Brian K. Kwon

Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon.

This review summarizes the current understanding of spinal cord injury pathophysiology and discusses important emerging regenerative approaches that have been translated into clinical trials or have a strong potential to do so. The pathophysiology of spinal cord injury involves a primary mechanical injury that directly disrupts axons, blood vessels, and cell membranes. This primary mechanical injury is followed by a secondary injury phase involving vascular dysfunction, edema, ischemia, excitotoxicity, electrolyte shifts, free radical production, inflammation, and delayed apoptotic cell death. Following injury, the mammalian central nervous system fails to adequately regenerate due to intrinsic inhibitory factors expressed on central myelin and the extracellular matrix of the posttraumatic gliotic scar. Regenerative approaches to block inhibitory signals including Nogo and the Rho-Rho-associated kinase pathways have shown promise and are in early stages of clinical evaluation. Cell-based strategies including using neural stem cells to remyelinate spared axons are an attractive emerging approach.

Survival and regeneration of rubrospinal neurons 1 year after spinal cord injury.

Scientific interest to find a treatment for spinal cord injuries has led to the development of numerous experimental strategies to promote axonal regeneration across the spinal cord injury site. Although these strategies have been developed in acute injury paradigms and hold promise for individuals with spinal cord injuries in the future, little is known about their applicability for the vast majority of paralyzed individuals whose injury occurred long ago and who are considered to have a chronic injury. Some studies have shown that the effectiveness of these approaches diminishes dramatically within weeks after injury. Here we investigated the regenerative capacity of rat rubrospinal neurons whose axons were cut in the cervical spinal cord 1 year before. Contrary to earlier reports, we found that rubrospinal neurons do not die after axotomy but, rather, they undergo massive atrophy that can be reversed by applying brain-derived neurotrophic factor to the cell bodies in the midbrain. This administration of neurotrophic factor to the cell body resulted in increased expression of growth-associated protein-43 and Tα1 tubulin, genes thought to be related to axonal regeneration. This treatment promoted the regeneration of these chronically injured rubrospinal axons into peripheral nerve transplants engrafted at the spinal cord injury site. This outcome is a demonstration of the regenerative capacity of spinal cord projection neurons a full year after axotomy.

Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury.

Over the past 2 decades, advances in understanding the pathophysiology of spinal cord injury (SCI) have stimulated the recent emergence of several therapeutic strategies that are being examined in Phase I/II clinical trials. Ten randomized controlled trials examining methylprednisolone sodium succinate, tirilizad mesylate, monosialotetrahexosylganglioside, thyrotropin releasing hormone, gacyclidine, naloxone, and nimodipine have been completed. Although the primary outcomes in these trials were laregely negative, a secondary analysis of the North American Spinal Cord Injury Study II demonstrated that when administered within 8 hours of injury, methylprednisolone sodium succinate was associated with modest clinical benefits, which need to be weighed against potential complications. Thyrotropin releasing hormone (Phase II trial) and monosialotetrahexosylganglioside (Phase II and III trials) also showed some promise, but we are unaware of plans for future trials with these agents. These studies have, however, yielded many insights into the conduct of clinical trials for SCI. Several current or planned clinical trials are exploring interventions such as early surgical decompression (Surgical Treatment of Acute Spinal Cord Injury Study) and electrical field stimulation, neuroprotective strategies such as riluzole and minocycline, the inactivation of myelin inhibition by blocking Nogo and Rho, and the transplantation of various cellular substrates into the injured cord. Unfortunately, some experimental and poorly characterized SCI therapies are being offered outside a formal investigational structure, which will yield findings of limited scientific value and risk harm to patients with SCI who are understandably desperate for any intervention that might improve their function. Taken together, recent advances suggest that optimism for patients and clinicians alike is justified, as there is real hope that several safe and effective therapies for SCI may become available over the next decade.

Causal assessment of occupational lifting and low back pain: results of a systematic review

BACKGROUND CONTEXT Low back pain (LBP) is a common and disabling musculoskeletal disorder that often occurs in a working-age population. Determining the precise causation of LBP remains difficult. Any attempt to implicate a specific occupational activity in the genesis of LBP requires a methodologically rigorous approach. PURPOSE To conduct a systematic review of the scientific literature focused on evaluating the causal relationship between occupational sitting and LBP. STUDY DESIGN Systematic review of the literature using Medline, EMBASE, CINAHL, Cochrane Library, Occupational Safety and Health database, grey literature, hand-searching occupational health journals, reference lists of included studies, and content experts. Evaluation of study quality using a modified version of the Newcastle-Ottawa Scale. Summary levels of evidence supporting Bradford-Hill criteria for different categories of sitting and types of LBP. SAMPLES Studies reporting an association between occupational sitting and LBP. OUTCOME MEASURES Numerical association between different levels of exposure to occupational sitting and the presence or severity of LBP. METHODS A systematic review was performed to identify, evaluate, and summarize the literature related to establishing a causal relationship, according to Bradford-Hill criteria, between occupational sitting and LBP. RESULTS This search yielded 2,766 citations. Twenty-four studies met the inclusion/exclusion criteria and five were high-quality studies, including two case-controls and three prospective cohorts. Strong, consistent evidence was found for no association between occupational sitting and LBP. A moderate level of evidence was found for the absence of any dose-response trend. Risk estimates evaluating temporality were not statistically significant. Biological plausibility was not discussed in these studies. No evidence was available to assess the experiment criterion. CONCLUSIONS This review failed to uncover high-quality studies to support any of the Bradford-Hill criteria to establish causality between occupational sitting and LBP. Strong and consistent evidence did not support criteria for association, temporality, and dose response. Based on these results, it is unlikely that occupational sitting is independently causative of LBP in the populations of workers studied.

A Systematic Review of Non-Invasive Pharmacologic Neuroprotective Treatments for Acute Spinal Cord Injury

An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically review the available pre-clinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we review treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications, or are available in a form that could be administered to humans. These include: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in-vivo animal model was utilized to assess the efficacy of the therapy in a traumatic SCI paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the pre-clinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation.

Animal models used in spinal cord regeneration research.

Study Design. A literature review was conducted. Objectives. To review animal models and injury paradigms used in the neurobiologic study of spinal cord regeneration, and to assist the spinal clinician in interpreting the many encouraging reports of potential therapies emerging from basic science laboratories. Summary of Background Data. An enormous amount of interest in spinal cord regeneration research has been generated within the past 20 years with the hope that experimental therapies will become available for individuals with spinal cord injuries. The use of various animal models in the laboratory setting has been critical to the development of such experimental therapies. Methods. A literature review was conducted. Results. Experimental interventions in animal models of spinal cord injury were evaluated both anatomically and functionally. Anatomic assessments use various histologic techniques and frequently include the use of anterograde and retrograde axonal tracers. Functional assessments can be performed neurophysiologically or by the observation of motor and sensory performance on a number of different tests. Sharp spinal cord injury paradigms in which the cord is completely or partially transected are useful for assessing axonal regeneration anatomically. In contrast, blunt injury models in which the cord is compressed or contused more accurately mimic the typical human injury and provide a good setting for the study of secondary pathophysiologic processes immediately after injury. Conclusions. Animal models will continue to play a critical role in the development of experimental therapies for spinal cord injuries. Both sharp and blunt spinal cord injury paradigms have unique characteristics that make them useful in addressing slightly different neurobiologic problems.

A Phase I/IIa Clinical Trial of a Recombinant Rho Protein Antagonist in Acute Spinal Cord Injury

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.

Promoting axonal regeneration in the central nervous system by enhancing the cell body response to axotomy

Neurons projecting into the peripheral nervous system (PNS) regenerate their axons after injury, in contrast to those confined to the central nervous system (CNS). Both neuronal and nonneuronal factors contribute to the lack of CNS regeneration. In this review we concentrate on the differential gene expression response to axotomy in PNS vs. CNS neurons. In general CNS neurons fail to up‐regulate or sustain the expression of regeneration‐associated proteins (RAGs), including trophic factors and their receptors. The presumed lack of trophic support of axotomized CNS neurons provided the rationale for the exogenous application of trophic factors, either to the lesion site or to the cell bodies. Here, we review our data on the application of trophic factors to rubrospinal and corticospinal neurons. Cell body treatment of axotomized rubrospinal neurons with brain‐derived neurotrophic factor (BDNF) reversed atrophy, increased GAP‐43 and Tα‐1 tubulin mRNA expression, and promoted axonal regeneration into peripheral nerve grafts. Importantly, BDNF cell body treatment was still effective in the chronic setting, i.e., when initiated 1 year after injury, but BDNF had no effect when applied to the chronic spinal cord injury site. The ability to promote regeneration in chronically injured neurons will hopefully contribute to the development of treatment strategies for chronic spinal injuries.

Causal assessment of occupational bending or twisting and low back pain: results of a systematic review

BACKGROUND CONTEXT Low back pain (LBP) is a common musculoskeletal disorder that often occurs in the working-age population. Although numerous physical activities have been implicated in its etiology, determining causation remains challenging and requires a methodologically rigorous approach. PURPOSE To conduct a systematic review focused on establishing a causal relationship between occupational bending or twisting and LBP. STUDY DESIGN A systematic review of the literature using Medline, Embase, CINAHL, Cochrane Library, and Occupational Safety and Health database, gray literature, hand-searching occupational health journals, reference lists of included studies, and experts. Evaluation of methodological quality using a modified Newcastle-Ottawa Scale for observational studies. Summary levels of evidence for each of the Bradford-Hill criteria for causality for each category of bending or twisting and type of LBP. SAMPLE Studies reporting an association between occupational bending or twisting and LBP. OUTCOME MEASURES Numerical association between different levels of exposure to bending or twisting and the presence or severity of LBP. METHODS A systematic review was performed to identify, evaluate, and summarize the literature related to establishing a causal relationship, according to Bradford-Hill criteria, between occupational bending or twisting and LBP. RESULTS This search yielded 2,766 citations. Ten high-quality studies reported on bending and LBP. Five were case-control studies and five were prospective cohort studies. There was conflicting evidence for association, with five studies demonstrating significant associations in the majority of their risk estimates, but no evidence for consistency. Seven studies assessed dose response, with four studies demonstrating a nonsignificant dose-response trend. Four studies were able to assess temporality, but only one demonstrated significant risk estimates. Biological plausibility was discussed by two studies. There was no available evidence for experiment. Seven high-quality studies reported on twisting and LBP. Two were case-control studies and five were prospective cohort studies. Three studies reported significant associations in the majority of their risk estimates, with no evidence for consistency. Three studies demonstrated a nonsignificant dose-response trend. Two studies were able to assess temporality, but only one study was able to demonstrate significant risk estimates. Two studies discussed biological plausibility. There was no available evidence for experiment. CONCLUSIONS A summary of existing studies was not able to find high-quality studies that satisfied more than three of the Bradford-Hill criteria for causation for either occupational bending or twisting and LBP. Conflicting evidence in multiple criteria was identified. This suggests that specific subcategories could contribute to LBP. However, the evidence suggests that occupational bending or twisting in general is unlikely to be independently causative of LBP.

Radiographic measurement parameters in thoracolumbar fractures: a systematic review and consensus statement of the spine trauma study group.

Study Design. Systematic review. Objectives. To review the various radiographic parameters currently used to assess traumatic thoracolumbar injuries, emphasizing the validity and technique behind each one, to formulate evidence-based guidelines for a standardized radiographic method of assessment of these fractures. Summary of Background Data. The treatment of thoracolumbar fractures is guided by various radiographic measurement parameters. Unfortunately, for each group of parameters, there has usually been more than 1 proposed measurement technique, thus creating confusion when gathering data and reporting outcomes. Ultimately, this effect results in clinical decisions being based on nonstandardized, nonvalidated outcome measures. Methods. Computerized bibliographic databases were searched up to January 2004 using key words and Medical Subject Headings on thoracolumbar spine trauma, radiographic parameters, and methodologic terms. Using strict inclusion criteria, 2 independent reviewers conducted study selection, data abstraction, and methodologic quality assessment. Results. There were 18 original articles that ultimately constituted the basis for the review. Of radiographic measurement parameters, 3 major groups were identified, depicting the properties of the injured spinal column: sagittal alignment, vertebral body compression, and spinal canal dimensions, with 14 radiographic parameters reported to assess these properties. Conclusions. Based on a systematic review of theliterature and expert opinion from an experienced group of spine trauma surgeons, it is recommended that the following radiographic parameters should be used routinely to assess thoracolumbar fractures: the Cobb angle, to assess sagittal alignment; vertebral body translation percentage, to express traumatic anterolisthesis; anterior vertebral body compression percentage, to assess vertebral body compression, the sagittal-to-transverse canal diameter ratio, and canal total cross-sectional area (measured or calculated); and the percent canal occlusion, to assess canal dimensions.