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OBJECTIVE: To determine the association between the apolipoprotein epsilon 4 allele and concussion. We hypothesized that apolipoprotein epsilon 4 carriers may be more likely to sustain a concussion. DESIGN: Prospective cohort study. SETTING: University of Toronto varsity athletics. PARTICIPANTS: Included 318 of 822 collegiate student athletes who participated in University of Toronto varsity sports from September 2002 to April 2006. ASSESSMENT OF RISK FACTORS: The presence of apolipoprotein epsilon 4 was described dichotomously after genotyping blood samples collected from participants. MAIN OUTCOME MEASUREMENTS: Concussions were identified by sport-medicine professionals present on the sidelines using on-field assessment forms. All concussion diagnoses were verified by a sports medicine physician. Survival analysis was used to determine the association between apolipoprotein epsilon 4 and first concussion. RESULTS: The unadjusted hazard ratio for concussion in the apolipoprotein epsilon 4 carriers was 1.18 (95% CI: 0.52, 2.69) compared to noncarriers. Adjustment for sex, weight, height, and team type resulted in a hazard ratio of 1.06 (95% CI: 0.41, 2.72), indicating little effect from confounding factors. CONCLUSIONS: There is no important association between carrying the apolipoprotein epsilon 4 allele and sustaining a concussion. At this time, we do not recommend preseason genetic testing for varsity athletes as a mechanism for targeting prevention strategies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine and assess the distribution and use of Sudden Impact, a video designed by Think First and SportsSmart Canada, to help prevent spinal cord injury caused by careless shallow water diving among teenagers in the high risk group (15-24 years old). DESIGN: Survey of 92 public secondary schools in Toronto, Canada. SUBJECTS: The heads of the physical and health education departments of the 92 secondary public schools in the Metropolitan Toronto region. RESULTS: The response rate was 64% (59 schools), of which 76% (45) had actually received the video. Forty one schools (91%) of those that received the video reported using it. Eighty per cent of responding schools showed it to grade 11 students. Eighty per cent of schools with swimming pools used the video compared with only 42% of schools without swimming pools. CONCLUSIONS: There is a need for improvements in the system of distribution to ensure greater use of material such as this video. These may include direct distribution to principals, continuing contact with the schools, or mandatory inclusion of diving safety into the school curriculum. [ABSTRACT FROM AUTHOR]

At the Canadian Concussion Centre, we treated 136 patients from 2000 to 2020 who sustained concussion plus persisting concussion symptoms (C+PCS) as motor vehicle occupants involved in motor vehicle crashes (MVCs). This center specializes in the treatment of patients with C+PCS. The objective of the present study was to identify strategies for preventing concussion among vehicle occupants involved in MVC. Indeed, this is the first study focused on C+PCS in MVC occupants, and our main purpose was to evaluate the effectiveness of onboard concussion prevention strategies. In this retrospective, consecutive cohort of 136 patients with C+PCS, we examined the patients' demographic and injury features in relation to the nature of the MVC including speed, direction of impact, and availability, deployment, and effectiveness of onboard occupant safety measures including seatbelts, head restraints, and airbags. The most frequent combination of factors was a belted female driver of an automobile struck from behind by another automobile. Surprisingly, the entire patient cohort comprised more females (69.1%) than males (30.9%), and rear-end collision was the most common type in females. Most injured occupants of both sexes were wearing seatbelts, but only a minority of the crashes caused airbag deployment. The seven most common symptoms were headache (84.6%), anxiety (72.8%), sensitivity to light (70.6%), memory problems (69.9%), sensitivity to noise (66.2%), irritability (56.6%), and depression (55.9%). Whiplash was a frequent associated injury in both sexes. Complete recovery from C+PCS was rare, and most patients with known follow-up continued to suffer from persisting symptoms for months to years. The median symptom duration for all 136 patients was 30.0 months (interquartile range: 16.8-56.0 months). Based on these findings, we conclude that females are indeed vulnerable road users with respect to C+PCS, and our literature search showed that there had been some previous evidence of increased injury risk of other injuries in female occupants. We recommend that additional prevention strategies are required to reduce the post-crash acceleration-deceleration "bobble-head" movement of the head on trunk causing both concussion and whiplash as has been accomplished in auto racing. Also, these prevention measures must be investigated in crash studies that include low-to-high speed rear-end collisions using anthropometrically appropriate models of male and female occupants reflecting the range of sizes of both sexes. There is a need for more concussion brain injury prevention research focusing on the vulnerability of female occupants, which has not been sufficiently addressed even though the deficiency was identified many years ago. The sex inequity of current onboard motor vehicle concussion brain injury prevention measures especially with respect to females should be addressed by governments and the automobile and insurance industries.

Falls in older adults and those with neurodegenerative disease (ND) are a current public health hazard and the primary cause of sustaining a mild traumatic brain injury (mTBI)/concussion. Little is known regarding how post-concussion symptoms present in older adults and patients with ND, even though they are the demographic at highest risk. A combination of under-reporting of falls and a lack of awareness regarding potential consequences of falls, results in the underdiagnosis of post-fall issues and concussions in this population. Our aim was to conduct a quality assessment survey to assess physician practice regarding falls and their general knowledge of concussion symptoms. We sent surveys through email to 1400 North American physicians, mostly those working at university affiliated hospitals, who specialized in seeing older adults and patients with ND. One hundred forty-one physicians completed the survey. 71.4% of all responding physicians either never inquired or inquired in less than 5% of their patients with ND or older adult patients, about history of falls. Over half of the physicians (51.8%) either never ask or do not consider it necessary to ask about concussion symptoms post-fall. The majority of physicians (92%) recognized that concussions can have lasting effects on patients, particularly on mood and demonstrated good knowledge of post-concussion symptoms by correctly identifying them. Additionally, more than 70% of responding physicians believed that patients with ND or older adults can fully recover from a concussion with the same probability as any other age group if treated. Only 50% of physicians felt confident in managing post-concussion symptoms themselves, 53.9% of physicians did not know of, or did not have nearby concussion clinics to refer patients to. The gaps in practice are clearly reflective of the gaps in the literature regarding falls and concussions in older adults and ND patients. There is a very low rate of physician inquiry about history of falls and concussion symptoms in older patients and those with NDs. Failure to recognize a concussion, can lead to missed opportunities for targeted interventions to address reversible symptoms. Additionally, the misattribution of post-concussion symptoms to disease progression in older patients or those with NDs may delay and hinder appropriate management., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Repulsive guidance molecule A (RGMa) is an inhibitor of neuronal growth and survival which is upregulated in the damaged central nervous system following acute spinal cord injury (SCI), traumatic brain injury, acute ischemic stroke (AIS), and other neuropathological conditions. Neutralization of RGMa is neuroprotective and promotes neuroplasticity in several preclinical models of neurodegeneration and injury including multiple sclerosis, AIS, and SCI. Given the limitations of current treatments for AIS due to narrow time windows to intervention (TTI), and restrictive patient selection criteria, there is significant unmet need for therapeutic agents that enable tissue survival and repair following acute ischemic damage for a broader population of stroke patients. In this preclinical study, we evaluated whether elezanumab, a human anti-RGMa monoclonal antibody, could improve neuromotor function and modulate neuroinflammatory cell activation following AIS with delayed intervention times up to 24 h using a rabbit embolic permanent middle cerebral artery occlusion model (pMCAO). In two replicate 28-day pMCAO studies, weekly intravenous infusions of elezanumab, over a range of doses and TTIs of 6 and 24 h after stroke, significantly improved neuromotor function in both pMCAO studies when first administered 6 h after stroke. All elezanumab treatment groups, including the 24 h TTI group, had significantly less neuroinflammation as assessed by microglial and astrocyte activation. The novel mechanism of action and potential for expanding TTI in human AIS make elezanumab distinct from current acute reperfusion therapies, and support evaluation in clinical trials of acute CNS damage to determine optimal dose and TTI in humans., (© 2023. The Author(s).)

It is important for patients and clinicians to know the potential for recovery from concussion as soon as possible after injury, especially in patients who do not recover completely in the first month and have concussion with persisting concussion symptoms (C+PCS). We assessed the association between the causes of concussion and recovery from C+PCS in a consecutive retrospective and prospective cohort of 600 patients referred to the Canadian Concussion Center (CCC) at Toronto Western Hospital. Data were obtained from clinical records and follow-up questionnaires and not from a standardized database. A novel method was used to assess long-term recovery, and multi-variable Cox proportional hazards models were used to assess relationships between cause of concussion and time to recovery. We examined the subsequent recovery of patients who had not recovered after at least one month from the time of concussion. Patients were grouped into the following four causes: sports and recreation (S&R, n  = 312, 52%); motor vehicle collisions (MVC, n  = 103, 17%); falls ( n  = 100, 17%); and being struck by an object including violence (SBOV, n  = 85, 14%). The MVC group had the highest percentage of females (75.7%), the oldest participants (median: 40.0 [interquartile range (IQR):30.5-49.0] years), the most symptoms (median:11.0 [IQR:8.5-15.0]), and the longest symptom duration (median: 28.0 [IQR:12.0-56.00] months). In contrast, the S&R group had the highest percentage of males (58.1%), the youngest participants (median:20.0 [IQR:17.0-30.0] years), the best recovery outcome, and shortest symptom duration (median:22.0 [IQR:8.0-49.5] months). Significant differences among the four causes included age ( p  < 0.001), sex ( p  < 0.001), number of previous concussions ( p  < 0.001), history of psychiatric disorders ( p  = 0.002), and migraine ( p  = 0.001). Recovery from concussion was categorized into three groups: (1) Complete Recovery occurred in only 60 (10%) patients with median time 8.0 (IQR:3.5-18.0) months and included 42 S&R, 7 MVC, 8 falls, and 3 SBOV; (2) Incomplete Recovery occurred in 408 (68.0%) patients with persisting median symptom time of 5.0 (IQR:2.0-12.0) months; and (3) Unknown Recovery occurred in 132 (22.0%) patients and was because of lack of follow-up. In summary, the cause of C+PCS was associated with the type, number, and duration of symptoms and time required for recovery, although all causes of C+PCS produced prolonged symptoms in a large percentage of patients, which emphasizes the importance of concussions as a public health concern necessitating improved prevention and treatment strategies.

Aims: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases., Methods: This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions., Results: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA., Conclusions: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions., (© 2024 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Changes in demography and injury patterns have altered the profile and outcome of acute spinal cord injury (SCI) over time. This study sought to describe recent trends in epidemiology and early clinical outcomes using the multi-center North American Clinical Trial Network (NACTN) for Spinal Cord Injury Registry. All participants with blunt acute traumatic SCI ( n  = 782) were grouped into three five-year time intervals from 2005 to 2019 (2005-2009, 2010-2014, and 2015-2019). Baseline demographics, clinical scores, medical co-morbidities, as well as early clinical outcomes were extracted. Categorical and continuous variables were analyzed to determine between-group differences. Subgroup analysis was performed for participants <50 and ≥50 years of age. Over the duration of the study period, there was an increase in age at presentation ( p  = 0.0077) as well as a greater incidence of falls as the mechanism of injury. Participants who were ≥50 years of age were more likely to sustain incomplete SCI (<0.0003) and central cord syndrome (< 0.0001). In the most recent period (2015-2019), a greater proportion of NACTN participants underwent surgery within 24 h of injury (63% vs. 41% vs. 41%, p  = 0.0001). There was a statistically significant increase in cardiac complications ( p  < 0.0001) and decrease in pulmonary complications ( p  < 0.0001) during the study period. Data from the NACTN registry shows that the age of participants with acute SCI is increasing, falls have become the major mechanism of injury, and central cord injury is becoming increasingly prevalent. While early surgical intervention for acute SCI is more common in recent years, cardiac complications are more prevalent while pulmonary complications are less prevalent.

This is a historical account of the origin and accomplishments of the North American Clinical Trials Network (NACTN) for traumatic spinal cord injury (SCI), which was established in 2004 by Christopher Reeve and Robert Grossman. Christopher Reeve was an actor who became quadriplegic and started the Christopher & Dana Reeve Foundation (CDRF), and Robert Grossman was a neurosurgeon experienced in neurotrauma and a university professor in Houston. NACTN has member investigators at university and military centers in North America and has contributed greatly to the improvement of care, primarily acute care, of patients sustaining traumatic SCI. Its accomplishments are a clinical registry database of >1000 acute SCI patients documenting the care pathways, including complications. NACTN has assessed the effectiveness of treatment, including pharmacotherapy and the role and timing of surgery, and has also identified barriers to early surgery. The principal focus has been on improving neurological recovery. NACTN has trained many SCI practitioners and has collaborated with other SCI networks and organizations internationally to promote the care of SCI patients.

Data supporting the benefits of early surgical intervention in acute spinal cord injury (SCI) is growing. For early surgery to be accomplished, understanding the causes of variabilities that effect the timing of surgery is needed to achieve this goal. The purpose of this analysis is to determine factors that affect the timing of surgery for acute cervical SCI within the North American Clinical Trials Network (NACTN) for SCI registry. Patients in the NACTN SCI registry from 2005 to 2019 with a cervical SCI, excluding acute traumatic central cord syndrome, were analyzed for time elapsed from injury to arrival to the hospital, and time to surgery. Two categories were defined: 1) Early Arrival with Early Surgery (EAES) commenced within 24 h of injury, and 2) Early Arrival but Delayed Surgery (EADS), with surgery occurring between 24 to 72 h post-injury. Patients' demographic features, initial clinical evaluation, medical comorbidities, neurological status, surgical intervention, complications, and outcome data were correlated with respect to the two arrival groups. Of the 222 acute cervical SCI patients undergoing surgery, 163 (73.4%) were EAES, and 59 (26.6%) were EADS. There was no statistical difference in arrival time between the EAES and EADS groups. There was a statistical difference in the median arrival time to surgery between the EAES group (9 h) compared with the EADS group (31 h; p  < 0.05). There was no statistical difference in race, sex, age, mechanism of injury, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores, or medical comorbidities between the two groups, but the EAES group did present with a significantly lower systolic blood pressure ( p  < 0.05). EADS patients were more likely to present as an American Spinal Injury Association Impairment Scale (AIS) D than EAES ( p  < 0.05). Early surgery was statistically more likely to occur if the injury occurred over the weekend ( p  < 0.05). There were variations in the rates of early surgery between the eight NACTN sites within the study, ranging from 57 to 100%. Of the 114 patients with 6-month outcome data, there was no significant change between the two groups regarding AIS grade change and motor/pin prick/light touch score recovery. A trend towards improved motor scores with early surgery was not statistically significant ( p  = 0.21). Although there is data that surgery within 24 h of injury improves outcomes and can be performed safely, there remain variations in care outside of clinical trials. In the present study of cervical SCI, NACTN achieved its goal of early surgery in 73.4% of patients from 2005-2019 who arrived within 24 h of their injury. Variability in achieving this goal was related to severity of neurological injury, the day of the week, and the treating NACTN center. Evaluating variations within our network improves understanding of potential systemic limitations and our decision-making process to accomplish the goal of early surgery.

Traumatic spinal cord injury (SCI) causes a sudden onset multi-system disease, permanently altering homeostasis with multiple complications. Consequences include aberrant neuronal circuits, multiple organ system dysfunctions, and chronic phenotypes such as neuropathic pain and metabolic syndrome. Reductionist approaches are used to classify SCI patients based on residual neurological function. Still, recovery varies due to interacting variables, including individual biology, comorbidities, complications, therapeutic side effects, and socioeconomic influences for which data integration methods are lacking. Infections, pressure sores, and heterotopic ossification are known recovery modifiers. However, the molecular pathobiology of the disease-modifying factors altering the neurological recovery-chronic syndrome trajectory is mainly unknown, with significant data gaps between intensive early treatment and chronic phases. Changes in organ function such as gut dysbiosis, adrenal dysregulation, fatty liver, muscle loss, and autonomic dysregulation disrupt homeostasis, generating progression-driving allostatic load. Interactions between interdependent systems produce emergent effects, such as resilience, that preclude single mechanism interpretations. Due to many interacting variables in individuals, substantiating the effects of treatments to improve neurological outcomes is difficult. Acute injury outcome predictors, including blood and cerebrospinal fluid biomarkers, neuroimaging signal changes, and autonomic system abnormalities, often do not predict chronic SCI syndrome phenotypes. In systems medicine, network analysis of bioinformatics data is used to derive molecular control modules. To better understand the evolution from acute SCI to chronic SCI multi-system states, we propose a topological phenotype framework integrating bioinformatics, physiological data, and allostatic load tested against accepted established recovery metrics. This form of correlational phenotyping may reveal critical nodal points for intervention to improve recovery trajectories. This study examines the limitations of current classifications of SCI and how these can evolve through systems medicine.

The bulbocavernosus reflex (BCR) has been used during the initial evaluation of a spinal cord injury patient as a metric to determine prognosis and whether the patient is in "spinal shock." This reflex has been less utilized over the last decade, and therefore a review was performed to assess the value of BCR in patient prognosis. The North American Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that includes a prospective SCI registry. The NACTN registry data was analyzed to evaluate the prognostic implication of the BCR during the initial evaluation of a spinal cord injury patient. SCI patients were divided into those with an intact or absent BCR during their initial evaluation. Associations of participants' descriptors and neurological status on follow-up were performed, followed by associations with the presence of a BCR. A total of 769 registry patients with recorded BCRs were included in the study. The median age was 49 years (32-61 years), and the majority were male ( n  = 566, 77%) and white ( n  = 519, 73%). Among included patients, high blood pressure was the most common comorbidity ( n  = 230, 31%). Cervical spinal cord injury was the most common ( n  = 470, 76%) with fall ( n  = 320, 43%) being the most frequent mechanism of injury. BCR was present in 311 patients (40.4%), while 458 (59.6%) had a negative BCR within 7 days of injury or before surgery. At 6 months post-injury, 230 patients (29.9%) followed up, of which 145 had a positive BCR, while 85 had a negative BCR. The presence/absence of BCR was significantly different in patients with cervical ( p  = 0.0015) or thoracic SCI ( p  = 0.0089), or conus medullaris syndrome ( p  = 0.0035), and in those who were American Spinal Injury Association Impairment Scale grade A ( p  = 0.0313). No significant relationship was observed between BCR results and demographics, AIS grade conversion, motor score changes ( p  = 0.1669), and changes in pin prick ( p  = 0.3795) and light touch scores ( p  = 0.8178). In addition, cohorts were not different in surgery decision ( p  = 0.7762) and injury to surgery time ( p  = 0.0681). In our review of the NACTN spinal cord registry, the BCR did not provide prognostic utility in the acute evaluation of spinal cord injury patients. Therefore, it should not be used as a reliable marker for predicting neurological outcomes post-injury.

Objectives: Youth hockey is a high-impact sport and can cause concussions with lasting effects. We hypothesized that important injury prevention information would accrue from longitudinal tracking of concussed players with persisting concussion symptoms (PCS)., Methods: This case series comprised 87 consecutive concussed ice hockey players aged 10-18 including 66 males and 21 females referred to our Concussion Clinic from 1997 to 2017 and followed longitudinally by clinic visits and questionnaires., Results: PCS occurred in 70 (80.4%) of 87 concussed players and lasted 1-168 months in males and 3-26 months in females. Bodychecking was the most common concussion mechanism in 34 (39.1%) players and caused PCS in 24 (70.6%) with symptom duration 4.00 [2.75, 14.50] months (median [IQR]). The remaining 53 players had other concussion mechanisms with PCS in 86.8% ( p = 0.113) with similar duration ( p = 0.848)., Conclusions: This is the first longitudinal study of concussion with PCS in youth hockey and showed that symptoms can last for several years. Bodychecking was the commonest mechanism of prolonged disability from concussion in boys and girls' hockey with average PCS duration of 12.3 months but several years in some players. The injury prevention message is to raise the age of permitted bodychecking to 18 in boys' hockey from age 13 to 14 where it is currently. In this case series, this change could have prevented the majority of the bodycheck concussions and several years of suffering from PCS and is strong evidence for raising the permitted age for bodychecking in boys' ice hockey to age 18.

Abstract The North America Clinical Trials Network (NACTN) for Spinal Cord Injury (SCI) is a consortium of tertiary medical centers that has maintained a prospective SCI registry since 2004, and it has espoused that early surgical intervention is associated with improved outcome. It has previously been shown that initial presentation to a lower acuity center and necessity of transfer to a higher acuity center reduce rates of early surgery. The NACTN database was evaluated to examine the association between interhospital transfer (IHT), early surgery, and outcome, taking into account distance traveled and site of origin for the patient. Data from a 15-year period of the NACTN SCI Registry were analyzed (years 2005-2019). Patients were stratified into transfers directly from the scene to a Level 1 trauma center (NACTN site) versus IHT from a Level 2 or 3 trauma facility. The main outcome was surgery within 24 hours of injury (yes/no), whereas secondary outcomes were length of stay, death, discharge disposition, and 6-month American Spinal Injury Association Impairment Scale (AIS) grade conversion. For the IHT patients, distance traveled for transfer was calculated by measuring the shortest distance between origin and NACTN hospital. Analysis was performed with Brown-Mood test and chi-square tests. Of 724 patients with transfer data, 295 (40%) underwent IHT and 429 (60%) were admitted directly from the scene of injury. Patients who underwent IHT were more likely to have a less severe SCI (AIS D; p  = 0.002), have a central cord injury ( p  = 0.004), and have a fall as their mechanism of injury ( p  < 0.0001) than those directly admitted to an NACTN center. Of the 634 patients who had surgery, direct admission to an NACTN site was more likely to result in surgery within 24 hours compared with IHT patients (52% vs. 38%) ( p  < 0.0003). Median IHT distance was 28 miles (interquartile range [IQR] = 13-62 miles). There was no significant difference in death, length of stay, discharge to a rehab facility versus home, or 6-month AIS grade conversion rates between the two groups. Patients who underwent IHT to an NACTN site were less likely to have surgery within 24 hours of injury, compared with those directly admitted to the Level 1 trauma facility. Although there was no difference in mortality rates, length of stay, or 6-month AIS conversion between groups, patients with IHT were more likely be older with a less severe level of injury (AIS D). This study suggests there are barriers to timely recognition of SCI in the field, appropriate admission to a higher level of care after recognition, and challenges related to the management of individuals with less severe SCI.

Objective: Concern exists about possible problems with later-in-life brain health, such as cognitive impairment, mental health problems and neurological diseases, in former athletes. We examined the future risk for adverse health effects associated with sport-related concussion, or exposure to repetitive head impacts, in former athletes., Design: Systematic review., Data Sources: Search of MEDLINE, Embase, Cochrane, CINAHL Plus and SPORTDiscus in October 2019 and updated in March 2022., Eligibility Criteria: Studies measuring future risk (cohort studies) or approximating that risk (case-control studies)., Results: Ten studies of former amateur athletes and 18 studies of former professional athletes were included. No postmortem neuropathology studies or neuroimaging studies met criteria for inclusion. Depression was examined in five studies in former amateur athletes, none identifying an increased risk. Nine studies examined suicidality or suicide as a manner of death, and none found an association with increased risk. Some studies comparing professional athletes with the general population reported associations between sports participation and dementia or amyotrophic lateral sclerosis (ALS) as a cause of death. Most did not control for potential confounding factors (eg, genetic, demographic, health-related or environmental), were ecological in design and had high risk of bias., Conclusion: Evidence does not support an increased risk of mental health or neurological diseases in former amateur athletes with exposure to repetitive head impacts. Some studies in former professional athletes suggest an increased risk of neurological disorders such as ALS and dementia; these findings need to be confirmed in higher quality studies with better control of confounding factors., Prospero Registration Number: CRD42022159486., Competing Interests: Competing interests: GLI serves as a scientific advisor for NanoDX, Sway Operations and Highmark. He has a clinical and consulting practice in forensic neuropsychology, including expert testimony, involving individuals who have sustained mild TBIs (including former athletes), and on the topic of suicide. He has received past research support or funding from several test publishing companies, including ImPACT Applications, CNS Vital Signs and Psychological Assessment Resources. He receives royalties from the sales of one neuropsychological test (WCST-64). He has received travel support and honorariums for presentations at conferences and meetings. He has received research funding as a principal investigator from the National Football League (NFL), and subcontract grant funding as a collaborator from the Harvard Integrated Programme to Protect and Improve the Health of NFL Players Association Members. He has received research funding from the Wounded Warrior Project. He acknowledges unrestricted philanthropic support from ImPACT Applications, the Mooney-Reed Charitable Foundation, the National Rugby League, Boston Bolts and the Schoen Adams Research Institute at Spaulding Rehabilitation. RJC is a collaborator on a grant funded by the NFL to study the spectrum of concussion, including possible long-term effects. He has a consulting practice in forensic neuropathology, including expert testimony, which has involved former athletes at amateur and professional levels. JDC has provided expert epidemiological testimony in court cases on the long-term effects of concussions in sports. GMS is an owner of a multidisciplinary practice (managing patients with MSK pain disorders). He is a board member of Hockey Calgary (Calgary, Alberta, Canada) and Chair of the Alberta Association of Physiotherapy. He received funding for the administrative aspects of the writing of two of the systematic reviews that informed the consensus process. KJS has received grant funding from the CIHR, NFL Scientific Advisory Board, International Olympic Committee Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary, with funds paid to her institution and not to her personally. She is an Associate Editor of BJSM (unpaid), Independent consultant to World Rugby and has received travel and accommodation support for meetings where she has presented. She coordinated the writing of the systematic reviews that informed Amsterdam International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews (with funds paid to her institution). She is a member of the AFL Concussion Scientific Committee (unpaid position), Brain Canada (unpaid positions) and Board member of the Concussion in Sport Group (CISG)(unpaid). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass roots to professional. RJE is a paid consultant for the NHL and cochair of the NHL/NHLPA Concussion Subcommittee. He is also a paid consultant and chair of the Major League Soccer concussion committee, and a consultant to the US Soccer Federation. He previously served as a neuropsychology consultant to Princeton University Athletic Medicine and EyeGuide. He is currently a co-Principal Investigator for a grant funded by the NFL (NFL-Long) through Boston Children’s Hospital. He occasionally provides expert testimony in matters related to MTBI and sports concussion, and occasionally receives honoraria and travel support/reimbursement for professional meetings. JB serves as the Chairman of the Medical Advisory Committee of Pop Warrner Football and is a member of the NFL Head, Neck, and Spine Committee, NFLPA Mackey-White Health and Safety Committee and the NCAA Concussion Task Force, all without remuneration. He is a consultant for BrainLab and has provided expert testimony on TBI medicolegal cases. IKK is a professor at Ludwig-Maximilians-Universität Munich (paid position). She serves as European Editor at Journal of Neurotrauma (unpaid position) and as Vice President of the European Neurotrauma Organisation (unpaid position). She receives research grant funding from the National Institutes of Health, the European Research Council, the German Ministry for Research and Education. She receives funding for a research study on sport-related concussion from Abbott. The university hospital received donations for her research from the Schatt Foundation and Mary Ann Liebert. She receives royalties for book chapters published by Thieme Publishers. Her spouse is employee at Siemens and she thus holds stock options at Siemens and Siemens Healthineers. In-kind contribution: PhD students working under her supervision receive scholarships from the Villigst Foundation, the China Scholarship Council collaboration with Ludwig-Maximilians-University Munich and Fulbright. GM discloses grants from the United States Department of Defense—TBI End points Development Initiative (grant #W81XWH-14-2-0176), TRACK-TBI Precision Medicine (grant # W81XWH-18-2-0042) and TRACK-TBI NETWORK (grant # W81XWH-15-9-0001); NIH-NINDS–TRACK-TBI (grant #U01NS086090) and the NFL Scientific Advisory Board—TRACK-TBI LONGITUDINAL. The United States Department of Energy supports GM for a precision medicine collaboration. One Mind has provided funding for TRACK-TBI patients stipends and support to clinical sites. He has received an unrestricted gift from the NFL to the UCSF Foundation to support research efforts of the TRACK-TBI NETWORK. GM has also received funding from NeuroTruama Sciences to support TRACK-TBI data curation efforts. Additionally, Abbott Laboratories has provided funding for add-in TRACK-TBI clinical studies. MMcN has the following disclosures: (i) Chair, Ethics Expert Group, WADA (2021–23) (paid); (ii) Member, International Boxing Association, Ethics and Integrity Committee, (2021–22; resigned October 2022) (paid); (iii) Chair, Therapeutic Use Exemption Fairness Committee (2020–Present) (paid); (iv) Member, Steering Group, Sex Segregation in Sport, IAAF/World Athletics (2019–20) (unpaid); (v) Member, International Ice Hockey Federation, Ethics and Integrity Committee (2019–21) (paid); (vi) Member, IOC Consensus Statement Expert Group on Injuries in Children and Adolescents (2017) (unpaid); (vii) Member, Ethics Expert Group, WADA (2016–21) (unpaid) and (viii) Member, IOC Consensus Statement Expert Group on Pain Management (2016) (unpaid). JP is a sports and exercise medicine physician at Waterfall Sports Orthopaedic Surgery, Johannesburg, South Africa. He is Director of Sports Concussion South Africa and a Visiting Professor, Wits Sport and Health (WiSH), School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand. As an Editor of BJSM, he receives an honorarium and serves as a consultant (unremunerated) to World Rugby Concussion Advisory Group, South African Rugby, EyeGuide Scientific Advisory Board and the Union of European Football Associations. He is co-chair of the Scientific Committee, 6th International Conference on Concussion in Sport (unpaid) and a Board member of the Concussion in Sport Group (unpaid). RCC serves as a scientific advisor for the NFL's Head Neck and Spine Committee, VP and Chair of the Scientific Advisory Committee for the National Operating Committee on Standards for Athletic Equipment (NOCSAE), and as co-founder and Medical Director of the Concussion Legacy Foundation. He currently receives research support from the NINDS UNITE and Diagnose CTE grants. He has received travel support and honorariums for presentations at conferences and meetings. He receives royalties from Houghton Mifflin Harcourt publishing. He has a clinical and consulting practice in forensic neurology and neurosurgery, including expert testimony, especially individuals with traumatic brain and spinal cord injuries. He is a member of the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation Medical Science Committee., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The adult spinal cord contains a population of ependymal-derived neural stem/progenitor cells (epNSPCs) that are normally quiescent, but are activated to proliferate, differentiate, and migrate after spinal cord injury. The mechanisms that regulate their response to injury cues, however, remain unknown. Here, we demonstrate that excitotoxic levels of glutamate promote the proliferation and astrocytic fate specification of adult spinal cord epNSPCs. We show that glutamate-mediated calcium influx through calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (CP-AMPARs) in concert with Notch signaling increases the proliferation of epNSPCs via pCREB, and induces astrocytic differentiation through Hes1 upregulation. Furthermore, the in vivo targeting of this pathway via positive modulation of AMPARs after spinal cord injury enhances epNSPC proliferation, astrogliogenesis, neurotrophic factor production and increases neuronal survival. Our study uncovers an important mechanism by which CP-AMPARs regulate the growth and phenotype of epNSPCs, which can be targeted therapeutically to harness the regenerative potential of these cells after injury., Competing Interests: Conflict of interests The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Concussion public policies have been developed to address the burden of concussions. The aim of the present study was to examine implementation compliance, barriers, and facilitators of Canada's first concussion public policy, Ontario's Policy/Program Memorandum 158: School Board Policies on Concussion (PPM158)., Methods: An electronic survey was sent to 515 randomly selected elementary and high school principals across specific geographic, language, and publicly funded school types in Ontario. Data were analyzed using both qualitative and quantitative methods., Results: One hundred and thirty-five principals responded to the survey (26%). Concussion education was provided to teachers in 81% of schools, to students in 83%, and coaches in 79%. Additionally, 89% reported having a return-to-learn protocol in place and 90% reported having a return-to-play protocol. Implementation barriers included difficulties in providing concussion education to parents (42%), obtaining notes from physicians, and maintaining the volume of documentation. Eighty-seven percent of respondents believed that PPM158 improves student well-being., Conclusions: Identified implementation barriers and facilitators can inform concussion policy practices to improve student well-being. We recommend: (1) an appointed concussion policy lead at each school, (2) electronic documentation, (3) determining the optimal education format to improve parent/guardian education, (4) fostering relationships between schools and health care professionals, and (5) student concussion education in every grade in Ontario schools., (© 2022 The Authors. Journal of School Health published by Wiley Periodicals LLC on behalf of American School Health Association.)

Pediatric acute hyperextension spinal cord injury (SCI) named as PAHSCI by us, is a special type of thoracolumbar SCI without radiographic abnormality and highly related to back-bend in dance training, which has been increasingly reported. At present, it has become the leading cause of SCI in children, and brings a heavy social and economic burden. Both domestic and foreign academic institutions and dance education organizations lack a correct understanding of PAHSCI and relevant standards, specifications or guidelines. In order to provide standardized guidance, the expert team formulated this guideline based on the principles of science and practicability, starting from the diagnosis, differential diagnosis, etiology, admission evaluation, treatment, complications and prevention. This guideline puts forward 23 recommendations for 14 related issues., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Spinal cord injury (SCI) elicits a cascade of degenerative events including cell death, axonal degeneration, and the upregulation of inhibitory molecules which limit repair. Repulsive guidance molecule A (RGMa) is an axon growth inhibitor which is also involved in neuronal cell death and differentiation. SCI causes upregulation of RGMa in the injured rodent, non-human primate, and human spinal cord. Recently, we showed that delayed administration of elezanumab, a high affinity human RGMa-specific monoclonal antibody, promoted neuroprotective and regenerative effects following thoracic SCI. Since most human traumatic SCI is at the cervical level, and level-dependent anatomical and molecular differences may influence pathophysiological responses to injury and treatment, we examined the efficacy of elezanumab and its therapeutic time window of administration in a clinically relevant rat model of cervical impact-compression SCI. Pharmacokinetic analysis of plasma and spinal cord tissue lysate showed comparable levels of RGMa antibodies with delayed administration following cervical SCI. At 12w after SCI, elezanumab promoted long term benefits including perilesional sparing of motoneurons and increased neuroplasticity of key descending pathways involved in locomotion and fine motor function. Elezanumab also promoted growth of corticospinal axons into spinal cord gray matter and enhanced serotonergic innervation of the ventral horn to form synaptic connections caudal to the cervical lesion. Significant recovery in grip and trunk/core strength, locomotion and gait, and spontaneous voiding ability was found in rats treated with elezanumab either immediately post-injury or at 3 h post-SCI, and improvements in specific gait parameters were found when elezanumab was delayed to 24 h post-injury. We also developed a new locomotor score, the Cervical Locomotor Score, a simple and sensitive measure of trunk/core and limb strength and stability during dynamic locomotion., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Postconcussion syndrome (PCS) or persistent symptoms of concussion refers to a constellation of symptoms that persist for weeks and months after a concussion. To better capture the heterogeneity of the symptoms of patients with PCS, we aimed to separate patients into clinical subtypes based on brain connectivity changes. Methods: Subject-specific structural and functional connectomes were created based on diffusion weighted and resting state functional magnetic resonance imaging, respectively. Following an informed dimensionality reduction, a Gaussian mixture model was used on patient-specific structural and functional connectivity matrices to find potential patient clusters. For validation, the resulting patient subtypes were compared in terms of cognitive, neuropsychiatric, and postconcussive symptom differences. Results: Multimodal analyses of brain connectivity were predictive of behavioral outcomes. Our modeling revealed two patient subtypes: mild and severe. The severe subgroup showed significantly higher levels of depression, anxiety, aggression, and a greater number of symptoms than the mild patient subgroup. Conclusion: This study suggests that structural and functional connectivity changes together can help us better understand the symptom severity and neuropsychiatric profiles of patients with PCS. This work allows us to move toward precision medicine in concussions and provides a novel machine learning approach that can be applicable to other heterogeneous conditions.

Spinal cord injury (SCI) is a devastating condition characterized by loss of function, secondary to damaged spinal neurons, disrupted axonal connections, and myelin loss. Spontaneous recovery is limited, and there are no approved pharmaceutical treatments to reduce ongoing damage or promote repair. Repulsive guidance molecule A (RGMa) is upregulated following injury to the central nervous system (CNS), where it is believed to induce neuronal apoptosis and inhibit axonal growth and remyelination. We evaluated elezanumab, a human anti-RGMa monoclonal antibody, in a novel, newly characterized non-human primate (NHP) hemicompression model of thoracic SCI. Systemic intravenous (IV) administration of elezanumab over 6 months was well tolerated and associated with significant improvements in locomotor function. Treatment of animals for 16 weeks with a continuous intrathecal infusion of elezanumab below the lesion was not efficacious. IV elezanumab improved microstructural integrity of extralesional tissue as reflected by higher fractional anisotropy and magnetization transfer ratios in treated vs. untreated animals. IV elezanumab also reduced SCI-induced increases in soluble RGMa in cerebrospinal fluid, and membrane bound RGMa rostral and caudal to the lesion. Anterograde tracing of the corticospinal tract (CST) from the contralesional motor cortex following 20 weeks of IV elezanumab revealed a significant increase in the density of CST fibers emerging from the ipsilesional CST into the medial/ventral gray matter. There was a significant sprouting of serotonergic (5-HT) fibers rostral to the injury and in the ventral horn of lower thoracic regions. These data demonstrate that 6 months of intermittent IV administration of elezanumab, beginning within 24 h after a thoracic SCI, promotes neuroprotection and neuroplasticity of key descending pathways involved in locomotion. These findings emphasize the mechanisms leading to improved recovery of neuromotor functions with elezanumab in acute SCI in NHPs., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Sport-related structural brain injury (SRSBI) is intracranial pathology incurred during sport. Management mirrors that of non-sport-related brain injury. An empirical vacuum exists regarding return to play (RTP) following SRSBI., Objective: To provide key insight for operative management and RTP following SRSBI using a (1) focused systematic review and (2) survey of expert opinions., Methods: A systematic literature review of SRSBI from 2012 to present in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a cross-sectional survey of RTP in SRSBI by 31 international neurosurgeons was conducted., Results: Of 27 included articles out of 241 systematically reviewed, 9 (33.0%) case reports provided RTP information for 12 athletes. To assess expert opinion, 31 of 32 neurosurgeons (96.9%) provided survey responses. For acute, asymptomatic SRSBI, 12 (38.7%) would not operate. Of the 19 (61.3%) who would operate, midline shift (63.2%) and hemorrhage size > 10 mm (52.6%) were the most common indications. Following SRSBI with resolved hemorrhage, with or without burr holes, the majority of experts (>75%) allowed RTP to high-contact/collision sports at 6 to 12 mo. Approximately 80% of experts did not endorse RTP to high-contact/collision sports for athletes with persistent hemorrhage. Following craniotomy for SRSBI, 40% to 50% of experts considered RTP at 6 to 12 mo. Linear regression revealed that experts allowed earlier RTP at higher levels of play (β = -0.58, 95% CI -0.111, -0.005, P = .033)., Conclusion: RTP decisions following structural brain injury in athletes are markedly heterogeneous. While individualized RTP decisions are critical, aggregated expert opinions from 31 international sports neurosurgeons provide key insight. Level of play was found to be an important consideration in RTP determinations., (© Congress of Neurological Surgeons 2021.)

Concussion imaging research has primarily focused on neuronal disruption with lesser emphasis directed toward vascular dysfunction. However, blood flow metrics may be more sensitive than measures of neuronal integrity. Vascular dysfunction can be assessed by measuring cerebrovascular reactivity (CVR)-the change in cerebral blood flow per unit change in vasodilatory stimulus. CVR metrics, including speed and magnitude of flow responses to a standardized well-controlled vasoactive stimulus, are potentially useful for assessing individual subjects following concussion given that blood flow dysregulation is known to occur with traumatic brain injury. We assessed changes in CVR metrics to a standardized vasodilatory stimulus during the acute phase of concussion. Using a case control design, 20 concussed participants and 20 healthy controls (HCs) underwent CVR assessment measuring blood oxygen-level dependent (BOLD) magnetic resonance imaging using precise changes in end-tidal partial pressure of CO 2 (PETCO 2 ). Metrics were calculated for the whole brain, gray matter (GM), and white matter (WM) using sex-stratification. A leave-one-out receiver operating characteristic (ROC) analysis classified concussed from HCs based on CVR metrics. CVR magnitude was greater and speed of response faster in concussed participants relative to HCs, with WM showing higher classification accuracy compared with GM. ROC analysis for WM-CVR metrics revealed an area under the curve of 0.94 in males and 0.90 in females for speed and magnitude of response respectively. These greater than normal responses to a vasodilatory stimulus warrant further investigation to compare the predictive ability of CVR metrics against structural injury metrics for diagnosis and prognosis in acute concussion.

Persisting concussion symptoms (PCS) can last for months, years, or indefinitely and affect a considerable number of concussion patients. The objectives of this study were to evaluate the prevalence of clinical symptoms of anxiety and depression and the relationship between PCS and quality of life in patients examined at the Canadian Concussion Centre. The Depression and Anxiety Stress Scale-42 (DASS-42) and the World Health Organization Quality of Life Assessment-BREF (WHOQOL-BREF) were sent to 526 adult patients diagnosed with PCS. Median with interquartile range follow-up time was 5 (4-7) years. Of the 105 respondents, 35.2% displayed mild or greater symptoms of anxiety, depression, or both. Importantly, the number of previous concussions was correlated with elevations on the DASS-42 Anxiety ( p  = 0.030) and Depression ( p  = 0.018) subscale scores, suggesting an acquired cause of symptoms. Patients with clinical elevations of depression, anxiety, or both exhibited poorer mean WHOQOL-BREF scores in each domain ( p  < 0.001) compared to those who scored in the normal range on the DASS-42. These findings indicate that depression and anxiety in PCS can endure for years and are associated with diminished quality of life. Consequently, depression and anxiety should be identified and treated early in PCS populations in order to optimize recovery. Although the underlying etiology of depression and anxiety cannot be ascertained with certainty in the present study, the association between depression and anxiety and the number of concussions may indicate an organic explanation. In the future, quality-of-life measures should be incorporated into treatment and research in PCS to improve intervention strategies and enhance understanding of the trajectory of recovery in this population.

Concussions are associated with a range of cognitive, neuropsychological and behavioral sequelae that, at times, persist beyond typical recovery times and are referred to as postconcussion syndrome (PCS). There is growing support that concussion can disrupt network-based connectivity post-injury. To date, a significant knowledge gap remains regarding the sex-specific impact of concussion on resting state functional connectivity (rs-FC). The aims of this study were to (1) investigate the injury-based rs-FC differences across three large-scale neural networks and (2) explore the sex-specific impact of injury on network-based connectivity. MRI data was collected from a sample of 80 concussed participants who fulfilled the criteria for postconcussion syndrome and 31 control participants who did not have any history of concussion. Connectivity maps between network nodes and brain regions were used to assess connectivity using the Functional Connectivity (CONN) toolbox. Network based statistics showed that concussed participants were significantly different from healthy controls across both salience and fronto-parietal network nodes. More specifically, distinct subnetwork components were identified in the concussed sample, with hyperconnected frontal nodes and hypoconnected posterior nodes across both the salience and fronto-parietal networks, when compared to the healthy controls. Node-to-region analyses showed sex-specific differences across association cortices, however, driven by distinct networks. Sex-specific network-based alterations in rs-FC post concussion need to be examined to better understand the underlying mechanisms and associations to clinical outcomes.

Background: While many patients with mild traumatic brain injury (mTBI) or concussion recover completely, prolonged postconcussion symptoms remain a challenge for patients and an opportunity for clinical research. This has led to numerous research initiatives over the last 2 decades., Objective: To review the characteristics of clinical studies on management of mTBI/concussion; and to examine their definitions of mTBI/concussion., Methods: This scoping review included all clinical studies on diagnosis and management of patients with mTBI/concussion registered at www.clinicaltrials.gov from 2000 to June/2019. The terms "mild TBI/concussion" were used for the primary search. Definitions of mTBI/concussion were obtained from the protocols. When a definition was missing in the website, the study's investigators were contacted for clarification., Results: There were 225 interventional and 95 observational studies. Most of the studies are focused on treatment (54.7%) or diagnosis (37.5%), while 3.4% examined preventive measures, 2.8% evaluated prognostic instruments, and 1.6% developed registries. Most of the studies in this American database were single-center initiatives led by American and Canadian institutions. The definitions of mTBI/concussion differed widely among 109 studies., Conclusion: The results of this review suggest that most of the clinical studies are focused on diagnosis and non-pharmacological therapies for patients with mTBI/concussion. The large number of differing definitions of mTBI/concussion among the studies creates significant limitations when comparing studies. The requirements for registering research protocols on mTBI/concussion should include the necessity to state the definition being used. There is a need for consensus on a uniform definition of concussion., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Spinal cord injury (SCI) often results in permanent functional loss due to a series of degenerative events including cell death, axonal damage, and the upregulation of inhibitory proteins that impede regeneration. Repulsive Guidance Molecule A (RGMa) is a potent inhibitor of axonal growth that is rapidly upregulated following injury in both the rodent and human central nervous system (CNS). Previously, we showed that monoclonal antibodies that specifically block inhibitory RGMa signaling promote neuroprotective and regenerative effects when administered acutely in a clinically relevant rat model of thoracic SCI. However, it is unknown whether systemic administration of RGMa blocking antibodies are effective for SCI after delayed administration. Here, we administered elezanumab, a human monoclonal antibody targeting RGMa, intravenously either acutely or at 3 h or 24 h following thoracic clip impact-compression SCI. Rats treated with elezanumab acutely and at 3 h post-injury showed improvements in overground locomotion and fine motor function and gait. Rats treated 24 h post-SCI trended towards better recovery demonstrating significantly greater stride length and swing speed. Treated rats also showed greater tissue preservation with reduced lesion areas. As seen with acute treatment, delayed administration of elezanumab at 3 h post-SCI also increased perilesional neuronal sparing and serotonergic and corticospinal axonal plasticity. In addition, all elezanumab treated rats showed earlier spontaneous voiding ability and less post-trauma bladder wall hypertrophy. Together, our data demonstrate the therapeutic efficacy of delayed systemic administration of elezanumab in a rat model of SCI, and uncovers a new role for RGMa inhibition in bladder recovery following SCI., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to assess the frequency of structural lesions on conventional magnetic resonance imaging (MRI) of the brain in a large prospective cohort of post-concussion syndrome (PCS) patients. Conventional 3T MRI was used to evaluate 127 prospectively enrolled PCS patients and 29 controls for non-specific white matter hyperintensities (WMH) and traumatic structural lesions, including encephalomalacia, atrophy, microhemorrhage, subarachnoid hemorrhage, and cortical siderosis. All PCS patients had a clinical diagnosis of one or more concussions based on the Concussion in Sport Group (CISG) consensus statements. Patients with recognized intracranial hemorrhage on prior head computed tomography (CT) and MRI were excluded. The differences between the PCS and control groups were analyzed. Four patients in the PCS group (3.1%) had positive findings, which included microhemorrhages in two patients and encephalomalacia in another two patients. None of these lesions was present in the control group, but there was no statistical difference between the two groups ( p  = 0.5 for microhemorrhage and p  = 0.5 for encephalomalacia). In the PCS group, 28 patients (22%) had WMH (15.7% had 1-10 lesions and 6.3% had >10 lesions), and these results did not differ from the age-matched control (20.6%, all with 1-10 lesions; p  = 0.9) The location of the WMH showed no significant difference in the number of juxtacortical WMH between the PCS and control groups ( p  = 0.5). Structural lesions were rare in PCS in this study, and the presence of such findings suggests a more severe form of traumatic brain injury. Our data support the role for MRI in the diagnosis of PCS by exclusion of atrophy, encephalomalacia, and all forms of intracranial hemorrhage. The presence of WMH irrespective of number is not an exclusion. This is the first description of the MRI criteria for PCS.

Background: Concussions among adult bicyclists are common, but little is known about the long-term effects of the consequences of these concussions such as postconcussion syndrome (PCS) including its occurrence, clinical features and recovery potential. Indeed, our study is the first to examine PCS due to bicycling in any age group., Objectives: We examined patient demographics, concussion mechanisms and persistent symptoms as factors leading to PCS in adults and the potential for recovery., Methods: We conducted a retrospective chart review of 28 patients age 18 or older who sustained a concussion while bicycling and were referred to the Canadian Concussion Centre for management of PCS., Results: Eighteen patients (64.3%) fell from their bicycles due to loss of control, attempts to avoid a crash or collision with an object. Eight patients (28.6%) were struck by a motor vehicle, and two patients (7.1%) were injured by collision with another bicycle. The mean duration of PCS was 23.7 months and at the time of the last follow-up, 23 (82.1%) patients had failed to recover completely. Patients with one or more previous concussions had a significantly longer duration of PCS (p=0.042). Bicycling concussions resulted in a greater mean duration of PCS (23.7 months) than a comparison group of patients with PCS due to collision sports (16.1 months) (p=0.07)., Conclusion: Adults who sustain bicycling-related concussions and develop PCS often have long-lasting symptoms; greater attention should be given to prevention strategies such as improved bicycling infrastructure and safer bicycling practices to reduce concussions in adult bicyclists., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nearly a century ago, the concept of the secondary injury in spinal cord trauma was first proposed to explain the complex cascade of molecular and cellular events leading to widespread neuronal and glial cell death after trauma. In recent years, it has been established that the ependymal region of the adult mammalian spinal cord contains a population of multipotent neural stem/progenitor cells (NSPCs) that are activated after spinal cord injury (SCI) and likely play a key role in endogenous repair and regeneration. How these cells respond to the various components of the secondary injury remains poorly understood. Emerging evidence suggests that many of the biochemical components of the secondary injury cascade which have classically been viewed as deleterious to host neuronal and glial cells may paradoxically trigger NSPC activation, proliferation, and differentiation thus challenging our current understanding of secondary injury mechanisms in SCI. Herein, we highlight new findings describing the response of endogenous NSPCs to spinal cord trauma, redefining the secondary mechanisms of SCI through the lens of the endogenous population of stem/progenitor cells. Moreover, we outline how these insights can fuel novel stem cell-based therapeutic strategies to repair the injured spinal cord., (© AlphaMed Press 2019.)

Objectives: To identify novel targets for neurorehabilitation of people with a remote history of multiple concussions by: (1) comprehensively characterizing neuropsychiatric and cognitive functioning in former professional football players, with a focus on executive functions; (2) distinguishing concussion-related findings from pre-morbid/cohort characteristics of professional football players; and, (3) exploring the relationship between executive functions and neuropsychiatric symptoms. Participants: Sixty-one high-functioning former professional football players and 31 age- and sex-matched control participants without history of concussion or participation in contact sports. Design: Between-groups analyses. Main measures: Neuropsychiatric . Personality Assessment Inventory (PAI) clinical scales plus the Aggression treatment consideration scale; the Mini International Neuropsychiatric Interview (MINI). Cognitive . Comprehensive clinical neuropsychological battery assessing domains of verbal and visuospatial attention; speed of processing and memory; current and estimated pre-morbid IQ; and, executive functioning, including two experimental measures that were novel for this population (i.e., response inhibition and inconsistency of responding on a go/no-go task). Results: (1) Compared to control participants, former professional football players scored significantly higher on the PAI Depression, Mania, and Aggression scales, and significantly lower on response inhibition. (2) Relative to controls, former players with >3 concussions ( x ¯ = 6 . 1 ), but not former players with ≤ 3 concussions ( x ¯ = 2 . 0 ), showed (i) significantly higher scores on the PAI Depression scale, (ii) significantly more MINI clinical diagnoses overall, and manic/hypomanic episodes specifically, and (iii) significantly poorer executive function. (3) Mediation analysis revealed that concussion exposure had a significant indirect effect on PAI Depression, Mania, and Aggression via inconsistency of responding on the go/no-go task. Conclusions: Notable impairments to neuropsychiatric functioning and worse performance on a sensitive experimental measure of executive function were observed; these were related to both concussion history and pre-morbid (cohort) factors. Therefore, neuropsychiatric and executive functioning should be carefully assessed in those with a remote history of multiple concussions. Moreover, former players' neuropsychiatric symptoms were associated with inconsistency of responding; this suggests that treatments targeted at response inconsistency could help to mitigate neuropsychiatric dysfunction.

Concussion has emerged as an important public health issue affecting thousands of Canadians annually. Health care providers including paediatricians, family and emergency medicine physicians, nurses, and nurse practitioners are commonly tasked with the responsibility of providing primary care to patients with acute concussion and those with persistent post-concussion symptoms. In July 2017, Parachute, in collaboration with the Public Health Agency of Canada and Sport Canada released the Canadian Guideline on Concussion in Sport that outlines a standardized and evidence-based approach to the recognition, diagnosis, and management of youth and adults with suspected concussion. In this report, we provide a brief overview of the important roles of primary care providers in the medical assessment, management, and prevention of concussion as outlined in this national best practice guideline.

The ideal biomarker for central nervous system (CNS) trauma in patients would be a molecular marker specific for injured nervous tissue that would provide a consistent and reliable assessment of the presence and severity of injury and the prognosis for recovery. One candidate biomarker is the protein tau, a microtubule-associated protein abundant in the axonal compartment of CNS neurons. Following axonal injury, tau becomes modified primarily by hyperphosphorylation of its various amino acid residues and cleavage into smaller fragments. These posttrauma products can leak into the cerebrospinal fluid or bloodstream and become candidate biomarkers of CNS injury. This review examines the primary molecular changes that tau undergoes following traumatic brain injury and spinal cord injury, and reviews the current literature in traumatic CNS biomarker research with a focus on the potential for hyperphosphorylated and cleaved tau as sensitive biomarkers of injury.

Background: Despite concussion now being recognized as a public health priority in Canada, recent studies-including our 2012 survey of Canadian medical schools-have revealed major gaps in concussion education at the undergraduate medical school level., Methods: We re-surveyed all 17 Canadian medical schools using a questionnaire divided in two categories: (1) concussion-specific education (2) head injury education incorporating a concussion component to determine whether there have been any improvements in concussion education at the medical school level during the last five years. For each year of medical school, respondents were asked to provide the estimated number of hours and teaching format for each category., Results: We received replies from 13 of the 17 medical schools (76%). 11 of the 13 (85%) medical schools now reported providing concussion-specific education compared to 29% in our 2012 survey. The mean number of hours dedicated to category 1 learning in 2017 was 2.65 h compared to 0.57 in 2012, and the mean number of hours of category 2 increased to 7.5 from 1.54., Conclusion: Our follow-up study reveals increased exposure to concussion-related teaching in Canadian medical schools during the last five years. Persistent deficiencies in a minority of schools are highlighted. These should be addressed by reiterating the importance of concussion education for undergraduate medical students and by developing clear concussion-specific objectives at the national licensure level.

Liquid crystal display (LCD) screens refresh at a rate of 60 times per second, which can be perceived by concussed individuals who have photosensitivity, leading to computer intolerance. A non-LCD computer screen that refreshes at a much lower rate could relieve this photosensitivity and computer screen intolerance in patients with post-concussion syndrome (PCS). Twenty-nine patients with PCS, computer intolerance, and photosensitivity performed a reading task for a maximum of 30 min, with an LCD computer or a non-LCD device, and were given a comprehension test after completion of the reading task. The Sport Concussion Assessment Tool 3 was administered before and after each reading task. Symptom scores, amount of time spent reading, and performance on the comprehension tests were compared between the two devices. Patients also completed a self-report questionnaire of their subjective experience. The LCD screen computer produced significantly greater symptom exacerbation (median difference = 5, W = 315, p < 0.01) and a greater number of symptoms (median difference = 1, W = 148, p < 0.01) than the non-LCD screens. The non-LCD screen resulted in a longer symptom-free reading time (median = 48 sec, W = 147, p < 0.01), but not a greater number of words read (median = 281, W = 148, p = 0.098). Females were more likely to have greater symptom exacerbation with the LCD screen (U = 14.0, p < 0.01). No significant difference was found in performance on the comprehension test. Subjective reports showed that the non-LCD experience was more favorable, and most patients stated they would recommend this device for other patients with PCS. This study is the first to show the clinical utility of non-LCD screen computers in the management of photosensitivity and computer screen intolerance in patients with PCS. The non-LCD screen computer has the potential to facilitate return-to-work or return-to-school in concussed individuals.

Current biomarker research in spinal cord injury (SCI) and traumatic brain injury has focused on a number of structural protein candidates, including the microtubule-associated protein tau. Evidence from models of traumatic brain injury has demonstrated that hyperphosphorylation of tau (p-tau) occurs in injured axons and demonstrates its utility as a biomarker for brain injury; however, the potential of p-tau as a biomarker for SCI is not yet known. Therefore, the present study determined whether tau is hyperphosphorylated in injured spinal cord axons, and then examined cerebrospinal fluid (CSF) and serum concentrations of p-tau and total-tau protein after a clinically relevant severe impact-compression SCI in rats. We found that severe SCI at T8 showed the presence of p-tau in damaged axons with a similar time course and distribution pattern to β-APP, a biomarker of axonal injury. The presence of p-tau and β-APP positive axons extended no farther than 5000 μm rostral and caudal to the injury epicenter, and was at its maximum at one day post-SCI. CSF levels of p-tau and total-tau significantly increased at one day post-SCI; however, only serum p-tau levels were significantly elevated in rats with SCI compared with naïve rats. These results suggest that CSF and serum p-tau may be a useful biomarker for severe traumatic SCI.

Background: Epidemiologic studies have suggested that concussion, or mild traumatic brain injury (mTBI), is associated with a twofold or greater increase in relative risk for the development of post-traumatic epilepsy. To assess the clinical validity of these findings, we analyzed the incidence of epilepsy in a large cohort of post-concussion patients in whom concussion was strictly defined according to international guidelines., Methods: A retrospective cohort study of 330 consecutive post-concussion patients followed by a single concussion specialist. Exclusion criteria: abnormal brain CT/MRI, Glasgow Coma Scale48 hours. Independent variable: concussion. Outcome measure: epilepsy incidence (dependent variable)., Results: The mean number of concussions/patient was 3.3 (±2.5), mean age at first clinic visit 28 years (±14.7), and mean follow-up after first concussion 7.6 years (±10.8). Eight patients were identified whose medical records included mention of seizures or convulsions or epilepsy. Upon review by an epileptologist none met criteria for a definite diagnosis of epilepsy: four had episodic symptoms incompatible with epileptic seizures (e.g., multifocal paraesthesiae, multimodality hallucinations, classic migraine) and normal EEG/MRI investigations; four had syncopal (n=2) or concussive (n=2) convulsions. Compared with annual incidence (0.5/1000 individuals) in the general population, there was no difference in this post-concussion cohort (p=0.49)., Conclusion: In this large cohort of post-concussion patients we found no increased incidence of epilepsy. For at least the first 5-10 years post-injury, concussion/mTBI should not be considered a significant risk factor for epilepsy. In patients with epilepsy and a past history of concussion, the epilepsy should not be presumed to be post-traumatic.

The objective of this study was to assess the incidence of motor impairment in former professional Canadian Football League (ex-CFL) players with multiple concussions. We investigated motor symptoms and signs in 45 ex-CFL players with multiple concussions and 25 age- and education-matched healthy controls with no history of concussion. Neurological assessment included items from the SCAT3 (Sport Concussion Assessment Tool 3) and the Unified Parkinson's Disease Rating Scale part III (UPDRS-Part III). A performance-based measurement of manual motor function was undertaken using the Grooved Pegboard test. Cognition was measured with patient-reported outcomes for memory, executive and behavioral symptoms as well as performance-based measures of memory and executive function. Symptoms of anxiety and depression were measured using the Personality Assessment Inventory. There was no significant difference between the ex-CFL players and controls on the UPDRS-Part III scores, and neither group reported clinically significant motor complaints. Ex-CFL players did not perform differently from control subjects on the Grooved Pegboard test. In contrast, with regard to cognitive and mood testing, players were more symptomatic: The ex-CFL players reported significantly more memory (77.8% vs. 16%, respectively, p < 0.001), executive (53.3% vs. 8%, respectively, p < 0.001), and behavioral symptoms (66.7% vs. 20%, respectively, p < 0.001). No significant differences were found when comparing ex-CFL players and controls in performance on memory and executive tests. In summary, in a group of retired CFL players who self-reported declines in memory, executive and behavioral symptoms, no motor symptoms were reported and no motor signs were detected.

OBJECTIVE A surgical series of 201 benign and malignant peripheral nerve sheath tumors (PNSTs) was assessed to characterize the anatomical and clinical presentation of tumors and identify predictors of neurological outcome, recurrence, and extent of resection. METHODS All surgically treated PNSTs from the Division of Neurosurgery at Toronto Western Hospital from 1993 to 2010 were reviewed retrospectively. Data were collected on patient demographics, clinical presentation, surgical technique, extent of resection, postoperative neurological outcomes, and recurrence. RESULTS One hundred seventy-five patients with 201 tumors had adequate follow-up for analysis. There were 182 benign and 19 malignant PNSTs. Of the benign lesions, 133 were schwannomas, 21 of which were associated with a diagnosis of schwannomatosis. There were 49 neurofibromas, and 26 were associated with neurofibromatosis Type 1 (NF1). Patients presenting with schwannomas were significantly older than those with neurofibromas. Schwannomas were more readily resected than neurofibromas, with the extent of resection of the former influenced by tumor location. Patients with benign PNSTs typically presented with a painful mass and less frequently with motor deficits. The likelihood of worsened postoperative motor function was decreased in patients with fully resected tumors or preoperative deficits. Recurrence of schwannomas and neurofibromas were seen more frequently in patients diagnosed with NF3 and NF1, respectively. Subtotal resection was associated with the increased recurrence of all benign lesions. CONCLUSIONS Outcomes following resection of benign PNSTs depend on tumor histopathology, tumor location, and genetic predisposition syndrome. Gross-total resection should be attempted for benign lesions where possible. The management of malignant PNSTs remains challenging, requiring a multimodal approach.

The Fifth International Conference on Concussion in Sport was held in Berlin in October 2016. A series of 12 questions and subquestions was developed and the expert panel members were required to perform a systematic review to answer each question. Following presentation at the Berlin meeting of the systematic review, poster abstracts and audience discussion, the summary Consensus Statement was produced. Further, a series of tools for the management of sport-related concussion was developed, including the Sport Concussion Assessment Tool Fifth edition (SCAT5), the Child SCAT5, and the Concussion Recognition Tool Fifth edition. This paper elaborates on this process, the outcomes, and explores the implications for neurosurgeons in the management of sport-related concussion., (Copyright © 2017 by the Congress of Neurological Surgeons.)

Transplantation of neural stem/progenitor cells (NSPCs) following spinal cord injury (SCI) is a promising strategy to enhance regeneration but is limited by poor survival of grafted cells. Determining methods to enhance survival of NSPCs is therefore essential. Positive modulation of AMPA receptors has been shown to enhance neurogenesis in various models of brain injury. Here we examined the effect of selective AMPA receptor modulation in adult rat spinal cord-derived NSPCs using a class of allosteric AMPA receptor modulators known as ampakines. NSPCs from the periventricular region of the adult rat spinal cord were treated with ampakines CX614 and CX546 for 72 h either alone or in the presence of low-dose glutamate (50 μM). Treatment with either agent in the presence of glutamate significantly increased cell survival and proliferation and reduced cell death. Moreover, ampakine/glutamate treatment reduced cell death in the setting of oxidative stress. Treatment with ampakines did not significantly alter cell phenotype. These findings offer important insight into a potential therapeutic strategy to positively regulate transplanted and endogenous adult spinal cord-derived NSPCs after SCI.

Traumatic spinal cord injury (SCI) causes a cascade of degenerative events including cell death, axonal damage, and the upregulation of inhibitory molecules which prevent regeneration and limit recovery. Repulsive guidance molecule A (RGMa) is a potent neurite growth inhibitor in the central nervous system, exerting its repulsive activity by binding the Neogenin receptor. Here, we show for the first time that inhibitory RGMa is markedly upregulated in multiple cell types after clinically relevant impact-compression SCI in rats, and importantly, also in the injured human spinal cord. To neutralize inhibitory RGMa, clinically relevant human monoclonal antibodies were systemically administered after acute SCI, and were detected in serum, cerebrospinal fluid, and in the injured tissue. Rats treated with RGMa blocking antibodies showed significantly improved recovery of motor function and gait. Furthermore, RGMa blocking antibodies promoted neuronal survival, and enhanced the plasticity of descending serotonergic pathways and corticospinal tract axonal regeneration. RGMa antibody also attenuated neuropathic pain responses, which was associated with fewer activated microglia and reduced CGRP expression in the dorsal horn caudal to the lesion. These results show the therapeutic potential of the first human RGMa antibody for SCI and uncovers a new role for the RGMa/Neogenin pathway on neuropathic pain.

Traumatic spinal cord injury (SCI) is a devastating event for which functional recovery remains elusive. Due to the complex nature of SCI pathology, a combination treatment strategy will likely be required for success. We hypothesized that tissue and functional repair would be achieved in a rat model of impact-compression SCI by combining degradation of the glial scar, using chondroitinase ABC (ChABC), with recruitment of endogenous neural precursor cells (NPCs), using stromal cell-derived factor 1α (SDF). To test this hypothesis, we designed a crosslinked methylcellulose hydrogel (XMC) for minimally invasive, localized, and sustained intrathecal drug delivery. ChABC was released from XMC using protein-peptide affinity interactions while SDF was delivered by electrostatic affinity interactions from polymeric nanoparticles embedded in XMC. Rats with SCI were treated acutely with a combination of SDF and ChABC, SDF alone, ChABC alone, or vehicle alone, and compared to injury only. Treatment with ChABC, both alone and in combination with SDF, resulted in faster and more sustained behavioural improvement over time than other groups. The significantly reduced chondroitin sulfate proteoglycan levels and greater distribution of NPCs throughout the spinal cord tissue with ChABC delivery, both alone and in combination with SDF, may explain the improved locomotor function. Treatment with SDF alone had no apparent effect on NPC number or distribution nor synergistic effect with ChABC delivery. Thus, in this model of SCI, tissue and functional repair is attributed to ChABC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)