Charles H. Tator

Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012

This paper is a revision and update of the recommendations developed following the 1st (Vienna 2001), 2nd (Prague 2004) and 3rd (Zurich 2008) International Consensus Conferences on Concussion in Sport and is based on the deliberations at the 4th International Conference on Concussion in Sport held in Zurich, November 2012.1–3nnThe new 2012 Zurich Consensus statement is designed to build on the principles outlined in the previous documents and to develop further conceptual understanding of this problem using a formal consensus-based approach. A detailed description of the consensus process is outlined at the end of this document under the Background section. This document is developed primarily for use by physicians and healthcare professionals who are involved in the care of injured athletes, whether at the recreational, elite or professional level.nnWhile agreement exists pertaining to principal messages conveyed within this document, the authors acknowledge that the science of concussion is evolving, and therefore management and return to play (RTP) decisions remain in the realm of clinical judgement on an individualised basis. Readers are encouraged to copy and distribute freely the Zurich Consensus document, the Concussion Recognition Tool (CRT), the Sports Concussion Assessment Tool V.3 (SCAT3) and/or the Child SCAT3 card and none are subject to any restrictions, provided they are not altered in any way or converted to a digital format. The authors request that the document and/or the accompanying tools be distributed in their full and complete format.nnThis consensus paper is broken into a number of sectionsnn1. A summary of concussion and its management, with updates from the previous meetings;nn2. Background information about the consensus meeting process;nn3. A summary of the specific consensus questions discussed at this meeting;nn4. The Consensus paper should be read in conjunction with the SCAT3 assessment tool, the Child SCAT3 and the CRT …

Advances in stem cell therapy for spinal cord injury

Spinal cord injury (SCI) is a devastating condition producing great personal and societal costs and for which there is no effective treatment. Stem cell transplantation is a promising therapeutic strategy, though much preclinical and clinical research work remains. Here, we briefly describe SCI epidemiology, pathophysiology, and experimental and clinical stem cell strategies. Research in stem cell biology and cell reprogramming is rapidly advancing, with the hope of moving stem cell therapy closer to helping people with SCI. We examine issues important for clinical translation and provide a commentary on recent developments, including termination of the first human embryonic stem cell transplantation trial in human SCI.

Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology

Background: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimers disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown. Methods: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline. Results: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Moreover, the CTE cases showed co-morbid pathology of cancer, vascular disease, and AD. Discussion: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE.

Review of transplantation of neural stem/progenitor cells for spinal cord injury

Spinal cord injury (SCI) is a debilitating condition often resulting in paralysis, yet currently there is no effective treatment. Stem cell transplantation is a promising therapeutic strategy for promoting tissue repair after SCI. Stem cells offer a renewable source of cells with inherent plasticity for tissue regeneration. Neural stem/progenitor cells (NSPCs) are multipotent cells that self‐renew and are committed to the neural lineage, and thus, they are especially suited to SCI repair. NSPCs may differentiate into neural cells after transplantation into the injured spinal cord, replacing lost or damaged cells, providing trophic support, restoring connectivity, and facilitating regeneration. Here, we review experimental studies and considerations for clinical translation of NSPC transplantation for SCI.

Consensus statement on Concussion in Sport - The 4th International Conference on Concussion in Sport held in Zurich, November 2012.

the 4th International Conference on Concussion in Sport held in Zurich, November 2012 Paul McCrory, Willem H Meeuwisse, Mark Aubry, Bob Cantu, Jiří Dvořák, Ruben J Echemendia, Lars Engebretsen, Karen Johnston, Jeffrey S Kutcher, Martin Raftery, Allen Sills, Brian W Benson, Gavin A Davis, Richard G Ellenbogen, Kevin Guskiewicz, Stanley A Herring, Grant L Iverson, Barry D Jordan, James Kissick, Michael McCrea, Andrew S McIntosh, David Maddocks, Michael Makdissi, Laura Purcell, Margot Putukian, Kathryn Schneider, Charles H Tator, Michael Turner

Neural Stem/Progenitor Cells from the Adult Human Spinal Cord Are Multipotent and Self-Renewing and Differentiate after Transplantation

Neural stem/progenitor cell (NSPC) transplantation is a promising therapy for spinal cord injury (SCI). However, little is known about NSPC from the adult human spinal cord as a donor source. We demonstrate for the first time that multipotent and self-renewing NSPC can be cultured, passaged and transplanted from the adult human spinal cord of organ transplant donors. Adult human spinal cord NSPC require an adherent substrate for selection and expansion in EGF (epidermal growth factor) and FGF2 (fibroblast growth factor) enriched medium. NSPC as an adherent monolayer can be passaged for at least 9 months and form neurospheres when plated in suspension culture. In EGF/FGF2 culture, NSPC proliferate and primarily express nestin and Sox2, and low levels of markers for differentiating cells. Leukemia inhibitory factor (LIF) promotes NSPC proliferation and significantly enhances GFAP expression in hypoxia. In differentiating conditions in the presence of serum, these NSPC show multipotentiality, expressing markers of neurons, astrocytes, and oligodendrocytes. Dibutyryl cyclic AMP (dbcAMP) significantly enhances neuronal differentiation. We transplanted the multipotent NSPC into SCI rats and show that the xenografts survive, are post-mitotic, and retain the capacity to differentiate into neurons and glia. Together, these findings reveal that multipotent self-renewing NSPC cultured and passaged from adult human spinal cords of organ transplant donors, respond to exogenous factors that promote selective differentiation, and survive and differentiate after transplantation into the injured spinal cord.

Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury.

There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium. The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria. In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.

Concussions and their consequences: current diagnosis, management and prevention

Concussion is the most common type of mild traumatic brain injury and can have serious consequences. Not just confined to high-profile athletes, concussions are frequent in all age groups and in a variety of settings, such as the work environment, motor vehicle crashes, sports and recreation, and

Spinal cord stimulation: therapeutic benefits and movement generation after spinal cord injury

Spinal cord injury (SCI) is a devastating neurological condition that leads to loss of motor and sensory function. It commonly causes impairments in limb movements, respiration, bowel and bladder function, as well as secondary complications including pain, spasticity, and pressure ulcers. Numerous interventions such as neuroprotection, regeneration, pharmacology, rehabilitation training, and functional electrical stimulation are under investigation for improving function after SCI. This chapter discusses the use of spinal cord stimulation (epidural and intraspinal electrical stimulation) for alleviating pain and spasticity, and restoring standing and walking. Epidural stimulation is effective in reducing the intensity of intractable pain, but its effectiveness in the treatment of spasticity remains unclear. It can induce rhythmic, locomotor-like movements in the legs, presumably due to the activation of afferent pathways. Intraspinal microstimulation is a new electrical stimulation approach that activates locomotor-related networks within the ventral regions of the lumbosacral spinal cord. In animals, this approach is capable of producing prolonged, fatigue-resistant standing and stepping of the hindlegs. While the results in animals have been very encouraging, technical advancements are necessary prior to its implementation in humans with SCI. Taken collectively, spinal cord stimulation holds substantial promise in restoring function after neural injury or disease.

Chronic traumatic encephalopathy: How serious a sports problem is it?

It is now recognised that there is a spectrum of concussion disorders ranging from acute concussion at one end to various forms of brain degeneration at the other end. The spectrum includes acute concussion, second impact syndrome or acute cerebral swelling, postconcussion syndrome, depression or anxiety, chronic traumatic encephalopathy (CTE) and possibly other forms of central nervous system degeneration. It is essential to carefully evaluate the clinical and neuropathological correlations of CTE that have been published. This has been accomplished in an excellent paper on this subject by Gardner and colleagues in this issue. There have been significant advances in our knowledge of the clinical and neuropathological features of CTE in athletes in the past 10u2005years. However, we are just at the beginning of our appreciation of this entity due to the paucity of research and the inability to diagnose CTE during life. At present, it is not possible to assess the validity of the proposed methods of classification and grading of the severity of the disease. Additional studies of large numbers of at-risk athletes are essential, especially prospective longitudinal studies. Obviously, such studies would be even more effective if reliable in vivo biomarkers were discovered, especially non-invasive ones such as advanced MRI or MR spectroscopy or invasive ones such as blood or cerebrospinal fluid tests. The major questions that remain unanswered include the frequency of CTE in various collision sports, the causal or otherwise relationship between concussions and CTE, the number of concussions that need to be involved and their management.