Keeping promises: translating basic research into new spinal cord injury therapies

Centuries of medical wisdom-namely that spinal cord injury (SCI) treatment was limited to caretaking until the patients inevitably succumbed to complications-has given way to tremendous medical and research advancements. The prognosis for survival after SCI improved significantly after World War II, leading to the largest population of people aging with chronic SCI in history. Despite the general lack of optimism for functional recovery after SCI, the spinal cord has proven to be one of the most attractive systems for studying central nervous system plasticity. Predictions of clinical applications derived from basic findings now routinely accompany reports of evidence for spinal axon regeneration. This has led to great debate in the SCI research community about the level and quality of evidence needed to select truly promising candidate therapies. This article reviews the basis for optimism in the new understanding of the processes of degeneration after SCI and the mechanisms of regeneration. The emphasis is on neuroprotective and reparative strategies emerging from the animal literature, and on the steps remaining to be taken to translate these into effective clinical trials of new therapies. Examples of the translational process in related areas of brain injury and stroke are cited, as well as the specific issues relating to the needs of individuals with SCI.     

急性中央型颈髓损伤综合征的临床治疗

目的探讨急性中央型颈髓损伤综合征的临床治疗.方法对30例急性中央型颈髓损伤综合征患者,根据病情分别采取保守治疗、颈椎前路、后路脊髓减压手术.结果平均随访4年8个月,根据ASIA分级标准,在21例非手术治疗组中,治疗前B级1例,C级5例,D级15例,治疗后恢复至D级者4例,恢复至E级者15例,无明显恢复者2例;在9例手术治疗组中,治疗前B级2例,C级4例,D级3例,治疗后恢复至C级者1例,恢复至D级者3例,恢复至E级者4例,无明显恢复者1例.结论对于MRI显示脊髓无明显受压的患者,经保守治疗多可取得满意疗效.对于MRI显示脊髓明显受压的患者,行颈椎前、后路脊髓减压手术,有利于脊髓功能的恢复.     

Clinical trials in spinal cord injury

Progress in promoting axonal plasticity and regeneration in animal models of spinal cord injury (SCI) has led to novel prospects for the initiation of human clinical trials in the near future. This review discusses a number of considerations in the path to translating a preclinical candidate from the laboratory to clinical testing. We will also briefly discuss issues associated with the design, performance, analysis, and reporting of human clinical trials in SCI. It is important, for both the medical community and the spinal cord injured community, that objective scientific and medical standards are adopted in the clinical translation of potentially promising, but as yet unproven, therapies for SCI.     

Naturally occurring disk herniation in dogs: an opportunity for pre-clinical spinal cord injury research

Traumatic spinal cord injuries represent a significant source of morbidity in humans. Despite decades of research using experimental models of spinal cord injury to identify candidate therapeutics, there has been only limited progress toward translating beneficial findings to human spinal cord injury. Thoracolumbar intervertebral disk herniation is a naturally occurring disease that affects dogs and results in compressive/contusive spinal cord injury. Here we discuss aspects of this disease that are analogous to human spinal cord injury, including injury mechanisms, pathology, and metrics for determining outcomes. We address both the strengths and weaknesses of conducting pre-clinical research in these dogs, and include a review of studies that have utilized these animals to assess efficacy of candidate therapeutics. Finally, we consider a two-species approach to pre-clinical data acquisition, beginning with a reproducible model of spinal cord injury in the rodent as a tool for discovery with validation in pet dogs with intervertebral disk herniation.     

脊髓损伤药物治疗新进展

随着对脊髓损伤（spinal cord injury,SCI）基础、临床研究的不断进步,在20世纪90年代确定了甲基强的松龙早期应用于脊髓伤肯定的临床效果后,又对其治疗机制不断深入研究。在此基础上一系列新药被开发用于实验性或临床脊髓损伤治疗。     

经颅磁刺激运动诱发电位在脊柱脊髓损伤的临床应用研究

目的评价经颅磁刺激运动诱发电位（ＴＭＳＭＥＰ）在脊柱脊髓损伤诊断中的作用。方法测定２１例完全性脊髓损伤患者、３５例不完全性脊髓损伤患者双侧胫前肌与腓肠肌的ＴＭＳＭＥＰ,随访６个月～２年,以２０例正常成人ＴＭＳＭＥＰ作对照。结果２１例完全性脊髓损伤患者中,１９例双侧胫前肌及腓肠肌ＴＭＳＭＥＰ消失,随访截瘫无恢复;２例圆锥损伤有异常ＴＭＳＭＥＰ,截瘫及ＴＭＳＭＥＰ基本恢复。３５例不完全性脊髓损伤患者中,每例均可记录到１块以上靶肌的ＴＭＳＭＥＰ,随访３３例,截瘫及ＴＭＳＭＥＰ均有不同程度的恢复,其中术前２５块靶肌肌力０级而有异常ＴＭＳＭＥＰ,术后肌力除２块无恢复外,其余均有明显恢复或正常。术后ＴＭＳＭＥＰ的恢复时间和程度均较体检所见早且明显。结论ＴＭＳＭＥＰ测定对于脊髓损伤的诊断和预后的估计,有重要的临床应用价值     

Clinical correlates of fatigue in spinal cord injury

STUDY DESIGN: Retrospective chart review. OBJECTIVES: To determine the prevalence of fatigue in an outpatient spinal cord injury population and to examine the clinical variables contributing to that fatigue. SETTING: GF Strong Rehabilitation Centre, Vancouver, British Columbia, Canada. METHODS: Medical charts of 76 individuals admitted to the GF Strong Outpatient SCI Program between December 2004 and December 2005 were reviewed. Data collected included information on clinical characteristics, demographics and Fatigue Severity Scale (FSS) scores. Multivariable analysis was completed to determine the independent association between these variables and fatigue severity. RESULTS: A total of 57% (95% confidence interval (CI)=45-67%) of the sample were found to have fatigue severe enough to interfere with function. People that were admitted for medical reasons; had pain, spasticity, incomplete injuries, and/or were on more that one medication with a known side effect of fatigue had significantly higher FSS scores. Multivariable analysis indicated incomplete injury was the only statistically significant predictor of a higher FSS scores; pain approached significance (P=0.07, CI=-0.09, 2.06). Together these variables account for 18% of the variance in FSS scores in this sample. CONCLUSION: Fatigue among individuals with spinal cord injury who are seeking outpatient rehabilitation is very common. The severity of fatigue was greater for individuals with incomplete lesions. Pain was also a potentially important covariate of fatigue. Further research is required to determine what else contributes to fatigue severity beyond these clinical variables as only minimal variance was accounted for in our model.     

椎间盘损伤相关颈脊髓损伤的临床研究

目的探讨与椎间盘损伤相关颈脊髓损伤的诊断和治疗方法。方法1997年1月～2003年1月，我院共收治创伤性颈脊髓损伤患1274例，对275例临床资料完整的患进行回顾和分析。结果275例影像学资料完整的患中颈椎间盘突(脱)出213例，占77．5％。213例颈椎间盘突(脱)出患中，82．2％的患椎间盘突出MRI图像显示有脊髓信号改变，94．4％的患神经损伤平面与椎间盘突出平面一致。手术结果行统计学分析显示椎间盘损伤相关颈脊髓损伤手术治疗疗效较为明确，手术时间距受伤时间越短疗效越好。结论对椎间盘损伤相关颈脊髓损伤诊断要明确，一旦明确诊断应手术治疗，且应尽早手术。     

Evaluation of an occupational therapy program for patients with spinal cord injury

STUDY DESIGN: Clinical controlled trial. OBJECTIVES: To evaluate the effectiveness of an occupational therapy (OT) program combined with neuromotor rehabilitation, by assessing the degree of functional independence reached by patients with spinal cord injuries at first hospitalization. SETTINGS: Subjects selected from the Spinal Cord Unit of the Rehabilitation Institute of Montecatone (Imola, Italy). PARTICIPANTS: Thirty-six male patients below age 60, with complete paraplegia (ASIA-A) in thoracic-lumbar level, at first hospitalization. METHODS: Patients were divided into experimental and control groups. Subjects in the experimental group underwent neuromotor rehabilitation coupled with an OT program, whereas those in the control group followed neuromotor rehabilitation only. Increase in functional independence at discharge was evaluated by the Valutazione Funzionale Mielolesi (VFM) assessment scale. RESULTS: Patients in the experimental group showed a significant increase in the total VFM score, and in domains concerning transfers and wheelchair use. A significant improvement was observed in unmarried patients as compared to married ones. CONCLUSION: An OT service within a Spinal Cord Unit allows us to achieve a higher level of functional independence.     

Glial implications in transplantation therapy of spinal cord injury

Spinal cord injuries are damages that result in complete or partial loss of sensation and/or mobility and affect the life qualities of many patients. Their pathophysiology in-cludes primary and secondary processes, which are related with the activation of astrocytes and microgliacytes and the degeneration of oligodendrocytes. Although transplan-tation of embryonic stem cells or neural progenitor cells is an attractive strategy for repair of the injured central ner-vous system (CNS), transplantation of these cells alone for acute spinal cord injuries has not resulted in robust axon regeneration beyond the injury sites. This may be due to the progenitor cells differentiating to the cell types that sup-port axon growth poorly and/or their inability to modify the inhibitory environment of adult CNS after injury. Recent studies indicate that transplantation of glial progenitor cells has exhibited beneficial effects on the recovery and promis-ing future for the therapy strategy of spinal cord injury. In this review, we summarized the data from recent literature regarding glial implications in transplantation therapy of spinal cord injury.     

Sexual issues in a sample of women with spinal cord injury

STUDY DESIGN: Semistructured interview. OBJECTIVES: To assess the degree of participation in sexual intercourse of a sample of women with spinal cord injury (SCI) in our community, to establish to what extent their sexual lives have been affected in comparison to before the injury, and to search for those factors that may have a major influence on both aspects. SETTING: Spinal Cord Injuries Unit, A Coruna, Spain. PARTICIPANTS: A total of 37 women, average age 40 years, time since onset average 10 years. RESULTS: In all, 62% claimed regular sexual activity after the injury. The women who suffered the injury before reaching the age of 18 years run a higher risk of not having physical relationships than those who were above that age when they incurred the SCI (P=0.04, OR 4.75). We discovered a significant drop in the frequency of intercourse (P=0.003) and the ability to reach an orgasm (P=0.008), after the injury. Of these women, 69% were satisfied with their current sexual activity and 77.4% considered the information they received from their doctors on the changes the SCI would cause in their sexuality to be either insufficient or nonexistent. CONCLUSIONS: There is a noticeable decrease in the frequency of intercourse as well as a significant reduction in the capability of reaching orgasm. Despite these changes and problems that ensue during intercourse as a result, most show satisfaction with their current sexual lives. On the other hand, the occurrence of the injury before the age of 18 years may imply a greater risk of not having an active sex life in adult years. We consider it is essential to provide the appropriate sexual information during the process of rehabilitation, aimed at helping women with SCI to adapt to their new situation.     

Cervical vertebral and spinal cord injury in intensive therapy

24 of 184 patients with vertebro-medullary trauma admitted to the Neurosurgery Clinic of Milan University in the years 1976-1988 have been examined. A common feature of these was a myelic lesion (transverse, complete or incomplete) at cervical level in which respiratory problems had made a period of intensive care indispensable. The purpose of the research was to assess the reliability of certain parameters in establishing patient prognosis. The following parameters were compared: clinical, objective and instrumental examination for a strictly neurological evaluation and for an evaluation of general condition, quantification of the same clinical examination through two scales, the Sunnybrook Cord Injury Scale (SCIS) for the neurological factor and the APACHE II for general condition, the type of treatment, with the same basic medical-resuscitation treatment. The result of the surgery or non-surgery was considered a posteriori. It is concluded that, in the case of the patients considered (high myelic lesion) the prognosis must be split into two different moments that the patient goes through in succession: the acute phase and the stabilisation phase. In the first phase, in which the vital functions are involved, the SCIS and APACHE II scales (with their sum) have great prognostic value; in the second phase, certain values, already considered on the APACHE II scale, are comparable in all patients and the prognostic problem is based on the other scale (SCIS) and on the adjuvant neurophysiological techniques. The very distinction between the two different phases that the patient traverses appears important also for the purposes of surgical indication.2     

Clinical activities of the model spinal cord injury system

OBJECTIVE: To review clinical activities that have resulted from funding of the Model Spinal Cord Injury System (MSCIS). METHODS: Review of the literature and responses from Model Systems Centers. RESULTS: Clinical benefits derived from MSCIS funding have been classified into 5 different areas: shift of spinal cord care from individual centers to care from a "Systems approach"; data collection as a stimulus for improved clinical care; service comprehensiveness to improve clinical care; research as a stimulus for improved clinical care; and dissemination of MSCIS research findings for educational purposes and to improve care provided by all SCI centers, including those not funded by the MSCIS. CONCLUSION: Many clinical benefits have been derived from the MSCIS program. Current research and developments being studied at model systems across the nation should continue to lead to new standards of care for persons with SCI.     

干细胞移植治疗脊髓损伤的研究进展

正脊髓损伤(spinal cord injury,SCI)是目前临床上最为棘手的创伤性神经疾病,由于脊髓特殊的构造和功能的独特性,目前尚无很好的治疗手段。自2001年Orlic等[1]首次开展干细胞移植治疗冠心病以来,应用干细胞移植治疗不同组织器官疾病的研究已广泛开展起来。尽管不同种类干细胞的生物学特性迥异,但目前研究认可的干细胞治疗作用主要表现在3个方面:(1)干细胞具有自身多分化潜能,可发挥替代退变坏死细胞的作用;(2)干细胞能分泌产生抗炎性因子,可抑制损伤病变微环境的炎性反应;(3)干     

Pharmacological therapy of spinal cord injury during the acute phase

STUDY DESIGN: Prospective, randomized clinical trial. SETTING: France. OBJECTIVES: To evaluate the safety and effect on neurological outcome of nimodipine, methylprednisolone, or both versus no medical treatment in spinal-cord injury during the acute phase. METHOD: One hundred and six patients who had spinal trauma (including 48 with paraplegia and 58 with tetraplegia) were randomly separated into four groups: M=methylprednisolone (30 mg x kg(-1) over 1 h, followed by 5.4 mg x kg(-1) x h(-1) for 23 h), N=nimodipine (0.015 mg x kg(-1) x h(-1) for 2 h followed by 0.03 mg x kg(-1)h(-1) for 7 days), MN (both agents) or P (neither medication). Neurological assessment (ASIA score) was performed by a blinded senior neurologist before treatment and at 1-year follow-up. Early spinal decompression and stabilization was performed as soon as possible after injury. RESULTS: One hundred patients were reassessed at 1 year. Neurological improvement was seen in each group (P<0.0001), however no additional neurological benefit from treatment was observed. Infectious complications occurred more often in patients treated with M. Early surgery (49 patients underwent surgery within 8 h of their accident) did not influence the neurological outcome. The only predictor of the latter was the extent of the spinal injury (complete or incomplete lesion). CONCLUSION: The present study confirms the absence of benefit of pharmacological therapy in this indication. Because of the paucity of clinical studies that demonstrate the efficacy of pharmacological treatment in spinal injury during the acute phase, systematic use of pharmaceutical agents should be reconsidered.