Changes in Brain Structure and Function in a Multisport Cohort of Retired Female and Male Athletes, Many Years after Suffering a Concussion: Implications for Neuroplasticity and Neurodegenerative Disease Pathogenesis.

Background: Cumulative effects of traumatic brain injury is of increasing concern, especially with respect to its role in the etiology and pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Objective: Compare regional brain volume and connectivity between athletes with a history of concussion and controls. Methods: We evaluated whole-brain volumetric effects with Bayesian regression models and functional connectivity with network-based statistics, in 125 retired athletes (a mean of 11 reported concussions) and 36 matched controls. Results: Brain regions significantly lower in volume in the concussed group included the middle frontal gyrus, hippocampus, supramarginal gyrus, temporal pole, and inferior frontal gyrus. Conversely, brain regions significantly larger included the hippocampal and collateral sulcus, middle occipital gyrus, medial orbital gyrus, caudate nucleus, lateral orbital gyrus, and medial postcentral gyrus. Functional connectivity analyses revealed increased edge strength, most marked in motor domains. Numerous edges of this network strengthened in athletes were significantly weakened with concussion. Aligned to meta-analytic neuroimaging data, the observed changes suggest functional enhancement within the motor, sensory, coordination, balance, and visual processing domains in athletes, attenuated by concussive head injury with a negative impact on memory and language. Conclusions: These findings suggest that engagement in sport may benefit the brain across numerous domains, but also highlights the potentially damaging effects of concussive head injury. Future studies with longitudinal cohorts including autopsy examination are needed to determine whether the latter reflects tissue loss from brain shearing, or the onset of a progressive Alzheimer's disease like proteinopathy.

A randomised, double blind, placebo-controlled trial of a two-week course of dexamethasone for adult patients with a symptomatic Chronic Subdural Haematoma (Dex-CSDH trial).

Background: Chronic subdural haematoma is a collection of 'old blood' and its breakdown products in the subdural space and predominantly affects older people. Surgical evacuation remains the mainstay in the management of symptomatic cases. Objective: The Dex-CSDH (DEXamethasone in Chronic SubDural Haematoma) randomised trial investigated the clinical effectiveness and cost-effectiveness of dexamethasone in patients with a symptomatic chronic subdural haematoma. Design: This was a parallel, superiority, multicentre, pragmatic, randomised controlled trial. Assigned treatment was administered in a double-blind fashion. Outcome assessors were also blinded to treatment allocation. Setting: Neurosurgical units in the UK. Participants: Eligible participants included adults (aged ≥ 18 years) admitted to a neurosurgical unit with a symptomatic chronic subdural haematoma confirmed on cranial imaging. Interventions: Participants were randomly assigned in a 1 : 1 allocation to a 2-week tapering course of dexamethasone or placebo alongside standard care. Main outcome measures: The primary outcome was the Modified Rankin Scale score at 6 months dichotomised to a favourable (score of 0-3) or an unfavourable (score of 4-6) outcome. Secondary outcomes included the Modified Rankin Scale score at discharge and 3 months; number of chronic subdural haematoma-related surgical interventions undertaken during the index and subsequent admissions; Barthel Index and EuroQol 5-Dimension 5-Level utility index score reported at discharge, 3 months and 6 months; Glasgow Coma Scale score reported at discharge and 6 months; mortality at 30 days and 6 months; length of stay; discharge destination; and adverse events. An economic evaluation was also undertaken, during which the net monetary benefit was estimated at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Results: A total of 748 patients were included after randomisation: 375 were assigned to dexamethasone and 373 were assigned to placebo. The mean age of the patients was 74 years and 94% underwent evacuation of their chronic subdural haematoma during the trial period. A total of 680 patients (91%) had 6-month primary outcome data available for analysis: 339 in the placebo arm and 341 in the dexamethasone arm. On a modified intention-to-treat analysis of the full study population, there was an absolute reduction in the proportion of favourable outcomes of 6.4% (95% confidence interval 11.4% to 1.4%; p = 0.01) in the dexamethasone arm compared with the control arm at 6 months. At 3 months, the between-group difference was also in favour of placebo (-8.2%, 95% confidence interval -13.3% to -3.1%). Serious adverse events occurred in 60 out of 375 (16.0%) in the dexamethasone arm and 24 out of 373 (6.4%) in the placebo arm. The net monetary benefit of dexamethasone compared with placebo was estimated to be -£97.19. Conclusions: This trial reports a higher rate of unfavourable outcomes at 6 months, and a higher rate of serious adverse events, in the dexamethasone arm than in the placebo arm. Dexamethasone was also not estimated to be cost-effective. Therefore, dexamethasone cannot be recommended for the treatment of chronic subdural haematoma in this population group. Future work and limitations: A total of 94% of individuals underwent surgery, meaning that this trial does not fully define the role of dexamethasone in conservatively managed haematomas, which is a potential area for future study. Trial registration: This trial is registered as ISRCTN80782810. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/15/02) and is published in full in Health Technology Assessment; Vol. 28, No. 12. See the NIHR Funding and Awards website for further award information.

Chronic subdural haematoma is one of the most common conditions managed in adult neurosurgery and mainly affects older people. It is an 'old' collection of blood and blood breakdown products found on the surface of the brain. Surgery to drain the liquid collection is effective, with most patients improving. Given that inflammation is involved in the disease process, a commonly used steroid, dexamethasone, has been used alongside surgery or instead of surgery since the 1970s. However, there is no consensus or high-quality studies confirming the effectiveness of dexamethasone for the treatment of chronic subdural haematoma. This study was designed to determine the effectiveness of adding dexamethasone to the normal treatment for patients with a symptomatic chronic subdural haematoma. The benefit of adding dexamethasone was measured using a disability score called the Modified Rankin Scale, which can be divided into favourable and unfavourable outcomes. This was assessed at 6 months after entry into the study. In total, 748 adults with a symptomatic chronic subdural haematoma treated in neurosurgical units in the UK participated. Each participant had an equal chance of receiving either dexamethasone or a placebo because they were assigned randomly. Neither the patients nor the investigators knew who received dexamethasone and who received placebo. Most patients in both groups had an operation to drain the haematoma and experienced significant functional improvement at 6 months compared with their initial admission to hospital. However, patients who received dexamethasone had a lower chance than patients who received placebo of favourable recovery at 6 months. Specifically, 84% of patients who received dexamethasone had recovered well at 6 months, compared with 90% of patients who received placebo. There were more complications in the group that received dexamethasone. This trial demonstrates that adding dexamethasone to standard treatment reduced the chance of a favourable outcome compared with standard treatment alone. Therefore, this study does not support the use of dexamethasone in treating patients with a symptomatic chronic subdural haematoma.

Neurotrauma-From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord.

Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations and often causes profound and irreversible disability. Pathophysiological responses to trauma exacerbate the damage of an index injury, propagating the loss of function that the central nervous system (CNS) cannot repair after the initial event is resolved. The way in which function is lost after injury is the consequence of a complex array of mechanisms that continue in the chronic phase post-injury to prevent effective neural repair. This review summarises the events after traumatic brain injury (TBI) and spinal cord injury (SCI), comprising a description of current clinical management strategies, a summary of known cellular and molecular mechanisms of secondary damage and their role in the prevention of repair. A discussion of current and emerging approaches to promote neuroregeneration after CNS injury is presented. The barriers to promoting repair after neurotrauma are across pathways and cell types and occur on a molecular and system level. This presents a challenge to traditional molecular pharmacological approaches to targeting single molecular pathways. It is suggested that novel approaches targeting multiple mechanisms or using combinatorial therapies may yield the sought-after recovery for future patients.

Consensus-based recommendations for diagnosis and surgical management of cranioplasty and post-traumatic hydrocephalus from a European panel.

Introduction: Planning cranioplasty (CPL) in patients with suspected or proven post-traumatic hydrocephalus (PTH) poses a significant management challenge due to a lack of clear guidance. Research question: This project aims to create a European document to improve adherence and adapt to local protocols based on available resources and national health systems. Methods: After a thorough non-systematic review, a steering committee (SC) formed a European expert panel (EP) for a two-round questionnaire using the Delphi method. The questionnaire employed a 9-point Likert scale to assess the appropriateness of statements inherent to two sections: "Diagnostic criteria for PTH" and "Surgical strategies for PTH and cranial reconstruction." Results: The panel reached a consensus on 29 statements. In the "Diagnostic criteria for PTH" section, five statements were deemed "appropriate" (consensus 74.2-90.3 %), two were labeled "inappropriate," and seven were marked as "uncertain."In the "Surgical strategies for PTH and cranial reconstruction" section, four statements were considered "appropriate" (consensus 74.2-90.4 %), six were "inappropriate," and five were "uncertain." Discussion and conclusion: Planning a cranioplasty alongside hydrocephalus remains a significant challenge in neurosurgery. Our consensus conference suggests that, in patients with cranial decompression and suspected hydrocephalus, the most suitable diagnostic approach involves a combination of evolving clinical conditions and neuroradiological imaging. The recommended management sequence prioritizes cranial reconstruction, with the option of a ventriculoperitoneal shunt when needed, preferably with a programmable valve. We strongly recommend to adopt local protocols based on expert consensus, such as this, to guide patient care.

Examining the validity of the Delis-Kaplan Executive Function System (D-KEFS) in traumatic brain injury.

This study examines the validity of the Delis-Kaplan Executive Function System (D-KEFS) in a traumatic brain injury (TBI) population compared to participants with orthopaedic injuries and normative controls. The utility of the D-KEFS was examined using a between groups design. One hundred patients with mild uncomplicated to severe TBI were recruited from a consecutive cohort of patients admitted as inpatients to a UK Major Trauma Centre and compared to 823 participants from the D-KEFS normative sample and 26 participants with orthopaedic injuries. Data were filtered for performance validity. Sample discrimination was calculated from D-KEFS subtest scores and derived index scores. Sensitivity to TBI severity was established. The TBI participants performed significantly lower on the D-KEFS Trail Making Test, Colour Word Interference, Colour Word Switching, Letter Fluency and Verbal Fluency Category Switching Total Words Correct. The D-KEFS index scores discriminated between TBI, orthopaedic and normative participants with large and moderate effect sizes, respectively. The D-KEFS demonstrated a dose-response relationship with TBI severity. These effects were robust to differences in premorbid intellectual functioning; however, D-KEFS performance was sensitive to performance on tests of mental processing speed. The use of a D-KEFS index score provides a robust and reliable discrimination of TBI patients from healthy control participants. This discrimination is not accounted for by premorbid intellect or the non-specific effects of trauma. The clinical and conceptual implications of these findings are considered.

Triage in major incidents: development and external validation of novel machine learning-derived primary and secondary triage tools.

BACKGROUND: Major incidents (MIs) are an important cause of death and disability. Triage tools are crucial to identifying priority 1 (P1) patients-those needing time-critical, life-saving interventions. Existing expert opinion-derived tools have limited evidence supporting their use. This study employs machine learning (ML) to develop and validate models for novel primary and secondary triage tools. METHODS: Adults (16+ years) from the UK Trauma Audit and Research Network (TARN) registry (January 2008-December 2017) served as surrogates for MI victims, with P1 patients identified using predefined criteria. The TARN database was split chronologically into model training and testing (70:30) datasets. Input variables included physiological parameters, age, mechanism and anatomical location of injury. Random forest, extreme gradient boosted tree, logistic regression and decision tree models were trained to predict P1 status, and compared with existing tools (Battlefield Casualty Drills (BCD) Triage Sieve, CareFlight, Modified Physiological Triage Tool, MPTT-24, MSTART, National Ambulance Resilience Unit Triage Sieve and RAMP). Primary and secondary candidate models were selected; the latter was externally validated on patients from the UK military's Joint Theatre Trauma Registry (JTTR). RESULTS: Models were internally tested in 57 979 TARN patients. The best existing tool was the BCD Triage Sieve (sensitivity 68.2%, area under the receiver operating curve (AUC) 0.688). Inability to breathe spontaneously, presence of chest injury and mental status were most predictive of P1 status. A decision tree model including these three variables exhibited the best test characteristics (sensitivity 73.0%, AUC 0.782), forming the candidate primary tool. The proposed secondary tool (sensitivity 77.9%, AUC 0.817), applicable via a portable device, includes a fourth variable (injury mechanism). This performed favourably on external validation (sensitivity of 97.6%, AUC 0.778) in 5956 JTTR patients. CONCLUSION: Novel triage tools developed using ML outperform existing tools in a nationally representative trauma population. The proposed primary tool requires external validation prior to consideration for practical use. The secondary tool demonstrates good external validity and may be used to support decision-making by healthcare workers responding to MIs.

Specialist healthcare services for concussion/mild traumatic brain injury in England: a consensus statement using modified Delphi methodology.

OBJECTIVE: To establish a consensus on the structure and process of healthcare services for patients with concussion in England to facilitate better healthcare quality and patient outcome. DESIGN: This consensus study followed the modified Delphi methodology with five phases: participant identification, item development, two rounds of voting and a meeting to finalise the consensus statements. The predefined threshold for agreement was set at ≥70%. SETTING: Specialist outpatient services. PARTICIPANTS: Members of the UK Head Injury Network were invited to participate. The network consists of clinical specialists in head injury practising in emergency medicine, neurology, neuropsychology, neurosurgery, paediatric medicine, rehabilitation medicine and sports and exercise medicine in England. PRIMARY OUTCOME MEASURE: A consensus statement on the structure and process of specialist outpatient care for patients with concussion in England. RESULTS: 55 items were voted on in the first round. 29 items were removed following the first voting round and 3 items were removed following the second voting round. Items were modified where appropriate. A final 18 statements reached consensus covering 3 main topics in specialist healthcare services for concussion; care pathway to structured follow-up, prognosis and measures of recovery, and provision of outpatient clinics. CONCLUSIONS: This work presents statements on how the healthcare services for patients with concussion in England could be redesigned to meet their health needs. Future work will seek to implement these into the clinical pathway.

Concussion in facial trauma patients: a retrospective analysis of 100 patients from a UK major trauma centre.

Concussion is a common and potentially debilitating condition. Research has shown that one-third of patients admitted with facial trauma have concurrent concussion. This study aimed to investigate the burden and management of concussion in patients presenting with acute facial trauma, and to identify potential risk factors within this population. A retrospective observational study was conducted at a UK major trauma centre between 1 January 2019 and 1 February2020. One hundred randomly selected patients who attended the acute clinic responsible for managing facial trauma were identified. No parametric data were included. The Mann-Whitney test was used to detect differences for continuous data, the X2 test for categorical data. Clinical significance was defined as p < 0.05. Forty of 100 patients (40%) had evidence of concussion, of which only 4/40 (10%) had evidence that head injury advice had been given. There was no statistically significant difference between the non-concussed and concussed groups for age (p = 0.145), gender (p = 0.921), mechanism of injury (p = 0.158), or location of facial injury (p = 0.451). Clinical features of concussion were found in 40% of patients suffering from facial injury. Despite this, we found that head injury advice was rarely given. In addition, we identified no risk factors for concussion within this population, highlighting the need to screen all patients who present with facial injury. To improve the identification and management of concussion in these patients, future work should focus on the development of simple screening tools for use in clinic, and the signposting of patients to existing written and online concussion resources.

Assessing blood oxygen level-dependent signal variability as a biomarker of brain injury in sport-related concussion.

Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level-dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level-dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level-dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level-dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury.

Cerebrospinal Fluid Diversion for Refractory Intracranial Hypertension in Traumatic Brain Injury: A Single Center Experience.

BACKGROUND: Diversion of cerebrospinal fluid (CSF) is a common neurosurgical procedure for control of intracranial pressure (ICP) in the acute phase after traumatic brain injury (TBI), where medical management is insufficient. CSF can be drained via an external ventricular drain (EVD) or, in selected patients, via a lumbar (external lumbar drain [ELD]) drainage catheter. Considerable variability exists in neurosurgical practice on their use. METHODS: A retrospective service evaluation was completed for patients receiving CSF diversion for ICP control after TBI, from April 2015 to August 2021. Patients were included whom fulfilled local criteria deeming them suitable for either ELD/EVD. Data were extracted from patient notes, including ICP values pre/postdrain insertion and safety data including infection or clinically/radiologically diagnosed tonsillar herniation. RESULTS: Forty-one patients were retrospectively identified (ELD = 30 and EVD = 11). All patients had parenchymal ICP monitoring. Both modalities affected statistically significant decreases in ICP, with relative reductions at 1, 6, and 24 hour pre/postdrainage (at 24-hour ELD P < 0.0001, EVD P < 0.01). Similar rates of ICP control failure, blockage and leak occurred in both groups. A greater proportion of patients with EVD were treated for CSF infection than with ELD. One event of clinical tonsillar herniation is reported, which may have been in part attributable to ELD overdrainage, but which did not result in adverse outcome. CONCLUSIONS: The data presented demonstrate that EVD and ELD can be successful in ICP control after TBI, with ELD limited to carefully selected patients with strict drainage protocols. The findings support prospective study to formally determine the relative risk-benefit profiles of CSF drainage modalities in TBI.

Decompressive Craniectomy versus Craniotomy for Acute Subdural Hematoma.

BACKGROUND: Traumatic acute subdural hematomas frequently warrant surgical evacuation by means of a craniotomy (bone flap replaced) or decompressive craniectomy (bone flap not replaced). Craniectomy may prevent intracranial hypertension, but whether it is associated with better outcomes is unclear. METHODS: We conducted a trial in which patients undergoing surgery for traumatic acute subdural hematoma were randomly assigned to undergo craniotomy or decompressive craniectomy. An inclusion criterion was a bone flap with an anteroposterior diameter of 11 cm or more. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOSE) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 12 months. Secondary outcomes included the GOSE rating at 6 months and quality of life as assessed by the EuroQol Group 5-Dimension 5-Level questionnaire (EQ-5D-5L). RESULTS: A total of 228 patients were assigned to the craniotomy group and 222 to the decompressive craniectomy group. The median diameter of the bone flap was 13 cm (interquartile range, 12 to 14) in both groups. The common odds ratio for the differences across GOSE ratings at 12 months was 0.85 (95% confidence interval, 0.60 to 1.18; P = 0.32). Results were similar at 6 months. At 12 months, death had occurred in 30.2% of the patients in the craniotomy group and in 32.2% of those in the craniectomy group; a vegetative state occurred in 2.3% and 2.8%, respectively, and a lower or upper good recovery occurred in 25.6% and 19.9%. EQ-5D-5L scores were similar in the two groups at 12 months. Additional cranial surgery within 2 weeks after randomization was performed in 14.6% of the craniotomy group and in 6.9% of the craniectomy group. Wound complications occurred in 3.9% of the craniotomy group and in 12.2% of the craniectomy group. CONCLUSIONS: Among patients with traumatic acute subdural hematoma who underwent craniotomy or decompressive craniectomy, disability and quality-of-life outcomes were similar with the two approaches. Additional surgery was performed in a higher proportion of the craniotomy group, but more wound complications occurred in the craniectomy group. (Funded by the National Institute for Health and Care Research; RESCUE-ASDH ISRCTN Registry number, ISRCTN87370545.).

Modifications in Macular Perfusion and Neuronal Loss After Acute Traumatic Brain Injury.

Purpose: Traumatic brain injury (TBI) causes structural damage and functional impairment in the visual system, often with retinal ganglion cell (RGC) degeneration occurring without visual symptoms. RGC degeneration is associated with reduced retinal blood-flow, however, it is not known whether reductions in perfusion precede or are secondary to neurodegeneration. Methods: We conducted a prospective observational single-center case series. Patients were included if they were admitted to the hospital after acute TBI and underwent ophthalmic clinical examination, including optical coherence tomography (OCT) and OCT angiography (OCTA) acutely and at follow-up. Ganglion cell layer thickness (GCL) thickness, vascular density in the superficial vascular plexus (SVP), and intermediate capillary plexus (ICP) were quantified. Results: Twenty-one patients aged 20 to 65 years (mean = 38 years) including 16 men and 5 women were examined less than 14 days after moderate to severe TBI, and again after 2 to 6 months. Macular structure and perfusion were normal at baseline in all patients. Visual function was abnormal at baseline in three patients and subsequent neurodegeneration and loss of perfusion corresponded to baseline visual function abnormalities. Nine patients (43%) had reduced macular GCL thickness at follow up. Perfusion in the SVP strongly associated with local GCL thickness. The strongest association of the SVP metrics was the sum of vessel density (P < 0.0001). Conclusions: In cases of reduced visual function after TBI, macular perfusion remained normal until reductions in GCL thickness occurred, indicating that perfusion changes were secondary to local GCL loss.

Cognitive Outcome After Complicated Mild Traumatic Brain Injury: A Literature Review and Meta-Analysis.

Cognitive outcome for mild traumatic brain injury (mTBI) with positive brain imaging (complicated mTBI) was compared with that for mTBI with normal imaging (uncomplicated mTBI) and with moderate to severe TBI, using meta-analysis. Twenty-three studies utilizing objective neurocognitive tests were included in the analysis. At less than 3 months post-injury, complicated mTBI was associated with poorer cognitive outcomes than uncomplicated mTBI, but deficits were not comparable to those with moderate-severe TBI. After 3 months post-injury, a similar pattern was detected. Beyond 3 months, deficits in complicated mTBI relative to those with uncomplicated mTBI were present in processing speed, memory, executive function, and language, although the latter may be the result of reduced semantic fluency. The effect size of deficits in these domains was more marked in moderate-severe TBI. The available data support the use of complicated mTBI as a distinct classification in the prediction of cognitive outcome. The extent of cognitive deficit in complicated mTBI was small and unlikely to cause significant disability. However, patients with complicated mTBI constitute a broad category encompassing individuals who may differ markedly in the nature and extent of intracranial imaging abnormality, and further studies are warranted. Limitations of the available studies include small, selected samples; variations in TBI severity classification; absence of validity ("effort") testing; differing imaging methodology; and lack of long-term follow-up.

Photobiomodulation in Acute Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Photobiomodulation (PBM) is a therapeutic modality that has gained increasing interest in neuroscience applications, including acute traumatic brain injury (TBI). Its proposed mechanisms for therapeutic effect when delivered to the injured brain include antiapoptotic and anti-inflammatory effects. This systematic review summarizes the available evidence for the value of PBM in improving outcomes in acute TBI and presents a meta-analysis of the pre-clinical evidence for neurological severity score (NSS) and lesion size in animal models of TBI. A systematic review of the literature was performed, with searches and data extraction performed independently in duplicate by two authors. Eighteen published articles were identified for inclusion: seventeen pre-clinical studies of in vivo animal models and one clinical study in human patients. The available human study supports safety and feasibility of PBM in acute moderate TBI. For pre-clinical studies, meta-analysis for NSS and lesion size were found to favor intervention versus control. Subgroup analysis based on PBM parameter variables for these outcomes was performed. Favorable parameters were identified as: wavelengths in the region of 665 nm and 810 nm; time to first administration of PBM ≤4 h; total number of daily treatments ≤3. No differences were identified between pulsed and continuous wave modes or energy delivery. Mechanistic substudies within included in vivo studies are presented and were found to support hypotheses of antiapoptotic, anti-inflammatory, and pro-proliferative effects, and a modulation of cellular metabolism. This systematic review provides substantial meta-analysis evidence of the benefits of PBM on functional and histological outcomes of TBI in in vivo mammalian models. Study design and PBM parameters should be closely considered for future human clinical studies.

External Lumbar Drainage for Refractory Intracranial Hypertension in Traumatic Brain Injury: A Systematic Review.

Considerable variation exists in the clinical practice of cerebrospinal fluid diversion for medically refractory intracranial hypertension in patients with acute traumatic brain injury (TBI), which is achievable via lumbar or ventricular drainage. This systematic review sought to compile the available evidence for the efficacy and safety of the use of lumbar drains for intracranial pressure (ICP) control. A systematic review of the literature was performed with the search and data extraction performed by two reviewers independently in duplicate. Nine independent studies were identified, enrolling 230 patients, 159 with TBI. Efficacy for ICP control was observed across all studies, with immediate and sustained effect, reducing medical therapy requirements. Lumbar drainage with medical therapy appears effective when used alone and as an adjunct to ventricular drainage. Safety reporting varied in quality. Clinical or radiological incidents of cerebral herniation (with an unclear relationship to lumbar drainage) were observed in 14/230 patients resulting in one incident of morbidity without adverse patient outcome. The available data is generally poor in quality and volume, but supportive of the efficacy of lumbar drainage for ICP control. Few reports of adverse outcomes are suggestive of, but are insufficient to confirm, the safety of use in the appropriate patient and clinical setting. Further large prospective observational studies are required to generate sufficient support of an acceptable safety profile.

Concussion in the UK: a contemporary narrative review.

Concussion has been receiving an increasing amount of media exposure following several high-profile professional sports controversies and multimillion-dollar lawsuits. The potential life-changing sequalae of concussion and the rare, but devasting, second impact syndrome have also gained much attention. Despite this, our knowledge of the pathological processes involved is limited and often extrapolated from research into more severe brain injuries. As there is no objective diagnostic test for concussion. Relying on history and examination only, the diagnosis of concussion has become the rate-limiting step in widening research into the disease. Clinical study protocols therefore frequently exclude the most vulnerable groups of patients such as those with existing cognitive impairment, concurrent intoxication, mental health issues or learning difficulties. This up-to-date narrative review aims to summarize our current concussion knowledge and provides an insight into promising avenues for future research.

Concussion in Non-athletes: Assessment of Cognition and Symptomatology (CONTACTS) study protocol - an exploratory cohort study investigating the utility of sports concussion assessment tools and salivary microRNAs to diagnose concussion in NHS patients.

INTRODUCTION: Concussion is a complex pathophysiological process with a wide range of non-specific signs and symptoms. There are currently no objective diagnostic tests to identify concussion, and diagnosis relies solely on history and examination. Recent research has identified a unique panel of microRNAs (miRNAs) that distinguish between concussed and non-concussed rugby players. This study aims to assess the diagnostic utility of salivary miRNAs in concussion for a sample of UK National Health Service patients and whether well-established sports-related concussion (SRC) assessment tools may be translated into the emergency department (ED). METHODS AND ANALYSIS: Concussion in Non-athletes: Assessment of Cognition and Symptomatology is a single-centre, prospective, two-phase cohort study. The concussed cohort will consist of participants with maxillofacial trauma and concurrent concussion. The control cohort will consist of participants with isolated limb trauma and no evidence of concussion. Participants will be recruited in the ED and saliva samples will be taken to identify the presence of miRNAs. The SRC assessments being investigated include the Sports Concussion Assessment Test, Fifth Edition (SCAT5), the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and the ImPACT Quick. Follow-up will be at 24-48 hours in-hospital and remotely via telephone and email at 14 days and 6 months. ETHICS AND DISSEMINATION: Ethical approval was granted in February 2021 by the West Midlands Coventry & Warwickshire Research Ethics Committee (ref 20/WM/0299). The investigators intend to submit their study findings for publication in peer-reviewed journals and to disseminate study findings via presentation at academic meetings. The results will also form part of a doctorate thesis, registered at the University of Birmingham.

The mechanism of action of a novel neuroprotective low molecular weight dextran sulphate: New platform therapy for neurodegenerative diseases like Amyotrophic Lateral Sclerosis.

Background: Acute and chronic neurodegenerative diseases represent an immense socioeconomic burden that drives the need for new disease modifying drugs. Common pathogenic mechanisms in these diseases are evident, suggesting that a platform neuroprotective therapy may offer effective treatments. Here we present evidence for the mode of pharmacological action of a novel neuroprotective low molecular weight dextran sulphate drug called ILB®. The working hypothesis was that ILB® acts via the activation of heparin-binding growth factors (HBGF). Methods: Pre-clinical and clinical (healthy people and patients with ALS) in vitro and in vivo studies evaluated the mode of action of ILB®. In vitro binding studies, functional assays and gene expression analyses were followed by the assessment of the drug effects in an animal model of severe traumatic brain injury (sTBI) using gene expression studies followed by functional analysis. Clinical data, to assess the hypothesized mode of action, are also presented from early phase clinical trials. Results: ILB® lengthened APTT time, acted as a competitive inhibitor for HGF-Glypican-3 binding, effected pulse release of heparin-binding growth factors (HBGF) into the circulation and modulated growth factor signaling pathways. Gene expression analysis demonstrated substantial similarities in the functional dysregulation induced by sTBI and various human neurodegenerative conditions and supported a cascading effect of ILB® on growth factor activation, followed by gene expression changes with profound beneficial effect on molecular and cellular functions affected by these diseases. The transcriptional signature of ILB® relevant to cell survival, inflammation, glutamate signaling, metabolism and synaptogenesis, are consistent with the activation of neuroprotective growth factors as was the ability of ILB® to elevate circulating levels of HGF in animal models and humans. Conclusion: ILB® releases, redistributes and modulates the bioactivity of HBGF that target disease compromised nervous tissues to initiate a cascade of transcriptional, metabolic and immunological effects that control glutamate toxicity, normalize tissue bioenergetics, and resolve inflammation to improve tissue function. This unique mechanism of action mobilizes and modulates naturally occurring tissue repair mechanisms to restore cellular homeostasis and function. The identified pharmacological impact of ILB® supports the potential to treat various acute and chronic neurodegenerative disease, including sTBI and ALS.