Gregory W.J. Hawryluk

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.

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition.

The scope and purpose of this work is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is evidence to support them. As such, they do not constitute a complete protocol for clinical use. Our intention is that these recommendations be used by others to develop treatment protocols, which necessarily need to incorporate consensus and clinical judgment in areas where current evidence is lacking or insufficient. We think it is important to have evidence-based recommendations to clarify what aspects of practice currently can and cannot be supported by evidence, to encourage use of evidence-based treatments that exist, and to encourage creativity in treatment and research in areas where evidence does not exist. The communities of neurosurgery and neuro-intensive care have been early pioneers and supporters of evidence-based medicine and plan to continue in this endeavor. The complete guideline document, which summarizes and evaluates the literature for each topic, and supplemental appendices (A-I) are available online at https://www.braintrauma.org/coma/guidelines.

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.

An In Vivo Characterization of Trophic Factor Production Following Neural Precursor Cell or Bone Marrow Stromal Cell Transplantation for Spinal Cord Injury

Cellular transplantation strategies for repairing the injured spinal cord have shown consistent benefit in preclinical models, and human clinical trials have begun. Interactions between transplanted cells and host tissue remain poorly understood. Trophic factor secretion is postulated a primary or supplementary mechanism of action for many transplanted cells, however, there is little direct evidence to support trophin production by transplanted cells in situ. In the present study, trophic factor expression was characterized in uninjured, injured-untreated, injured-treated with transplanted cells, and corresponding control tissue from the adult rat spinal cord. Candidate trophic factors were identified in a literature search, and primers were designed for these genes. We examined in vivo trophin expression in 3 paradigms involving transplantation of either brain or spinal cord-derived neural precursor cells (NPCs) or bone marrow stromal cells (BMSCs). Injury without further treatment led to a significant elevation of nerve growth factor (NGF), leukemia inhibitory factor (LIF), insulin-like growth factor-1 (IGF-1), and transforming growth factor-β1 (TGF-β1), and lower expression of vascular endothelial growth factor isoform A (VEGF-A) and platelet-derived growth factor-A (PDGF-A). Transplantation of NPCs led to modest changes in trophin expression, and the co-administration of intrathecal trophins resulted in significant elevation of the neurotrophins, glial-derived neurotrophic factor (GDNF), LIF, and basic fibroblast growth factor (bFGF). BMSCs transplantation upregulated NGF, LIF, and IGF-1. NPCs isolated after transplantation into the injured spinal cord expressed the neurotrophins, ciliary neurotrophic factor (CNTF), epidermal growth factor (EGF), and bFGF at higher levels than host cord. These data show that trophin expression in the spinal cord is influenced by injury and cell transplantation, particularly when combined with intrathecal trophin infusion. Trophins may contribute to the benefits associated with cell-based repair strategies for spinal cord injury.

Management of anticoagulation following central nervous system hemorrhage in patients with high thromboembolic risk

Summary.  Background: Patients who present with central nervous system (CNS) hemorrhage while on anticoagulation (AC) for thromboembolic (TE) risk factors are a challenge to manage. Objective: We sought to inform decisions surrounding the timing and intensity of AC resumption by performing a systematic review. Methods: Three reviewers screened publications from Medline and EMBASE and extracted data. Hemorrhagic and TE adverse events that occurred subsequent to the index hemorrhage were recorded, as was their timing relative to presentation and covariates that might influence their occurrence. Results: Data were extracted from 63 publications detailing 492 patients; 7.7% of patients experienced hemorrhagic complications and 6.1% experienced TE complications. Hemorrhagic complications were more common within 72 h of presentation while TE complications were more common thereafter. Patients restarted on AC after 72 h were significantly more likely to have a TE complication (P = 0.006) and those restarted before 72 h were more likely to hemorrhage (P = 0.0727). Factors associated with re‐hemorrhage included younger age, traumatic cause, subdural hematomas and failure to reverse AC. TE complications were more common in younger patients and those with spinal hemorrhage, multiple hemorrhages, and non‐traumatic causes of the index hemorrhage. Re‐initiation of AC at a lower intensity also significantly increased the risk of TE complications. Interpretation: Our results suggest that it may be prudent to re‐initiate AC earlier than previously thought, with the timing and intensity modified based on predictors of TE and hemorrhagic complications. These findings must be explored in a prospective study because of limitations inherent to the analyzed studies.

In Vitro Characterization of Trophic Factor Expression in Neural Precursor Cells

In cellular transplantation strategies for repairing the injured central nervous system, interactions between transplanted neural precursor cells (NPCs) and host tissue remain incompletely understood. Although trophins may contribute to the benefits observed, little research has explored this possibility. Candidate trophic factors were identified, and primers were designed for these genes. Template RNA was isolated from 3 NPC sources, and also from bone marrow stromal cells (BMSCs) and embryonic fibroblasts as comparative controls. Quantitative polymerase chain reaction was performed to determine the effect of cell source, passaging, cellular differentiation, and environmental changes on trophin factor expression in NPCs. Results were analyzed with multivariate statistical analyses. NPCs, BMSCs, and fibroblasts each expressed trophic factors in unique patterns. Trophic factor expression was similar among NPCs whether harvested from rat or mouse, brain or spinal cord, or their time in culture. The expression of neurotrophin NT-3, NT-4/5, glial-derived neurotrophic factor, and insulin-like growth factor-1 decreased with time in culture. Induced differentiation of NPCs led to a marked and statistically significant increase in the expression of trophic factors. Culture conditions and environmental changes were also associated with significant changes in trophin expression. These results suggest that trophins could contribute to the benefits associated with transplantation of NPCs as well as BMSCs. Trophic factor expression changes with NPC differentiation and environmental conditions, which could have important implications with regard to their behavior after in vivo transplantation.

Imaging concussion: a review.

Concussion is a significant public health problem that is receiving increased attention from physicians, the media, and the public. Recent studies suggest that persistent symptoms after concussion/mild traumatic brain injury (mTBI) may arise from structural or metabolic alterations in the brain, despite normal conventional neuroimaging studies. New, advanced neuroimaging techniques show promise in refining diagnosis and outcome prediction in concussion/mTBI. Here, we review some of these techniques, including diffusion tensor imaging, task-based and resting-state functional magnetic resonance imaging, as well as positron emission tomography, H magnetic resonance spectroscopy, and perfusion imaging. Although further validation is needed through large prospective studies that correlate these techniques with patient outcome, it is likely that the definitions of pathoanatomic lesions, and a better understanding of their relationship to symptoms and prognosis, will continue to evolve as neuroimaging techniques continue to progress.Concussion is a significant public health problem that is receiving increased attention from physicians, the media, and the public. Recent studies suggest that persistent symptoms after concussion/mild traumatic brain injury (mTBI) may arise from structural or metabolic alterations in the brain, despite normal conventional neuroimaging studies. New, advanced neuroimaging techniques show promise in refining diagnosis and outcome prediction in concussion/mTBI. Here, we review some of these techniques, including diffusion tensor imaging, task-based and resting-state functional magnetic resonance imaging, as well as positron emission tomography, 1 H magnetic resonance spectroscopy, and perfusion imaging. Although further validation is needed through large prospective studies that correlate these techniques with patient outcome, it is likely that the definitions of pathoanatomic lesions, and a better understanding of their relationship to symptoms and prognosis, will continue to evolve as neuroimaging techniques continue to progress.

Classification of traumatic brain injury: past, present, and future

Disease classification is central to the practice of medicine; it systematizes clinical knowledge and experience. Classification is essential for diagnosis and effective treatment of human disease. Progress in classifying traumatic brain injury (TBI) for targeted treatment has lagged behind other diseases such as cancer, and has contributed to a lack of progress in the field. Today TBI is most frequently classified as mild, moderate, or severe using the Glasgow Coma Scale (GCS). However, the GCS is symptoms-based and does not allow for targeting of specific pathology. Here we review general schemas for disease classification and how they have evolved over time. We discuss the characteristics of an ideal classification system and the unique challenges inherent to achieving such a system for TBI. Current means of classifying TBI are reviewed, as are the strengths and limitations of these approaches. Generating the data required to modernize TBI classification and to perhaps facilitate a targeted, precision medicine approach to its management will require a highly collaborative international effort. Fortunately these efforts are underway and will benefit from the lessons and tools that have come from other areas of medicine that have already found success with this approach.

An examination of the mechanisms by which neural precursors augment recovery following spinal cord injury: a key role for remyelination.

The mechanisms by which neural precursor cells (NPCs) enhance functional recovery from spinal cord injury (SCI) remain unclear. Spinal cord injured rats were transplanted with wild-type mouse NPCs, shiverer NPCs unable to produce myelin, dead NPCs, or media. Most animals also received minocycline, cyclosporine, and perilesional infusion of trophins. Motor function was graded according to the BBB scale. H&E/LFB staining was used to assess gray and white matter, cyst, and lesional tissue. Mature oligodendrocytes and ED1+ inflammatory cells were quantitated. Confocal and electron microscopy were used to assess the relationship between the transplanted cells and axons. Pharmacotherapy and trophin infusion preserved gray matter, white matter, and oligodendrocytes. Trophin infusion also significantly increased cyst and lesional tissue volume as well as inflammatory infiltrate, and functional recovery was reduced. Animals transplanted with wild-type NPCs showed greatest functional recovery; animals transplanted with shiverer NPCs performed the worst. Wild-type NPCs remyelinated host axons. Shiverer NPCs ensheathed axons but did not produce MBP. These results suggest that remyelination by NPCs is an important contribution to functional recovery following SCI. Shiverer NPCs may prevent remyelination by endogenous cells capable of myelin formation. These findings suggest that remyelination is an important therapeutic target following SCI.

Past, Present, and Future of Traumatic Brain Injury Research

Traumatic brain injury (TBI) is the greatest cause of death and severe disability in young adults; its incidence is increasing in the elderly and in the developing world. Outcome from severe TBI has improved dramatically as a result of advancements in trauma systems and supportive critical care, however we remain without a therapeutic which acts directly to attenuate brain injury. Recognition of secondary injury and its molecular mediators has raised hopes for such targeted treatments. Unfortunately, over 30 late-phase clinical trials investigating promising agents have failed to translate a therapeutic for clinical use. Numerous explanations for this failure have been postulated and are reviewed here. With this historical context we review ongoing research and anticipated future trends which are armed with lessons from past trials, new scientific advances, as well as improved research infrastructure and funding. There is great hope that these new efforts will finally lead to an effective therapeutic for TBI as well as better clinical management strategies.