Time-related effects of general functional training in spinal cord-injured rats

OBJECTIVES: This prospective, randomized, experimental study with rats aimed to investigate the influence of general treatment strategies on the motor recovery of Wistar rats with moderate contusive spinal cord injury. METHODS: A total of 51 Wistar rats were randomized into five groups: control, maze, ramp, runway, and sham (laminectomy only). The rats underwent spinal cord injury at the T9-T10 levels using the NYU-Impactor. Each group was trained for 12 minutes twice a week for two weeks before and five weeks after the spinal cord injury, except for the control group. Functional motor recovery was assessed with the Basso, Beattie, and Bresnahan Scale on the first postoperative day and then once a week for five weeks. The animals were euthanized, and the spinal cords were collected for histological analysis. RESULTS: Ramp and maze groups showed an earlier and greater functional improvement effect than the control and runway groups. However, over time, unexpectedly, all of the groups showed similar effects as the control group, with spontaneous recovery. There were no histological differences in the injured area between the trained and control groups. CONCLUSION: Short-term benefits can be associated with a specific training regime; however, the same training was ineffective at maintaining superior long-term recovery. These results might support new considerations before hospital discharge of patients with spinal cord injuries.

IL-12p40 Deficiency Leads to Uncontrolled Trypanosoma cruzi Dissemination in the Spinal Cord Resulting in Neuronal Death and Motor Dysfunction

Chagas' disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-alpha, IFN-gamma, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-gamma were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.

Impaired blood-brain/spinal cord barrier in ALS patients

Vascular pathology, including blood-brain/spinal cord barrier (BBB/BSCB) alterations, has recently been recognized as a key factor possibly aggravating motor neuron damage, identifying a neurovascular disease signature for ALS. However, BBB/BSCB competence in sporadic ALS (SALS) is still undetermined. In this study, BBB/BSCB integrity in postmortem gray and white matter of medulla and spinal cord tissue from SALS patients and controls was investigated. Major findings include (1) endothelial cell damage and pericyte degeneration, (2) severe intra- and extracellular edema, (3) reduced CD31 and CD105 expressions in endothelium, (4) significant accumulation of perivascular collagen IV, and fibrin deposits (5) significantly increased microvascular density in lumbar spinal cord, (6) IgG microvascular leakage, (7) reduced tight junction and adhesion protein expressions. Microvascular barrier abnormalities determined in gray and white matter of the medulla, cervical, and lumbar spinal cord of SALS patients are novel findings. Pervasive barrier damage discovered in ALS may have implications for disease pathogenesis and progression, as well as for uncovering novel therapeutic targets. (C) 2012 Elsevier B.V. All rights reserved.

Proteome analysis of spinal cord during the clinical course of monophasic experimental autoimmune encephalomyelitis

The induction of autoimmune encephalomyelitis (EAE) in Lewis rats results in a period of exacerbation followed by complete recovery. Therefore, this model is widely used for studying the evolution of multiple sclerosis. In the present investigation, differentially expressed proteins in the spinal cord of Lewis rats during the evolution of EAE were assessed using the combination of 2DE and MALDI-TOF MS. The majority of the differentially expressed proteins were identified during the acute phase of EAE, in relation to naive control animals. On the other hand, recovered rats presented a similar protein expression pattern in comparison with the naive ones. This observation can be explained, at least in part, by the intense catabolism existent in acute phase due to nervous tissue damage. In recovered rats, we have described the upregulation of proteins that are apparently involved in the recovery of damaged tissue, such as light and medium neurofilaments, glial fibrillary acidic protein, tubulins subunits, and quaking protein. These proteins are involved mainly in cell growth, myelination, and remyelination as well as in astrocyte and oligodendrocyte maturation. The present study has demonstrated that the inflammatory response, characterized by an increase of the proliferative response and infiltration of autoreactive T lymphocytes in the central nervous system, occurs simultaneously with neurodegeneration.

Diaphragmatic pacing stimulation in spinal cord injury: anesthetic and perioperative management

OBJECTIVE: The standard therapy for patients with high-level spinal cord injury is long-term mechanical ventilation through a tracheostomy. However, in some cases, this approach results in death or disability. The aim of this study is to highlight the anesthetics and perioperative aspects of patients undergoing insertion of a diaphragmatic pacemaker. METHODS: Five patients with quadriplegia following high cervical traumatic spinal cord injury and ventilator-dependent chronic respiratory failure were implanted with a laparoscopic diaphragmatic pacemaker after preoperative assessments of their phrenic nerve function and diaphragm contractility through transcutaneous nerve stimulation. ClinicalTrials.gov:NCT01385384. RESULTS: The diaphragmatic pacemaker placement was successful in all of the patients. Two patients presented with capnothorax during the perioperative period, which resolved without consequences. After six months, three patients achieved continuous use of the diaphragm pacing system, and one patient could be removed from mechanical ventilation for more than 4 hours per day. CONCLUSIONS: The implantation of a diaphragmatic phrenic system is a new and safe technique with potential to improve the quality of life of patients who are dependent on mechanical ventilation because of spinal cord injuries. Appropriate indication and adequate perioperative care are fundamental to achieving better results.

Temporal modifications in bone following spinal cord injury in rats

Introduction: The aim of this study was to investigate the temporal modifications in bone mass, bone biomechanical properties and bone morphology in spinal cord injured rats 2, 4 and 6 weeks after a transection. Material and methods: Control animals were randomly distributed into four groups (n = 10 each group): control group (CG) - control animals sacrificed immediately after surgery; spinal cord-injured 2 weeks (2W) - spinal cord-injured animals sacrificed 2 weeks after surgery; spinal cord-injured 4 weeks (4W) - spinal cord-injured animals sacrificed 4 weeks after surgery; spinal cord-injured 6 weeks (6W) - spinal cord-injured animals sacrificed 6 weeks after surgery. Results: Biomechanical properties of the right tibia were determined by a threepoint bending test and injured animals showed a statistically significant decrease in maximal load compared to control animals. The right femur was used for densitometric analysis and bone mineral content of the animals sacrificed 4 and 6 weeks after surgery was significantly higher compared to the control animals and animals sacrificed 2 weeks after surgery. Histopathological and morphological analysis of tibiae revealed intense resorptive areas in the group 2 weeks after injury only. Conclusions: The results of this study show that this rat model is a valuable tool to investigate bone remodeling processes specifically associated with SCI. Taken together, our results suggest that spinal cord injury induced bone loss within 2 weeks after injury in rats.

Cannabidiol-treated Rats Exhibited Higher Motor Score After Cryogenic Spinal Cord Injury

Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5 s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20 mg/kg) immediately before, 3 h after and daily for 6 days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion + vehicle, day 1: zero, day 7: four, and lesion + Cannabidiol 20 mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions.

Burden of care and its impact on health-related quality of life of caregivers of individuals with spinal cord injury

Objective: to analyze the impact and burden of care on the Health-Related Quality of Life (HRQOL) of caregivers of individuals with a spinal cord injury (SCI). Method: cross-sectional observational study carried out by reviewing medical records and applying questionnaires. The scale Short Form 36 (SF-36) was used to assess HRQOL and the Caregiver Burden Scale (CBScale) for care burden. Results were analyzed quantitatively. Most patients with SCIs were male, aged 35.4 years old on average, with a predominance of thoracic injuries followed by cervical injuries. Most caregivers were female aged 44.8 years old on average. Results: tetraplegia and secondary complications stand out among the clinical characteristics that contributed to greater care burden and worse HRQOL. Association between care burden with HRQOL revealed that the greater the burden the worse the HRQOL. Conclusion: Preventing care burden through strategies that prepare patients for hospital discharge, integrating the support network, and enabling access to health care services are interventions that could minimize the effects arising from care burden and contribute to improving HRQOL.

Influence of different types of seat cushions on the static sitting posture in individuals with spinal cord injury

Study design: Cross-sectional study. Objectives: To evaluate the efficacy of the Postural Assessment Software PAS/SAPO in the posture analysis of individuals with spinal cord injury (SCI) during sitting position and to analyze if the use of different types of seat cushions-gel and foam, with no cushion-can interfere in the individual's posture during sitting position. Setting: Centre of Rehabilitation at the University Hospital (FMRP-USP), Ribeirao Preto, Brazil. Methods: Eight individuals, four paraplegics and four tetraplegics with SCI and 20 healthy individuals participated in the study. Photos were taken of individuals in the sitting position using foam, gel cushions and with no cushion. They were analyzed using the PAS/SAPO. The alignment of the anterior-superior iliac spine (ASIS) and the posterior pelvic tilt were evaluated from the angle formed between the ASIS and the greater trochanter of the femur. Results: The group of healthy individuals presented the best postural alignment when compared with the group with SCI, both for the ASIS alignment (P < 0.05) and for the degree of posterior pelvic tilt (P < 0.05). No significant differences were found in the variables analyzed when the seat cushions were compared. Conclusion: The different types of cushions did not alter the sitting posture; however, individuals with SCI showed worse postural alignment than the healthy individuals. PAS/SAPO was demonstrated to be useful for postural assessment. Spinal Cord (2012) 50, 627-631; doi:10.1038/sc.2012.7; published online 21 February 2012

Evaluation of the effects of hyperbaric oxygen therapy for spinal cord lesion in correlation with the moment of intervention

Study design: Experimental, controlled, animal study. Objectives: To evaluate the functional effect of hyperbaric oxygen therapy administered shortly, one day after, and no intervention (control) in standardized experimental spinal cord lesions in Wistar rats. Setting: Sao Paulo, Brazil. Methods: In all, 30 Wistar rats with spinal cord lesions were divided into three groups: one group was submitted to hyperbaric oxygen therapy beginning half an hour after the lesion and with a total of 10 one-hour sessions, one session per day, at 2 atm; the second received the same treatment, but beginning on the day after the lesion; and the third received no treatment (control). The Basso, Beattie and Bresnahan scales were used for functional evaluation on the second day after the lesion and then weekly, until being killed 1 month later. Results: There were no significant differences between the groups in the functional analysis on the second day after the lesion. There was no functional difference comparing Groups 1 and 2 (treated shortly after or one day after) in any evaluation moment. On the 7th day, as well as on the 21st and 28th postoperative days, the evaluation showed that Groups 1 and 2 performed significantly better than the control group (receiving no therapy). Conclusion: Hyperbaric chamber therapy is beneficial in the functional recovery of spinal cord lesions in rats, if it is first administered just after spinal cord injury or within 24 h. Spinal Cord (2012) 50, 502-506; doi: 10.1038/sc.2012.16; published online 6 March 2012

Spinal cord injury as a trigger to develop periodic leg movements during sleep: an evolutionary perspective

The primary trigger to periodic limb movement (PLM) during sleep is still unknown. Its association with the restless legs syndrome (RLS) is established in humans and was reported in spinal cord injury (SCI) patients classified by the American Spinal Injury Association (ASIA) as A. Its pathogenesis has not been completely unraveled, though recent advances might enhance our knowledge about those malfunctions. PLM association with central pattern generator (CPG) is one of the possible pathologic mechanisms involved. This article reviewed the advances in PLM and RLS genetics, the evolution of CPG functioning, and the neurotransmitters involved in CPG, PLM and RLS. We have proposed that SCI might be a trigger to develop PLM.

Therapeutic approaches for spinal cord injury

This study reviews the literature concerning possible therapeutic approaches for spinal cord injury. Spinal cord injury is a disabling and irreversible condition that has high economic and social costs. There are both primary and secondary mechanisms of damage to the spinal cord. The primary lesion is the mechanical injury itself. The secondary lesion results from one or more biochemical and cellular processes that are triggered by the primary lesion. The frustration of health professionals in treating a severe spinal cord injury was described in 1700 BC in an Egyptian surgical papyrus that was translated by Edwin Smith; the papyrus reported spinal fractures as a ''disease that should not be treated.'' Over the last biological or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at minimum, allow for partial functional recoveries for these patients, which could improve their quality of life.

Multiple Intravenous Administrations of Human Umbilical Cord Blood Cells Benefit in a Mouse Model of ALS

Background: A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) is the use of cell-based therapies that can protect motor neurons and thereby retard disease progression. We recently showed that a single large dose (25x10(6) cells) of mononuclear cells from human umbilical cord blood (MNC hUCB) administered intravenously to pre-symptomatic G93A SOD1 mice is optimal in delaying disease progression and increasing lifespan. However, this single high cell dose is impractical for clinical use. The aim of the present pre-clinical translation study was therefore to evaluate the effects of multiple low dose systemic injections of MNC hUCB cell into G93A SOD1 mice at different disease stages. Methodology/Principal Findings: Mice received weekly intravenous injections of MNC hUCB or media. Symptomatic mice received 10(6) or 2.5x10(6) cells from 13 weeks of age. A third, pre-symptomatic, group received 10(6) cells from 9 weeks of age. Control groups were media-injected G93A and mice carrying the normal hSOD1 gene. Motor function tests and various assays determined cell effects. Administered cell distribution, motor neuron counts, and glial cell densities were analyzed in mouse spinal cords. Results showed that mice receiving 10(6) cells pre-symptomatically or 2.5x10(6) cells symptomatically significantly delayed functional deterioration, increased lifespan and had higher motor neuron counts than media mice. Astrocytes and microglia were significantly reduced in all cell-treated groups. Conclusions/Significance: These results demonstrate that multiple injections of MNC hUCB cells, even beginning at the symptomatic disease stage, could benefit disease outcomes by protecting motor neurons from inflammatory effectors. This multiple cell infusion approach may promote future clinical studies.

Extra and intradural spinal Hemangioblastoma

Hemangioblastomas of the central nervous system (CNS) are low-grade highly vascularized tumors that may be sporadic or associated with Von Hippel-Lindau disease. Extradural hemangioblastomas are uncommon and those located extra and intradurally are even rarer. This study uses an illustrative case and literature review to discuss the difficulties to consider the correct diagnosis and to select the best surgical approach. A 57 years-old white male patient presented with myelopathy and right C5 radiculopathy. The images showed a lobulated, hourglass shaped, highly enhanced extra/intradural lesion that occupied the spinal canal and widened the C4-C5 right intervertebral foramen. Total resection of the intradural lesion was achieved through a posterior approach, but the extradural part could only be partially removed. Complete improvement was observed after four months of follow-up and the residual tumor has been followed up clinically and radiologically. Even though the preoperative impression was of a spinal schwannoma, the histopathological examination revealed grade I hemangioblastoma as per WHO. Despite their rarity, current complementary exams allow considering the diagnosis of hemangioblastoma preoperatively. That is essential to a better surgical planning in view of the particular surgical features of this lesion.