DAI) in separate groups of rats. The purpose of the present protocol is to evaluate the differences in learning acquisition and memory retention impairments between these two types of injured rats in the chronic stage using the MWM technique. CC and DAI rats are respectively induced by lateral and midline fluid percussion. We also compare the histological differences between these two different types of traumatic brain injury. The results show statistically significant differences in learning acquisition impairment between the sham and CC rats and between the sham and DAI rats. However, a difference in memory retention impairment was expected to be seen only between the sham and DAI rats. Histologically, the loss of CA3 pyramidal cells in the hippocampus was observed ipsilaterally in the CC and bilaterally in DAI. Neuronal cell loss was observed in bilaterally in layer II of the entorhinal cortex in DAI, but not in CC.

Animals↗

[Contusion-suction trauma after globe injuries].

An analysis of ball injuries treated during the last 3 years at Münster University Eye Hospital revealed a difference in the kind of traumata caused by air-filled balls and by solid, inelastic balls. The pathomechanism of a "contusion-suction trauma" is discussed; this would offer a satisfactory explanation not only for injuries of the anterior segment, but also for retinal changes at the outer periphery and the posterior pole.

Athletic Injuries↗

Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury.

We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at approximately 4-8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg/kg administered 1 h after SCI followed by 45 mg/kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2',3' cyclic nucleotide 3' phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.

Animals↗

Cerebellar contusion associated with type I Chiari malformation following supratentorial head trauma: case report.

Acute presentation of Type I Chiari malformation in children is distinctly rare. An 11 year old male suffered a trauma to the right temporal-parietal region in a tobogganing accident resulting in an open depressed skull fracture. Radiographic evaluation included a Computed Tomographic scan which also demonstrated a significant cerebellar contusion and the presence of subarachnoid hemorrhage in the region of craniovertebral junction. Magnetic Resonance imaging revealed an underlying Type I Chiari malformation. Somatosensory evoked responses shortly following the injury demonstrated slowing of conduction across the lower brainstem. The open depressed fracture was debrided and elevated. Subsequent observation resulted in slow improvement in neurological function. A followup somatosensory evoked potential study performed 21 days following the accident showed improvement in conduction across the craniovertebral junction. The tonsillar ectopia associated with Type I Chiari malformation may predispose to cerebellar, upper spinal and brainstem injury following supratentorial trauma.

Arnold-Chiari Malformation↗

Automated quantitative gait analysis during overground locomotion in the rat: its application to spinal cord contusion and transection injuries.

Analysis of locomotion is an important tool in the study of peripheral and central nervous system damage. Most locomotor scoring systems in rodents are based either upon open field locomotion assessment, for example, the BBB score or upon foot print analysis. The former yields a semiquantitative description of locomotion as a whole, whereas the latter generates quantitative data on several selected gait parameters. In this paper, we describe the use of a newly developed gait analysis method that allows easy quantitation of a large number of locomotion parameters during walkway crossing. We were able to extract data on interlimb coordination, swing duration, paw print areas (total over stance, and at 20-msec time resolution), stride length, and base of support: Similar data can not be gathered by any single previously described method. We compare changes in gait parameters induced by two different models of spinal cord injury in rats, transection of the dorsal half of the spinal cord and spinal cord contusion injury induced by the NYU or MASCIS device. Although we applied this method to rats with spinal cord injury, the usefulness of this method is not limited to rats or to the investigation of spinal cord injuries alone.

Abdomen↗

Effects of enriched housing on functional recovery after spinal cord contusive injury in the adult rat.

To date, most research performed in the area of spinal cord injury focuses on treatments designed to either prevent spreading lesion (secondary injury) or to enhance outgrowth of long descending and ascending fiber tracts around or through the lesion. In the last decade, however, several authors have shown that it is possible to enhance locomotor function after spinal cord injury in both animals and patients using specific training paradigms. As a first step towards combining such training paradigms with pharmacotherapy, we evaluated recovery of function in adult rats sustaining a spinal cord contusion injury (MASCIS device, 12.5 mm at T8), either housed in an enriched environment or in standard cages (n = 15 in both groups). The animals in the enriched environment were stimulated to increase their locomotor activity by placing water and food on opposite sides of the cage. As extra stimuli, a running wheel and several other objects were added to the cage. We show that exposure to the enriched environment improves gross and fine locomotor recovery as measured by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, the BBB subscale, the Gridwalk, and the Thoracolumbar height test. However, no group differences were found on our electrophysiological parameters nor on the amount of spared white matter. These data justify further studies on enriched housing and more controlled exercise training, with their use as potential additive to pharmacological intervention.

Age Factors↗

BetaIII tubulin-expressing neurons reveal enhanced neurogenesis in hippocampal and cortical structures after a contusion trauma in rats.

Neurogenesis is not only restricted to embryonic development, but also occurs in adult mammalian brains, including human. In this study, evidence is provided, that neurogenesis is involved in the repair of hippocampal and cortical structures after CNS injury. Cortical contusion was induced in 8-week-old Wistar rats. This trauma resulted in a primary cortical lesion and ipsilateral distant remote hippocampal damage, involving primarily CA3-pyramidal cells. The progression of injury was followed over a time course of 7 days, using Nissl-staining and a monoclonal antibody against betaIII tubulin-a specific marker for neurogenic cells. Nissl staining showed a partial recovery of damaged cortical and hippocampal cells at day 7. This recovery was accompanied by an increase of neurogenic cells in these structures, particularly in the dentate gyrus and the neocortical areas. Taken together, these findings provide evidence for the involvement of neurogenesis in the repair processes after traumatic brain injury.

Animals↗

Moderate controlled cortical contusion in pigs: effects on multi-parametric neuromonitoring and clinical relevance.

Over the last decade, routine neuromonitoring of ICP and CPP has been extended with new on-line techniques such as microdialysis, tissue oxygen (ptiO(2)), acid-base balance (ptiCO(2), pH) and CBF measurements, which so far have not lead to clear-cut therapy approaches in the neurointensive care unit. This is partially due to the complex pathophysiology following a wide-range of brain injuries, and the lack of suitable animal models allowing simultaneous, clinically relevant neuromonitoring under controlled conditions. Therefore, a controlled cortical impact (CCI) model in large animals (pig) has been developed. After placement of microdialysis, ptiO(2), temperature and ICP catheters, an unilateral CCI injury (2.6-2.8 m/sec velocity, 9 mm depth, 400 ms dwell time) was applied and neuromonitoring continued for 10 h. CCI caused a rapid drop in CPP, ptiO(2) and glucose, whereas ICP, glutamate and lactate increased significantly. Most parameters returned to baseline values within hours. Lactate stayed elevated significantly throughout the experiment, but the lactate-to-pyruvate ratio (LPR) changed only slightly, indicating no severely ischemic CBF. Contralateral parameters were not affected significantly. Evaluation of brain water content and histology (12 h post-CCI) showed ipsilateral brain swelling by 5% and massive cell damage underneath the injury site which correlated with changes of ICP, CPP, glutamate, lactate, and ptiO(2) within the first hours post-CCI. Moderate controlled cortical contusion in pigs induced a complex pattern of pathophysiological processes which led to 'early' histological damage. Thus, this new large animal model will enable us to investigate the effect of therapeutic interventions on multi-parametric neuromonitoring and histological outcome, and to translate the data into clinical practice.

Animals↗

Metabolic changes in the vicinity of brain contusions: a proton magnetic resonance spectroscopy and histology study.

Proton MR spectroscopy (1H-MRS) has been previously used to monitor metabolic changes in areas of diffuse brain injury. We studied metabolism in the close vicinity of experimental traumatic brain contusions and remote on the contralateral side from 1h to 28d post-injury. Changes of creatine and phosphocreatine (Cr&PCr), N-acetylaspartate (NAA), choline (Cho), inositol (Ino), taurine (Tau), glutamate (Glu), and lactate (Lac) were assessed and compared to neuronal, glial and inflammatory changes in histology. In the pericontusional zone Cr&PCr, NAA, and Glu decreased immediately after trauma by -35%, -60%, and -37%, respectively, related to primary cell disintegration and secondary perturbations as reflected in histology. These metabolites partially recovered at 7d (-15%, -37%, and -21% respectively), in parallel to indicators of repair in immunhistochemistry. Control levels were not regained at 28d, in correlation to a decrease of viable neurons. Cho and Ino, initially lowered by -26% and -31% respectively, increased at 7d by +74% and 31%, reflecting glial activation and proliferation. The signal including the lactate resonance increased by >1000% with a maximum at 7d, possibly related to energy failure, inflammation and glial activation. A partial contribution of lipids to this signal cannot be fully excluded. The contralateral side showed mild astroglial activation in histology, but no changes in 1H-MRS. The study demonstrates the feasibility of volume selective 1H-MRS using the LCModel (Linear Combination of Model in vitro spectra of metabolites solutions) to monitor metabolic changes close to focal traumatic lesions and suggests how metabolic alterations can be differentiated in cause.

Animals↗

Locomotor recovery after spinal cord contusion injury in rats is improved by spontaneous exercise.

We have recently shown that enriched environment (EE) housing significantly enhances locomotor recovery following spinal cord contusion injury (SCI) in rats. As the type and intensity of locomotor training with EE housing are rather poorly characterized, we decided to compare the effectiveness of EE housing with that of voluntary wheel running, the latter of which is both well characterized and easily quantified. Female Wistar rats were made familiar with three types of housing conditions, social housing (nine together) in an EE (EHC), individual housing in a running wheel cage (RUN, n = 8), and standard housing two together (CON, n = 10). Subsequently, a 12.5 gcm SCI at Th8 was produced and animals were randomly divided over the three housing conditions. Locomotor function was measured regularly, once a week by means of the BBB score, BBB sub score, TLH test, Gridwalk test, and CatWalk test. In the RUN group, daily distance covered was also measured. Locomotor recovery in the EHC and the RUN groups was equal and significantly better than in the CON group. The extent of recovery at 8 weeks post injury in the RUN group did not correlate with distance covered. We conclude that locomotor training needs to exceed a given threshold in order to be effective in enhancing locomotor recovery in this experimental model, but that once this threshold is exceeded no further improvement occurs, and that the specificity of locomotor training plays little role.

Animals↗

Neuroprotective effects of recombinant thrombomodulin in controlled contusion spinal cord injury implicates thrombin signaling.

Although the central nervous system (CNS) of mammals has had poor prospects for regeneration, recent studies suggest this might improve from blocking "secondary cell loss" or apoptosis. In this regard, intravenous activated protein C (aPC) improved neurologic outcomes in a rat compression spinal cord injury (SCI) model. Protein C activation occurs when the serine protease thrombin binds to the cell surface proteoglycan thrombomodulin (TM) forming a complex that halts coagulation. In culture, rTM blocks thrombin's activation of protease-activated receptors (PARs), that mediate thrombin killing of neurons and glial reactivity. Both PAR1 and prothrombin are rapidly upregulated after contusion SCI in rats, prior to peak apoptosis. We now report neuroprotective effects of intraperitoneal soluble recombinant human rTM on open-field locomotor rating scale (BBB) and spinal cord lesion volume when given 1 h after SCI. BBB scores from four separate experiments showed a 7.6 +/- 1.4 absolute score increase (p < 0.05) at 3 days, that lasted throughout the time course. Histological sections at 14 days were even more dramatic where a twofold reduction in lesion volume was quantified in rTM-treated rats. Thionin staining revealed significant preservation of motor neuronal profiles both at, and two segments below, the lesion epicenter. Activated caspase-3 immunocytochemistry indicated apoptosis was quite prominent in motor neurons in vehicle (saline) controls, but was dramatically reduced by rTM. Microglia, increased and activated after injury, were reduced with rTM treatment. Taken together, these and previous results support a prominent role for coagulation-inflammation signaling cascades in the subacute changes following SCI. They identify a neuroprotective role for rTM by its inhibition of thrombin generation and blockade of PAR activation.

Animals↗

The use of hyperbaric oxygen to modify the effects of recent contusion injury to the spinal cord.

Studies on the experimental spinal contusion injury in animals confirm that posttraumatic ischemia contributes to central cystic necrosis or fibrosis occurring at the level of the spinal cord lesion. Hyperbaric oxygen (HBO) modifies the degree and extent of the pathology in the spinal cord of the experimental animals. HBO has been used for 45 patients with recent spinal cord injuries. The extent of recovery in 27 patients with upper motor neuron lesions treated with adequate HBO is reported. Fifteen of the 27 patients had useful functional recovery.

Adult↗

Three-dimensional computer-assisted analysis of graded contusion lesions in the spinal cord of the rat.

Histological analysis of spinal cord injury in experimental animals has focused primarily on the microanatomy of damaged tissue. The current study presents an analysis of the three-dimensional structure of lesion sites in the spinal cord of rats contused with an injury device which produces consistent lesions. Three levels of injury were produced by systematically varying the cord displacement and the duration of the displacement during impact. The resulting groups of subjects exhibited mild, moderate, and severe neurological deficits. Comparisons of equivalent mild impacts made at thoracic versus lumbar spinal cord levels were also made. The results indicate that the overall shape of the lesions is generally biconical, with extensions in the base of the dorsal funiculus, irrespective of the degree of damage or the spinal level of the injury. Lower displacement injuries yielded shorter lesions rostrocaudally with less spread into the white matter. Similar impacts in the lumbar versus thoracic spinal cord produced shorter, more truncated lesion sites at lumbar levels with less involvement of the white matter than in the thoracic lesions. Three-dimensional analyses can can provide additional information about the lesion beyond that available from conventional histopathological measures. Such information could be useful in assessing the results of posttraumatic manipulations which are directed at reducing tissue damage or tissue replacement via transplantation.

Animals↗

Analysis of TGF-beta 1 gene expression in contused rat spinal cord using quantitative RT-PCR.

We have used northern blot analysis and quantitative reverse transcription polymerase chain reaction (RT-PCR) to determine the postinjury expression profile of the transforming growth factor-beta 1 (TGF-beta 1) gene in the contused rat spinal cord. Spectrophotometric estimates of total sample RNA and quantitative analyses of cyclophilin mRNA using RT-PCR served as controls for comparisons between samples. No changes in cyclophilin gene expression were found at any postinjury survival times. The results of the TGF-beta 1 analyses, which were carried out on spinal cord samples taken at postinjury intervals ranging from 6 h to 10 days, show that the amount of TGF-beta 1 mRNA present in spinal cord increases rapidly following injury, reaching maximum levels 7 days postinjury. Unoperated control samples contained approximately 2 x 10(8) molecules of TGF-beta 1 mRNA/0.5 microgram total RNA. By 1 day postinjury, the amount of TGF-beta 1 mRNA in the cord had increased by a factor of 2.5 to 5 x 10(8) molecules/0.5 microgram total RNA. At 7 days postinjury, there were approximately 15 x 10(8) molecules of TGF-beta 1 mRNA/0.5 microgram total RNA. By 10 days postinjury the amount of TGF-beta 1 mRNA present in the spinal cord had declined to 8 x 10(8) molecules of TGF-beta 1 mRNA/0.5 microgram total RNA, a value similar to that observed at 3 days postinjury. The roles that TGF-beta 1 might play in modifying cellular responses in injured spinal cord are discussed.

Animals↗

Continuous measurement of changes in regional cerebral blood flow following cortical compression contusion trauma in the rat.

Laser Doppler flowmetry (LDF) was used to study acute ipsilateral and contralateral disturbances of regional cerebral blood flow (rCBF) in a rat model of cerebral cortical contusion trauma. Twelve rats were intubated and artificially ventilated during and after trauma. Injury was produced with a weight drop technique (21 g from 35 cm) allowing 1.5 mm maximum compression of the right parietal cortex. Stationary laser Doppler probes were used for continuous blood flow measurements on the ipsilateral side adjacent to the traumatized tissue and on the contralateral side. Within 2 min blood flow decreased to 60% (+/- 9%) of the pretrauma rCBF level on the ipsilateral side and remained at this level for at least 20 min. On the contralateral side there was an initial increase to 172% (+/- 27%) at 4 min. This hyperperfusion phase was followed by a mild hypoperfusion phase with a flow of 78% (+/- 8%) of baseline, lasting approximately 60 min. An attempt was made to measure rCBF++ within the trauma site using a removable probe. We found that probe replacement in traumatized (as compared to control) animals caused a baseline shift with a considerable variability making interpretation difficult. However, the pattern of rCBF change did not differ from the measurements adjacent to the injury site. We tentatively conclude that the posttraumatic hypoperfusion phase was similar within the trauma region. The observed rCBF changes following trauma are similar to those seen following cortical spreading depression (CSD). We propose that CSD, known to occur on the ipsilateral side in our model, is one of the factors involved in acute blood flow decreases seen following cerebral trauma.

Analysis of Variance↗