The diagnostic and prognostic utility of oxidative stress circulatory biomarkers in traumatic brain injury patients: a systematic review.

OBJECTIVE: The objective of this review is to qualitatively appraise the available literature to evaluate the efficacy of circulatory systemic oxidative stress markers (OSMx) in determining the diagnosis and outcome of TBI. METHODS: A systematic review was conducted of PubMed/Medline, Embase and Google Scholar databases per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) for studies which employed serum or plasma OSMx analysis for diagnostic or prognostic purposes in patients with TBI. RESULTS: Eight studies were included. There were 654 patients across the eight studies, of which 518 (79.2%) patients had sustained a TBI. The heterogeneity between studies in terms of OSMxs analyzed ultimately made collective analysis inappropriate. Nevertheless, several studies highlighted the potential role of circulatory OSMx levels in determining the diagnosis (presence and severity) and prognosis (functional outcome and mortality) of TBI. CONCLUSION: The care for patients with TBI remains a complex clinical challenge with a high morbidity and mortality profile. Evidenced by this review, circulatory OSMxs appear to have the potential to supplement current diagnostic measures, in addition to identifying new treatment strategies and monitoring recovery. Despite early promise, the evidence for such markers remains in its infancy and robust prospective studies are needed.

Arachnoid Cysts in Athletes with Sports-Related Concussion: A Case Series and Literature Review.

BACKGROUND: Arachnoid cysts (AC) are associated with a risk of rupture or haemorrhage following head impact and pose a potential predisposing factor for significant complications of sport-related concussion. Despite a recognised association between ACs and intracranial haemorrhage/cyst rupture, the risk profile of participating in contact sports with AC is not well defined. We report a retrospective case series of players presenting to the Birmingham Sports Concussion Clinic between 2017 and 2023 and underwent MRI head, with a comprehensive review of the prior literature. RESULTS: 432 athletes underwent MRI of which 11 were identified to have AC (middle fossa n = 8; posterior fossa n = 2, intraventricular n = 1). Average maximal diameter was 4.1 ± 1.2 cm. 64% had a protracted recovery (≥ 3 months). 9% experienced an AC specific complication (cyst rupture, complete neurological recovery, maximal diameter 6.5 cm, Galassi II, 4 previous concussions). 91% of patients (mean maximal diameter 3.9 ± 1.0 cm) experienced no complications despite multiple previous accumulated sports-related concussions (mean 3.3, range 1-9). Case studies from the literature are summarised (n = 63), with 98% reporting complications, none of which resulted in adverse or unfavourable neurological outcomes. Across prospective and retrospective cohort studies, 1.5% had a structural injury, and (where outcome was reported) all had a favourable outcome. CONCLUSIONS: AC is an incidental finding in athletes, with the majority in our cohort having sustained serial concussions without AC complication. The single complication within this cohort occurred in the largest AC, and AC size is proposed as a tentative factor associated with increased risk of contact sports participation. Complications of AC appear to be a rare occurrence. This case series and review has not identified evidence to suggest that participation in sports with AC is of significant risk, though individualised assessment and discussion of the potential risks of contact sports participation should be offered.

Management of Traumatic Cerebral Venous Sinus Thrombosis: A United Kingdom and Ireland Survey on Practice Variation.

Traumatic cerebral venous sinus thrombosis (tCVST) is an increasingly recognized sequela of traumatic brain injury (TBI), with skull fractures and extradural hematomas overlying venous sinuses recognized as risk factors. Although it may be treated with anticoagulation, the decision to treat tCVST is nuanced by the risk of new or worsening hemorrhage. Presently, there are no guidelines on the investigation and management of tCVST. Therefore, we conducted a UK- and Ireland-wide practice variation survey. A 17-question survey was sent via Google Forms to neurosurgeons and intensive care doctors of at least ST3 (registrar) level and above in the UK and Ireland and distributed by the Society of British Neurological Surgeons and investigators of the Sugar or Salt trial between May 9, 2023, and September 15, 2023. Data were extracted from the survey for both qualitative and quantitative analyses. There were 41 respondents to the survey, 18 (43.9%) of whom were consultant neurosurgeons. Fifty-four percent of the respondents performed a computed tomography intracranial venogram to investigate for tCVST where there was a skull fracture overlying or adjacent to a venous sinus, whereas 43.9% performed these at the time of TBI diagnosis. Around three-fourth of the respondents anticoagulate for tCVST, largely within 3 days post-TBI. A range of hemorrhagic and thrombotic complications have been observed following decisions to treat and withhold treatment of tCVST, respectively. Around two-third of the respondents conducted follow-up imaging in confirmed tCVST. None of the respondents had an established departmental protocol for the management of tCVST. This UK- and Ireland-wide survey on the management of tCVST revealed a variation in its diagnosis, treatment, and follow-up with no departmental protocol established. The optimal diagnostic pathway, management protocol, and follow-up of patients with tCVST remain unknown and should be the subject of future studies.

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.

Raman Spectroscopy as a Neuromonitoring Tool in Traumatic Brain Injury: A Systematic Review and Clinical Perspectives.

Traumatic brain injury (TBI) is a significant global health problem, for which no disease-modifying therapeutics are currently available to improve survival and outcomes. Current neuromonitoring modalities are unable to reflect the complex and changing pathophysiological processes of the acute changes that occur after TBI. Raman spectroscopy (RS) is a powerful, label-free, optical tool which can provide detailed biochemical data in vivo. A systematic review of the literature is presented of available evidence for the use of RS in TBI. Seven research studies met the inclusion/exclusion criteria with all studies being performed in pre-clinical models. None of the studies reported the in vivo application of RS, with spectral acquisition performed ex vivo and one performed in vitro. Four further studies were included that related to the use of RS in analogous brain injury models, and a further five utilised RS in ex vivo biofluid studies for diagnosis or monitoring of TBI. RS is identified as a potential means to identify injury severity and metabolic dysfunction which may hold translational value. In relation to the available evidence, the translational potentials and barriers are discussed. This systematic review supports the further translational development of RS in TBI to fully ascertain its potential for enhancing patient care.

Photobiomodulation reduces hippocampal apoptotic cell death and produces a Raman spectroscopic "signature".

Apoptotic cell death within the brain represents a significant contributing factor to impaired post-traumatic tissue function and poor clinical outcome after traumatic brain injury. After irradiation with light in the wavelength range of 600-1200 nm (photobiomodulation), previous investigations have reported a reduction in apoptosis in various tissues. This study investigates the effect of 660 nm photobiomodulation on organotypic slice cultured hippocampal tissue of rats, examining the effect on apoptotic cell loss. Tissue optical Raman spectroscopic changes were evaluated. A significantly higher proportion of apoptotic cells 62.8±12.2% vs 48.6±13.7% (P<0.0001) per region were observed in the control group compared with the photobiomodulation group. After photobiomodulation, Raman spectroscopic observations demonstrated 1440/1660 cm-1 spectral shift. Photobiomodulation has the potential for therapeutic utility, reducing cell loss to apoptosis in injured neurological tissue, as demonstrated in this in vitro model. A clear Raman spectroscopic signal was observed after apparent optimal irradiation, potentially integrable into therapeutic light delivery apparatus for real-time dose metering.

Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM).

OBJECTIVE: To investigate the role of salivary small non-coding RNAs (sncRNAs) in the diagnosis of sport-related concussion. METHODS: Saliva was obtained from male professional players in the top two tiers of England's elite rugby union competition across two seasons (2017-2019). Samples were collected preseason from 1028 players, and during standardised head injury assessments (HIAs) at three time points (in-game, post-game, and 36-48 hours post-game) from 156 of these. Samples were also collected from controls (102 uninjured players and 66 players sustaining a musculoskeletal injury). Diagnostic sncRNAs were identified with next generation sequencing and validated using quantitative PCR in 702 samples. A predictive logistic regression model was built on 2017-2018 data (training dataset) and prospectively validated the following season (test dataset). RESULTS: The HIA process confirmed concussion in 106 players (HIA+) and excluded this in 50 (HIA-). 32 sncRNAs were significantly differentially expressed across these two groups, with let-7f-5p showing the highest area under the curve (AUC) at 36-48 hours. Additionally, a combined panel of 14 sncRNAs (let-7a-5p, miR-143-3p, miR-103a-3p, miR-34b-3p, RNU6-7, RNU6-45, Snora57, snoU13.120, tRNA18Arg-CCT, U6-168, U6-428, U6-1249, Uco22cjg1,YRNA_255) could differentiate concussed subjects from all other groups, including players who were HIA- and controls, immediately after the game (AUC 0.91, 95% CI 0.81 to 1) and 36-48 hours later (AUC 0.94, 95% CI 0.86 to 1). When prospectively tested, the panel confirmed high predictive accuracy (AUC 0.96, 95% CI 0.92 to 1 post-game and AUC 0.93, 95% CI 0.86 to 1 at 36-48 hours). CONCLUSIONS: SCRUM, a large prospective observational study of non-invasive concussion biomarkers, has identified unique signatures of concussion in saliva of male athletes diagnosed with concussion.

Development and Characterization of a Probe Device toward Intracranial Spectroscopy of Traumatic Brain Injury.

Traumatic brain injury is a leading cause of mortality worldwide, often affecting individuals at their most economically active yet no primary disease-modifying interventions exist for their treatment. Real-time direct spectroscopic examination of the brain tissue within the context of traumatic brain injury has the potential to improve the understanding of injury heterogeneity and subtypes, better target management strategies and organ penetrance of pharmacological agents, identify novel targets for intervention, and allow a clearer understanding of fundamental biochemistry evolution. Here, a novel device is designed and engineered, delivering Raman spectroscopy-based measurements from the brain through clinically established cranial access techniques. Device prototyping is undertaken within the constraints imposed by the acquisition and site dimensions (standard intracranial access holes, probe's dimensions), and an artificial skull anatomical model with cortical impact is developed. The device shows a good agreement with the data acquired via a standard commercial Raman, and the spectra measured are comparable in terms of quality and detectable bands to the established traumatic brain injury model. The developed proof-of-concept device demonstrates the feasibility for real-time optical brain spectroscopic interface while removing the noise of extracranial tissue and with further optimization and in vivo validation, such technology will be directly translatable for integration into currently available standards of neurological care.

Cerebral perfusion and blood-brain barrier assessment in brain trauma using contrast-enhanced near-infrared spectroscopy with indocyanine green: A review.

Contrast-enhanced near-infrared spectroscopy (NIRS) with indocyanine green (ICG) can be a valid non-invasive, continuous, bedside neuromonitoring tool. However, its usage in moderate and severe traumatic brain injury (TBI) patients can be unprecise due to their clinical status. This review is targeted at researchers and clinicians involved in the development and application of contrast-enhanced NIRS for the care of TBI patients and can be used to design future studies. This review describes the methods developed to monitor the brain perfusion and the blood-brain barrier integrity using the changes of diffuse reflectance during the ICG passage and the results on studies in animals and humans. The limitations in accuracy of these methods when applied on TBI patients and the proposed solutions to overcome them are discussed. Finally, the analysis of relative parameters is proposed as a valid alternative over absolute values to address some current clinical needs in brain trauma care. In conclusion, care should be taken in the translation of the optical signal into absolute physiological parameters of TBI patients, as their clinical status must be taken into consideration. Discussion on where and how future studies should be directed to effectively incorporate contrast-enhanced NIRS into brain trauma care is given.

Rapid optofluidic detection of biomarkers for traumatic brain injury via surface-enhanced Raman spectroscopy.

Current technologies for the point-of-care diagnosis of traumatic brain injury (TBI) lack sensitivity, require specialist handling or involve complicated and costly procedures. Here, we report the development and testing of an optofluidic device for the rapid and label-free detection, via surface-enhanced Raman scattering (SERS), of picomolar concentrations of biomarkers for TBI in biofluids. The SERS-active substrate of the device consists of electrohydrodynamically fabricated submicrometre pillars covered with a plasmon-active nanometric gold layer, integrated in an optofluidic chip. We show that the device can detect N-acetylasparate in finger-prick blood samples from patients with TBI, and that the biomarker is released immediately from the central nervous system after TBI. The simplicity, sensitivity and robustness of SERS-integrated optofluidic technology might eventually help the triaging of TBI patients and assist clinical decision making at point-of-care settings.

Differential Expression of Circulating Inflammatory Proteins Following Sport-Related Traumatic Brain Injury.

Sport-related traumatic brain injury (TBI) elicits a multifaceted inflammatory response leading to brain injury and morbidity. This response could be a predictive tool for the progression of TBI and to stratify the injury of which mild TBI is most prevalent. Therefore, we examined the differential expression of serum inflammatory markers overtime and identified novel markers in repetitively concussed athletes. Neuropsychological assessment by Wechsler Adult Intelligence Scale (WAIS) and Immediate Post Concussion Assessment and Cognitive Test (ImPACT) was performed on rugby players and serum was taken from healthy, concussed and repetitively concussed athletes. Serum was also obtained <1 week and >1 week after trauma and analyzed for 92 inflammatory protein markers. Fibroblast growth factor 21 (FGF21) and interleukin-7 (IL-7) differentiated repetitively concussed athletes. Macrophage chemotactic protein-1 (MCP-1), tumor necrosis factor superfamily member 14 (TNFSF14) were significantly reduced >1 week and chemokine (C-X3-C motif) ligand 1 (CX3CL1) upregulated <1 week after injury. FGF21 and MCP-1 negatively correlated with symptoms and their severity. We have identified dynamic changes in the inflammatory response overtime and in different classes of concussion correlating with disease progression. This data supports the use of inflammatory biomarkers as predictors of symptom development due to secondary complications of sport-related mTBI.

Investigation into repetitive concussion in sport (RECOS): study protocol of a prospective, exploratory, observational cohort study.

INTRODUCTION: Sport-related concussion management remains a diagnostic dilemma to clinicians in all strata of care, coaching staff and players alike. The lack of objective diagnostic and prognostic biomarkers and over-reliance on subjective clinical assessments carries a significant health risk of undiagnosed concussive episodes and early return to play before full recovery increasing the risk of sustaining additional concussion, and leading to long-term sequelae and/or unfavourable outcome. OBJECTIVE: To identify a set of parameters (neuroimaging with neurophysiological, biological and neuropsychological tests) that may support pitch-side and outpatient clinical decision-making in order to objectively diagnose concussion, determine the severity of injury, guide a safe return to play and identify the potential predictors of the long-term sequelae of concussion. METHODS AND ANALYSIS: An exploratory, observational, prospective, cohort study recruiting between 2017 and 2020. The participants will have a baseline preseason screening (brain imaging, neuropsychological assessments, serum, urine and saliva sampling). If a screened player later suffers a concussion and/or multiple concussions then he/she will be assessed again with the same protocol within 72 hours, and their baseline data will be used as internal control as well as normative data. Inferential statistical analysis will be performed to determine correlations between biological, imaging techniques and neuropsychological assessments. ETHICS AND DISSEMINATION: This study was approved by the East of England-Essex Research Ethics Committee on 22 September 2017-REC 17/EE/0275; IRAS 216703. The results of this study will be presented at national and international conferences and submitted for publication in peer reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN16974791; Pre-results.

Study of Concussion in Rugby Union through MicroRNAs (SCRUM): a study protocol of a prospective, observational cohort study.

INTRODUCTION: The diagnosis of mild traumatic brain injury or sports-related concussion is a challenge for all clinicians, players, coaches and parents involved in contact sports. Currently, there is no validated objective biomarker available to assess the presence or severity of concussion in sport, and so it is necessary to rely on subjective measures like self-reporting of symptoms which depend on the cooperation of the athlete. There is a significant health risk associated with repetitive injury if the diagnosis is missed, and so there is great value in an objective biomarker to assist diagnostic and prognostic decisions. OBJECTIVE: To establish a panel of non-invasive MicroRNA biomarkers in urine and saliva for the rapid diagnosis of sports-related concussion and investigate the kinetics and clinical utility of these biomarkers in assisting diagnostic, prognostic and return-to-play decisions. METHODS AND ANALYSIS: Observational, prospective, multicentre cohort study recruiting between the 2017-2018 and 2018-2019 Rugby Union seasons. Professional rugby players in the two highest tiers of senior professional domestic rugby competition in England will be recruited prospectively to the study. During the season, three groups will be identified: athletes entering the World Rugby Head Injury Assessment (HIA) protocol, uninjured control athletes and control athletes with musculoskeletal injuries. Saliva and urine will be collected from these athletes at multiple timepoints, coinciding with key times in the HIA protocol and return-to-play process. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The compiled and analysed results will be presented at national and international conferences concerning the care of patients with traumatic brain injury. Results will also be submitted for peer review and publication in the subject journals/literature.

Endotheliopathy of Trauma is an on-Scene Phenomenon, and is Associated with Multiple Organ Dysfunction Syndrome: A Prospective Observational Study.

BACKGROUND: Trauma patients are vulnerable to coagulopathy and inflammatory dysfunction associated with endotheliopathy of trauma (EoT). In vitro evidence has suggested that tranexamic acid (TXA) may ameliorate endotheliopathy. We aimed to investigate how soon after injury EoT occurs, its association with multiple organ dysfunction syndrome (MODS), and whether TXA ameliorates it. METHODS: A prospective observational study included 91 trauma patients enrolled within 60 min of injury and 19 healthy controls. Blood was sampled on enrolment and again 4 to 12 h later. ELISAs measured serum concentrations of syndecan-1 and thrombomodulin as biomarkers of EoT. MODS was compared between groups according to biomarker dynamics: persistently abnormal; abnormal to normal; and persistently normal. Timing of EoT was estimated by plotting biomarker data against time, and then fitting generalized additive models. Biomarker dynamics were compared between those who did or did not receive prehospital TXA. RESULTS: Median age was 38 (interquartile range [IQR] 24-55) years; 78 of 91 were male. Median injury severity score (ISS) was 22 (IQR 12-36). EoT was estimated to occur at 5 to 8 min after injury. There were no significant differences in ISS between those with or without prehospital EoT. Forty-two patients developed MODS; 31 of 42 with persistently abnormal; 8 of 42 with abnormal to normal; and 3 of 42 with persistently normal biomarkers; P < 0.05. There were no significant differences between TXA and non-TXA groups. CONCLUSIONS: EoT was present at the scene of injury. MODS was more likely when biomarkers of EoT were persistently raised. There were no significant differences between TXA and non-TXA groups. Prehospital interventions aimed at endothelial restoration may represent a clinically meaningful target for prehospital resuscitation.

Vitamin D Deficiency in Traumatic Brain Injury and Its Relationship with Severity of Injury and Quality of Life: A Prospective, Observational Study.

This single-center prospective observational study aims to describe the prevalence of vitamin D deficiency (VDD) in the traumatic brain injury (TBI) population and identify any relationship between vitamin D and severity of head injury or quality of life. One hundred twenty-four TBI patients had serum vitamin D (25-OHD) levels measured at the local post-TBI endocrine screening clinic over 20 months. Quality of Life after Brain Injury questionnaires were completed by the patient concurrently. A multivariate regressional analysis was performed, controlling for age, season, ethnicity, time since injury, TBI severity, and gender. A total of 34% (n = 42) of the cohort were vitamin D deficient (25-OHD <25 nmol/L), with a further 23% (n = 29) having insufficient levels (25-OHD 25-50 nmol/L). Vitamin D was significantly lower in patients with severe TBI than in patients with mild TBI (n = 95; p = 0.03; confidence interval [CI] 95% -23.60 to -1.21; mean effect size 12.40 nmol/L). There was a trend for self-reported quality of life to be better in patients with optimum vitamin D levels than in patients with deficient vitamin D levels, controlling for severity of injury (n = 81; p = 0.05; CI 95% -0.07 to 21.27). This is the first study to identify a significant relationship between vitamin D levels and severity of head injury. Clinicians should actively screen for and treat VDD in head-injured patients to reduce the risk of further morbidity, such as osteomalacia and cardiovascular disease. Future research should establish the natural history of vitamin D levels following TBI to identify at which stage VDD develops and whether vitamin D replacement could have a beneficial effect on recovery and quality of life.

Near-Infrared Spectroscopy in the Monitoring of Adult Traumatic Brain Injury: A Review.

Cerebral near-infrared spectroscopy (NIRS) has long represented an exciting prospect for the noninvasive monitoring of cerebral tissue oxygenation and perfusion in the context of traumatic brain injury (TBI), although uncertainty still exists regarding the reliability of this technology specifically within this field. We have undertaken a review of the existing literature relating to the application of NIRS within TBI. We discuss current "state-of-the-art" NIRS monitoring, provide a brief background of the technology, and discuss the evidence regarding the ability of NIRS to substitute for established invasive monitoring in TBI.

A novel series of benzimidazole NR2B-selective NMDA receptor antagonists.

A series of novel benzimidazoles are discussed as NR2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists. High throughput screening (HTS) efforts identified a number of potent and selective NR2B antagonists such as 1. Exploration of the substituents around the core of this template identified a number of compounds with high potency for NR2B (pIC(50) >7) and good selectivity against the NR2A subunit (pIC(50) <4.3) as defined by FLIPR-Ca(2+) and radioligand binding studies. These agents offer potential for the development of therapeutics for a range of nervous system disorders including chronic pain, neurodegeneration, migraine and major depression.

Synthesis and structure-activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor.

High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.