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Background: Cortical contusions are common in moderate-severe traumatic brain injury (TBI). Cortical contusions often expand, potentially causing neuro-worsening several hours to days post-trauma. While contusion expansion (CE) may affect outcome, potential clinical and radiological markers that can predict CE have been insufficiently explored. In the present single-center retrospective observational cohort study, we evaluated clinical outcome by the Glasgow Outcome Scale extended (GOSE) scale and evaluated risk factor for CE., Method: Adult TBI patients > 18 years of age, and of all injury severities, were included. Main variables of interest were low platelet count, defined as < 150 × 10 9 /L, presence of bifrontal contusions and CE, defined as absolute contusion volume increase in cm 3 . Factors associated with CE and clinical outcome according to GOSE were analyzed., Results: Between 2012-2022, 272 patients were included. Contusion size on admission correlated positively with CE, as did the Marshall and Rotterdam radiological classification scores. Bifrontal contusions were significantly larger at admission, experienced larger CE, and had a worse outcome than contusions in other locations. Patients with a platelet count < 150 × 10 9 /L experienced a greater volume CE and had a worse outcome when compared to patients with a normal platelet count. In a multivariate analysis, CE remained significantly associated with a poor outcome six months post- injury., Conclusion: Contusion volume at admission, Marshall CT classification and Rotterdam CT score, positively correlated to CE. Bifrontal contusions and a platelet count < 150 × 10 9 /L were associated with CE, and a poor clinical outcome. Large CE volumes were associated with a worse clinical outcome, and CE was per se associated with outcome in a multivariate analysis. Management of these risk factors for CE in the acute post-injury setting may be needed to attenuate contusion expansion and to improve clinical outcome in TBI patients suffering from cortical contusion injuries., (© 2024. The Author(s).)

Introduction: A subgroup of severe Traumatic Brain Injury (TBI) patients, known as ultra-severe (us-TBI), is most commonly defined as a post-resuscitation Glasgow Coma Scale (GCS) of 3-5. There is uncertainty on whether these critically injured patients can benefit from neurosurgical intervention., Research Question: The available evidence regarding the decision-making and outcome following management of us-TBI patients is critically reviewed., Material and Methods: Selected databases (PubMed, Google Scholar, Scopus and Cochrane Library) were searched from 1979 to May 2024 for publications on us-TBI patients, with a focus on treatment strategy, mortality and functional outcomes. Inclusion criteria were adult patients >18 years old with closed head trauma and admission post-resuscitation GCS 3-5. Studies were independently assessed for inclusion by two reviewers, and potential disagreements were solved by consensus., Results: Where such data could be extracted, mortality rate was 27-100%, and favorable outcome was observed in 4-30% of us-TBI patients. While early aggressive neurosurgical management was associated with decreased mortality, a high proportion of patients survived with unfavorable functional status., Discussion and Conclusion: With supportive care only, outcome of patients with us-TBI is almost universally poor. Early and aggressive neurosurgical intervention in addition to best medical management can lead to favorable functional outcome in selected cases particularly in younger patients with an initial GCS>3 and traumatic mass lesions. There is insufficient data regarding the effectiveness of neurosurgical management on the outcome of us-TBI patients. and the decision to initiate treatment should be based on an individual basis., Competing Interests: Not applicable. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Sports-related concussions may cause white matter injuries and persistent post-concussive symptoms (PPCS). We hypothesized that athletes with PPCS would have neurocognitive impairments and white matter abnormalities that could be revealed by advanced neuroimaging using ultra-high field strength diffusion tensor (DTI) and diffusion kurtosis (DKI) imaging metrics and cerebrospinal fluid (CSF) biomarkers. A cohort of athletes with PPCS severity limiting the ability to work/study and participate in sport school and/or social activities for ≥6 months completed 7T magnetic resonance imaging (MRI) (morphological T1-weighed volumetry, DTI and DKI), extensive neuropsychological testing, symptom rating, and CSF biomarker sampling. Twenty-two athletes with PPCS and 22 controls were included. Concussed athletes performed below norms and significantly lower than controls on all but one of the psychometric neuropsychology tests. Supratentorial white and gray matter, as well as hippocampal volumes did not differ between concussed athletes and controls. However, of the 72 examined white matter tracts, 16% of DTI and 35% of DKI metrics (in total 28%) were significantly different between concussed athletes and controls. DKI fractional anisotropy and axial kurtosis were increased, and DKI radial diffusivity and radial kurtosis decreased in concussed athletes when compared with controls. CSF neurofilament light (NfL; an axonal injury marker), although not glial fibrillary acidic protein, correlated with several diffusion metrics. In this first 7T DTI and DKI study investigating PPCS, widespread microstructural alterations were observed in the white matter, correlating with CSF markers of axonal injury. More white matter changes were observed using DKI than using DTI. These white matter alterations may indicate persistent pathophysiological processes following concussion in sport.

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood-brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [ 18 F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R 2 = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [ 18 F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion.

Introduction: Traumatic brain injury to thalamo-cortical pathways is associated with posttraumatic morbidity. Diffuse mechanical forces to white matter tracts and deep grey matter regions induce an inflammatory response and vascular damage resulting in progressive neurodegeneration. Pro-inflammatory cytokines, including interleukin-1β (IL-1β), may contribute to the link between inflammation and the injured capillary network after TBI. This study investigates whether IL-1β is a key contributor to capillary alterations and changes in pericyte coverage in the thalamus and cortex after TBI., Methods: Animals were subjected to central fluid percussion injury (cFPI), a model of TBI causing widespread axonal and vascular pathology, or sham injury and randomized to receive a neutralizing anti-IL-1β or a control, anti-cyclosporin A antibody, at 30 min post-injury. Capillary length and pericyte coverage of cortex and thalamus were analyzed by immunohistochemistry at 2- and 7-days post-injury., Results and Conclusion: Our results show that early post-injury attenuation of IL-1β dependent inflammatory signaling prevents capillary damage by increasing pericyte coverage in the thalamus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Özen, Clausen, Flygt, Marklund and Paul.)

Introduction: The American Association of Neurologic Surgeons guidelines on the management of traumatic spinal cord injury (SCI), updated in 2013, focus on spinal cord perfusion, early decompressive surgery, and venous thromboembolism (VTE) prophylaxis to improve neurological outcome., Research Question: How neurocritical care and initial management have changed with the implementation of updated management guidelines, focusing on guidelines adherence and neurological outcome., Material and Methods: Systemic physiological variables, time to neurosurgical treatment and VTE prophylaxis, and neurological outcome, were retrospectively collected from adult patients treated for cervical SCI 2001-2021., Results: Fifty-two patients were included. Mean arterial blood pressure (MAP) was significantly higher after 2013 (86±9.9 mmHg) when compared to before 2013 (79±9.9 mmHg), p = 0.041. Median time to surgery was 41 h before, and 20 h after 2013 (p = 0.029). Time to VTE prophylaxis was six days before and four days after 2013. Most neurocritical care complications were less commonly observed after 2013. Despite improved adherence to treatment goals, 44 % of MAP levels were below target, and 33% of patients were operated beyond 24h post-injury. Neurological outcome was not improved after implementation of the revised guidelines., Discussion and Conclusion: While implementation of the revised 2013 guidelines improved most aspects of the acute SCI management, many guideline targets were not met in a large subset of patients. Strict adherence to the acute neurocritical management goals, and early surgical treatment, is likely crucial when aiming to improve SCI outcome., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Niklas Marklund reports a relationship with Polarcool Inc that includes: consulting or advisory. Niklas Marklund reports a relationship with Teqcool that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Mild traumatic brain injury is common in children and it can be challenging to accurately identify those in need of urgent medical intervention. The Scandinavian guidelines for management of minor and moderate head trauma in children, the Scandinavian Neurotrauma Committee guideline 2016 (SNC16), were developed to aid in risk stratification and decision-making in Scandinavian emergency departments (EDs). This guideline has been validated externally with encouraging results, but internal validation in the intended healthcare system is warranted prior to broad clinical implementation., Objective: We aim to validate the diagnostic accuracy of the SNC16 to predict clinically important intracranial injuries (CIII) in paediatric patients suffering from blunt head trauma, assessed in EDs in Sweden and Norway., Methods and Analysis: This is a prospective, pragmatic, observational cohort study. Children (aged 0-17 years) with blunt head trauma, presenting with a Glasgow Coma Scale of 9-15 within 24 hours postinjury at an ED in 1 of the 16 participating hospitals, are eligible for inclusion. Included patients are assessed and managed according to the clinical management routines of each hospital. Data elements for risk stratification are collected in an electronic case report form by the examining doctor. The primary outcome is defined as CIII within 1 week of injury. Secondary outcomes of importance include traumatic CT findings, neurosurgery and 3-month outcome. Diagnostic accuracy of the SNC16 to predict endpoints will be assessed by point estimate and 95% CIs for sensitivity, specificity, likelihood ratio, negative predictive value and positive predictive value., Ethics and Dissemination: The study is approved by the ethical board in both Sweden and Norway. Results from this validation will be published in scientific journals, and a tailored development and implementation process will follow if the SNC16 is found safe and effective., Trial Registration Number: NCT05964764., Competing Interests: Competing interests: JU, NM and OC are members of the SNC committee, a non-profit organisation independent from financial company support, who are responsible for the SNC16 guidelines. None of the authors have any financial competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Senescence is a negative prognostic factor for outcome and recovery following traumatic brain injury (TBI). TBI-induced white matter injury may be partially due to oligodendrocyte demise. We hypothesized that the regenerative capacity of oligodendrocyte precursor cells (OPCs) declines with age. To test this hypothesis, the regenerative capability of OPCs in young [(10 weeks ±2 (SD)] and aged [(62 weeks ±10 (SD)] mice was studied in mice subjected to central fluid percussion injury (cFPI), a TBI model causing widespread white matter injury. Proliferating OPCs were assessed by immunohistochemistry for the proliferating cell nuclear antigen (PCNA) marker and labeled by 5-ethynyl-2'-deoxyuridine (EdU) administered daily through intraperitoneal injections (50 mg/kg) from day 2 to day 6 after cFPI. Proliferating OPCs were quantified in the corpus callosum and external capsule on day 2 and 7 post-injury (dpi). The number of PCNA/Olig2-positive and EdU/Olig2-positive cells were increased at 2dpi (p < .01) and 7dpi (p < .01), respectively, in young mice subjected to cFPI, changes not observed in aged mice. Proliferating Olig2+/Nestin+ cells were less common (p < .05) in the white matter of brain-injured aged mice, without difference in proliferating Olig2+/PDGFRα+ cells, indicating a diminished proliferation of progenitors with different spatial origin. Following TBI, co-staining for EdU/CC1/Olig2 revealed a reduced number of newly generated mature oligodendrocytes in the white matter of aged mice when compared to the young, brain-injured mice (p < .05). We observed an age-related decline of oligodendrogenesis following experimental TBI that may contribute to the worse outcome of elderly patients following TBI., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Introduction: Sport-related concussions (SRC) have been a concern in all sports, including soccer. The long-term effects of soccer-related head injuries are a public health concern. The Concussion in Sport Group (CISG) released a consensus statement in 2017 and several soccer governing associations have published their own SRC guidelines while referring to it but it is unclear whether this has been universally adopted., Research Question: We aimed to investigate whether guidelines published by soccer associations have any discrepancies; and the extent to which they follow the CISG recommendations., Materials and Methods: A scoping review of available soccer-specific SRC guidelines was performed via databases PubMed, Google Scholar, and official soccer association websites via web browser Google. The inclusion criteria were soccer-specific SRC guidelines. Comparisons between guidelines were made concerning the following index items: initial (on-site) assessment, removal from play, re-evaluation with neuroimaging, return-to-sport protocol, special populations, and education., Results: Nine soccer associations with available guidelines were included in this review. Guidelines obtained were from official associations in the United Kingdom, United States of America, Canada, Australia, and New Zealand. When compared to each other and the CISG recommendations, discrepancies were found within guidelines regarding the index items. Additionally, major soccer associations in some countries famous for soccer were found to have not published any publicly available guidelines., Discussion and Conclusion: SRC guidelines from different soccer associations contain discrepancies which may be detrimental to athletes, both short and long-term. We recommend that all major soccer governing associations publish guidelines that are standardised and accessible to all athletes., Competing Interests: The authors declare no financial conflicts of interest., (© 2024 The Authors.)

Background: All available recommendations about the management of antithrombotic therapies (ATs) in patients who experienced traumatic brain injury (TBI) are mainly based on expert opinion because of the lack of strength in the available evidence-based medicine. Currently, the withdrawal and the resumption of AT in these patients is empirical, widely variable, and based on the individual assessment of the attending physician. The main difficulty is to balance the thrombotic and hemorrhagic risks to improve patient outcome., Methods: Under the endorsement of the Neurotraumatology Section of Italian Society of Neurosurgery, the Italian Society for the Study about Haemostasis and Thrombosis, the Italian Society of Anaesthesia, Analgesia, Resuscitation, and Intensive Care, and the European Association of Neurosurgical Societies, a working group (WG) of clinicians completed two rounds of questionnaires, using the Delphi method, in a multidisciplinary setting. A table for thrombotic and bleeding risk, with a dichotomization in high risk and low risk, was established before questionnaire administration. In this table, the risk is calculated by matching different isolated TBI (iTBI) scenarios such as acute and chronic subdural hematomas, extradural hematoma, brain contusion (intracerebral hemorrhage), and traumatic subarachnoid hemorrhage with patients under active AT treatment. The registered indication could include AT primary prevention, cardiac valve prosthesis, vascular stents, venous thromboembolism, and atrial fibrillation., Results: The WG proposed a total of 28 statements encompassing the most common clinical scenarios about the withdrawal of antiplatelets, vitamin K antagonists, and direct oral anticoagulants in patients who experienced blunt iTBI. The WG voted on the grade of appropriateness of seven recommended interventions. Overall, the panel reached an agreement for 20 of 28 (71%) questions, deeming 11 of 28 (39%) as appropriate and 9 of 28 (32%) as inappropriate interventions. The appropriateness of intervention was rated as uncertain for 8 of 28 (28%) questions., Conclusions: The initial establishment of a thrombotic and/or bleeding risk scoring system can provide a vital theoretical basis for the evaluation of effective management in individuals under AT who sustained an iTBI. The listed recommendations can be implemented into local protocols for a more homogeneous strategy. Validation using large cohorts of patients needs to be developed. This is the first part of a project to update the management of AT in patients with iTBI., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

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., Competing Interests: No conflict of interest is to be disclosed by Salvatore Chibbaro, Thomas Sauvigny, Ivan Timofeev, Harry Mee, and Ismail Zaed. Corrado Iaccarino received educational grants from 10.13039/100009006Integra Lifescience. Franco Servadei received consultancy and speaker fees from Finceramica, Integra Life Sciences, and Upsurgeon. Silvio Franchetti received education grants producing HA., (© 2024 The Authors.)

Background: The early management of polytrauma patients with traumatic spinal cord injury (tSCI) is a major challenge. Sparse data is available to provide optimal care in this scenario and worldwide variability in clinical practice has been documented in recent studies., Methods: A multidisciplinary consensus panel of physicians selected for their established clinical and scientific expertise in the acute management of tSCI polytrauma patients with different specializations was established. The World Society of Emergency Surgery (WSES) and the European Association of Neurosurgical Societies (EANS) endorsed the consensus, and a modified Delphi approach was adopted., Results: A total of 17 statements were proposed and discussed. A consensus was reached generating 17 recommendations (16 strong and 1 weak)., Conclusions: This consensus provides practical recommendations to support a clinician's decision making in the management of tSCI polytrauma patients., (© 2024. The Author(s).)

Introduction: A blood-based biomarker (BBBM) test could help to better stratify patients with traumatic brain injury (TBI), reduce unnecessary imaging, to detect and treat secondary insults, predict outcomes, and monitor treatment effects and quality of care., Research Question: What evidence is available for clinical applications of BBBMs in TBI and how to advance this field?, Material and Methods: This narrative review discusses the potential clinical applications of core BBBMs in TBI. A literature search in PubMed, Scopus, and ISI Web of Knowledge focused on articles in English with the words "traumatic brain injury" together with the words "blood biomarkers", "diagnostics", "outcome prediction", "extracranial injury" and "assay method" alone-, or in combination., Results: Glial fibrillary acidic protein (GFAP) combined with Ubiquitin C-terminal hydrolase-L1(UCH-L1) has received FDA clearance to aid computed tomography (CT)-detection of brain lesions in mild (m) TBI. Application of S100B led to reduction of head CT scans. GFAP may also predict magnetic resonance imaging (MRI) abnormalities in CT-negative cases of TBI. Further, UCH-L1, S100B, Neurofilament light (NF-L), and total tau showed value for predicting mortality or unfavourable outcome. Nevertheless, biomarkers have less role in outcome prediction in mTBI. S100B could serve as a tool in the multimodality monitoring of patients in the neurointensive care unit., Discussion and Conclusion: Largescale systematic studies are required to explore the kinetics of BBBMs and their use in multiple clinical groups. Assay development/cross validation should advance the generalizability of those results which implicated GFAP, S100B and NF-L as most promising biomarkers in the diagnostics of TBI., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Iftakher Hossain reports financial support was provided by The Finnish medical Foundation. Peter Hutchinson reports financial support was provided by 10.13039/501100000297Royal College of Surgeons of England. Iftakher Hossain reports financial support was provided by The 10.13039/501100007417Paulo Foundation. Iftakher Hossain reports financial support was provided by The 10.13039/501100003125Finnish Cultural Foundation. Niklas Marklund reports financial support was provided by 10.13039/501100011077Skåne University Hospital ALF funds. Niklas Marklund reports financial support was provided by 10.13039/501100017237Hans-Gabriel af Trolle Wachtmeister Foundation. Niklas Marklund reports financial support was provided by Swedish 10.13039/501100003792Brain Foundation. Peter Hutchinson reports a relationship with NIHR Cambridge Clinical Research Facility, Addenbrookes Hospital that includes: funding grants., (© 2023 The Authors.)

Background: Rehabilitation is suggested to improve outcomes following traumatic brain injury (TBI), however, the extent of access to rehabilitation among TBI patients remains unclear., Objective: To examine the level of access to rehabilitation after TBI, and its association with health and sociodemographic factors., Method: We conducted a longitudinal cohort study using Swedish nationwide healthcare and sociodemographic registers. We identified 15 880 TBI patients ≥18 years hospitalized ≥3 days from 2008 to 2012 who were stratified into 3 severity groups; grade I (n = 1366; most severe), grade II (n = 5228), and grade III (n = 9268; least severe). We examined registered contacts with specialized rehabilitation or geriatric care (for patients ≥65 years) during the hospital stay, and/or within 1 year post-discharge. We performed a generalized linear model analysis to estimate the risk ratio (RR) for receiving specialized rehabilitation or geriatric care after a TBI based on sociodemographic and health factors., Results: Among TBI patients, 46/35% (grade I), 14/40% (grade II), and 5/18% (grade III) received specialized rehabilitation or geriatric care, respectively. Being currently employed or studying was positively associated (RR 1.7, 2.3), while living outside of a city area was negatively associated (RR 0.36, 0.79) with receiving specialized rehabilitation or geriatric care. Older age and a prior substance use disorder were negatively associated with receiving specialized rehabilitation (RR 0.51 and 0.81)., Conclusion: Our results suggest insufficient and unequal access to rehabilitation for TBI patients, highlighting the importance of organizing and standardizing post-TBI rehabilitation to meet the needs of patients, regardless of their age, socioeconomic status, or living area., Competing Interests: Data AvailabilityData may be obtained from a third party and are not publicly available. The Public Access to Information and Secrecy Act in Sweden prohibits us from making individual level data publicly available due to ethical concerns about identification. Researchers who are interested in replicating our work can apply for individual level data from: Statistics Sweden (mikrodata@scb.se) for data from the Total Population Register and the Longitudinal Integrated database for Health Insurance and Labour Market Studies; The National Board of Health and Welfare (registerservice@socialstyrelsen.se) for data from The Patient Register and Cause of Death Register. Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.M. is scientific advisor for PolarCool Inc, outside the submitted work. HL reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals, and Evolan Pharma AB; and sponsorship for a conference on attention-deficit/hyperactivity disorder from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work. The other authors have no competing/conflict of interests to declare.

Purpose of Review: To provide an overview of recent studies discussing novel strategies, controversies, and challenges in the management of severe traumatic brain injury (sTBI) in the initial postinjury hours., Recent Findings: Prehospital management of sTBI should adhere to Advanced Trauma Life Support (ATLS) principles. Maintaining oxygen saturation and blood pressure within target ranges on-scene by anesthetist, emergency physician or trained paramedics has resulted in improved outcomes. Emergency department (ED) management prioritizes airway control, stable blood pressure, spinal immobilization, and correction of impaired coagulation. Noninvasive techniques such as optic nerve sheath diameter measurement, pupillometry, and transcranial Doppler may aid in detecting intracranial hypertension. Osmotherapy and hyperventilation are effective as temporary measures to reduce intracranial pressure (ICP). Emergent computed tomography (CT) findings guide surgical interventions such as decompressive craniectomy, or evacuation of mass lesions. There are no neuroprotective drugs with proven clinical benefit, and steroids and hypothermia cannot be recommended due to adverse effects in randomized controlled trials., Summary: Advancement of the prehospital and ED care that include stabilization of physiological parameters, rapid correction of impaired coagulation, noninvasive techniques to identify raised ICP, emergent surgical evacuation of mass lesions and/or decompressive craniectomy, and temporary measures to counteract increased ICP play pivotal roles in the initial management of sTBI. Individualized approaches considering the underlying pathology are crucial for accurate outcome prediction., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Statistics from the Swedish Social Insurance Agency show a sharp increase in the number of sick leave cases with the diagnoses Concussion, S06.0, and Postconcussional syndrome, F07.2, between the years 2010 and 2022. The reason for the increase has not been established and needs further investigation. One possible reason is that the acute phase treatment recommendations of individuals with mild traumatic brain injury have changed during the relevant time period. Future guidelines must ensure that treatment and management recommendations are based on controlled studies of an adequate population and that treatment outcomes are continuously evaluated.

A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising ≤ 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-α, IL-15, TNF-β, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < - 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion., (© 2023. BioMed Central Ltd., part of Springer Nature.)

A sports-related concussion (SRC) is most commonly sustained in contact sports, and is defined as a mild traumatic brain injury. An exercise-induced elevation of core body temperature is associated with increased brain temperature that may accelerate secondary injury processes following SRC, and exacerbate the brain injury. In a recent pilot study, acute head-neck cooling of 29 concussed ice hockey players resulted in shorter time to return-to-play. Here, we extended the clinical trial to include players of 19 male elite Swedish ice hockey teams over five seasons (2016-2021). In the intervention teams, acute head-neck cooling was implemented using a head cap for ≥45 min in addition to the standard SRC management used in controls. The primary endpoint was time from SRC until return-to-play (RTP). Sixty-one SRCs were included in the intervention group and 71 SRCs in the control group. The number of previous SRCs was 2 (median and interquartile range [IQR]: 1.0-2.0) and 1 (IQR 1.0-2.0) in the intervention and control groups, respectively; p  = 0.293. Median time to initiate head-neck cooling was 10 min (IQR 7-15; range 5-30 min) and median duration of cooling was 45 min (IQR 45-50; range 45-70 min). The median time to RTP was 9 days in the intervention group (IQR 7.0-13.5 days) and 13 days in the control group (IQR 9-30; p  < 0.001). The proportion of players out from play for more than the expected recovery time of 14 days was 24.7% in the intervention group, and 43.7% in controls ( p  < 0.05). Study limitations include that: 1) allocation to cooling or control management was at the discretion of the medical staff of each team, decided prior to each season, and not by strict randomization; 2) no sham cap was used and evaluations could not be performed by blinded assessors; and 3) it could not be established with certainty that injury severity was similar between groups. While the results should thus be interpreted with caution, early head-neck cooling, with the aim of attenuating cerebral hyperthermia, may reduce post-SRC symptoms and lead to earlier return-to-play in elite ice hockey players.

Background: Core outcome sets (COSs) are important and necessary as they help standardize reporting in research studies. Cranioplasty following traumatic brain injury (TBI) or stroke is becoming increasingly common, leading to an ever-growing clinical and research interest, especially regarding the optimal material, cost-effectiveness, and timing of cranioplasty concerning neurological recovery and complications. Consequently, heterogeneous reporting of outcomes from such diverse studies has led to limited meta-analysis ability and an ongoing risk of outcome reporting bias. This study aims to define a standardized COS for reporting in all future TBI and stroke cranioplasty studies., Objective: This study has four aims: (1) undertake a systematic review to collate the most current outcome measures used within the cranioplasty literature; (2) undertake a qualitative study to understand better the views of clinicians, patients' relatives, and allied health professionals regarding clinical outcomes following cranioplasty; (3) undertake a Delphi survey as part of the process of gaining consensus for the COS; and (4) finalize consensus through a consensus meeting resulting in the COS., Methods: An international steering committee has been formed to guide the development of the COS. In addition, recommendations from other clinical initiatives such as COMET (Core Outcomes and Effectiveness Trials) and OMERACT (Outcome Measures in Rheumatology) have been adhered to. Phase 1 is data collection through a systematic review and qualitative study. Phase 2 is the COS development through a Delphi survey and consensus meetings with consensus definitions decided and agreed upon before the Delphi survey begins to avoid bias., Results: Phase 1 started at the end of 2019, following ethical approval in December 2019, and the project completion date is planned for the end of 2022 or beginning of 2023., Conclusions: This study should result in a consensus on a COS for cranioplasty, following TBI or stroke, to help standardize outcome reporting for future studies, which can be applied to future research and clinical services, help align future studies, build an increased understanding of cranioplasty and its impact on a patient's function and recovery, and help standardize the evidence base., International Registered Report Identifier (irrid): DERR1-10.2196/37442., (©Harry Mee, Ana M Castaño-Leon, Ivan Timofeev, Amos Adeleye, Indira Devi Bhagavatula, Niklas Marklund, Susanne Muehlschlegel, Katie Bond, Clare Clement, Kirsty Grieve, Nicola Owen, Gemma Whiting, Carole Turner, Andres Mariano Rubiano Escobar, Dhaval Shukla, Maria Paul, Judith Allanson, Valerie Pomeroy, Edoardo Viaroli, Elizabeth Warburton, Adam Wells, Gregory Hawryluk, Adel Helmy, Fahim Anwar, Stephen Honeybul, Peter Hutchinson, Angelos Kolias. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.04.2023.)

Background: A neuroinflammatory response that may lead to edema and secondary brain damage is elicited in severe traumatic brain injury (TBI). Previous studies using microdialysis (MD) membranes with 100 k Dalton (kDa) cut-off found a transient intracerebral release of cytokines and chemokines without significant correlations to clinical course, intracranial pressure (ICP) or metabolites. In this study, a (300 kDa) MD probe was used to measure the levels of cytokines and chemokines in relation to ICP and metabolites., Methods: Seven patients with severe TBI received 2 MD catheters. In four patients sufficient dialysate could be retrieved for analysis from both catheters. MD samples were analyzed bedside, then frozen and analyzed for chemokines and cytokines using a multiplex assay (Mesoscale Discovery)., Results: MD sampling was performed from 9 to 350 h. In total, 17 chemokines and cytokines were detected. Of these, IL-6, IL-8, IP-10, MCP-1 and MIP-1β were consistently elevated, and investigated further in relation to metabolites, and ICP. Levels of chemokines and cytokines were higher than previously reported from TBI patients, and partially higher than those reported in patients with cytokine release syndrome. There were no significant differences between the two catheters regarding cytokine/chemokine concentrations, except for IL-6 which was higher in the peri-contusional area. No correlation with metabolites and ICP was observed. No significant increase or decline of chemokine or cytokine secretion was observed during the study period., Conclusion: Our data suggest that cytokine and chemokine levels reflect a perpetual, potent and pan-cerebebral inflammatory response that persists beyond 15 days following TBI., (Copyright © 2023. Published by Elsevier B.V.)

Previous reports of mortality and morbidity in pediatric severe traumatic brain injury (TBI) vary considerably, with few population-based studies. Mortality rates from 3-33 % and varying morbidity have been reported, most commonly using the Extended Glasgow Outcome Scale (eGOS). The Lund concept is a treatment algorithm for severe TBI aiming at controlling intracranial pressure (ICP) by reducing cerebral perfusion pressure (CPP). The aim of the present study was to retrospectively assess mortality and morbidity in a population of pediatric TBI treated according to the Lund concept. All cases of severe pediatric TBI (age <18 years) in the southern region of Sweden during 19 years were identified. Patients were treated according to the Lund concept. Mortality, eGOS, ICP, CPP, time in the neurosurgical intensive care unit (NICU), drugs delivered and surgical procedures were recorded. Data were analyzed both by dichotomized outcomes and by ordinal statistics. A total of 135 cases of severe TBI <18 years of age were recorded (incidence 2.0/100000) and 86 patients were admitted to the tertiary NICU. Mortality including all cases was 43% (mortality rate 0.7/100,000) and in NICU 10%. Outcome was good in 60%, moderate in 25%, unfavorable in 15%, with none in a vegetative status. In both dichotomized and ordinal analyses, CPP <40 mm Hg and ICP >15 were associated with poor outcome, supporting current guidelines. However, high CPP also was associated with increased mortality and morbidity, supporting that elevated CPP might increase cerebral edema. In this study, the Lund concept resulted in low mortality and a favorable outcome in a majority of severe pediatric TBI patients; however, randomized controlled trials are warranted to verify this.

Objective: To investigate long-term survival, neurologic outcome, and quality of life in patients with spontaneous supratentorial intracerebral hemorrhage (ICH) treated with craniotomy and hematoma evacuation., Methods: A nationwide multicenter retrospective analysis of 341 patients who underwent craniotomy and evacuation of supratentorial ICH between January 1, 2011, and December 31, 2015, was performed. Baseline characteristics associated with 6-month mortality and long-term mortality were investigated. Survivors received a questionnaire about their state of health from which EuroQol 5D (EQ-5D) and modified Rankin scale (mRS) were obtained. Predictors of mortality, unfavorable outcome, and life quality were analyzed., Results: The mean follow-up time was 55.2 months. Predictors of 6-month mortality in multiple regression analysis were age ≥75 years, previous myocardial infarction, lower level of consciousness, and mechanical ventilation. Predictors of long-term mortality were higher age and mechanical ventilation. At follow-up, 49.5% of survivors had a favorable neurologic outcome (mRS ≤3). Predictors of an unfavorable functional outcome were higher age and ICH volume ≥50 mL. The mean EQ-5D health index was 0.719, and the mean EQ-5D visual analog scale score was 53.9. In multiple regression, only a higher mRS score was significantly associated with worse life quality., Conclusions: Knowledge about survival, functional outcome, and life quality as well as their predictors in this specific patient group is previously primarily described in short-term follow-up. This multicenter study provides novel information in the long-term perspective, which is important for improved surgical decision-making and prognostication., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is the leading cause of death among the young, and has an increasing incidence among the elderly. In Sweden there are 20 000 new TBI cases each year, of which most are mild. The primary impact can lead to different types of brain hemorrhages, fractures and diffuse axonal injuries. The level of consciousness is used to define injury severity. Of all TBIs,  4-5 percent require surgical intervention. The primary impact initiates injury processes exacerbating the initial brain injury, and the goal of the acute management and neurointensive care treatment is to prevent these secondary insults. Among unconscious TBI patients, monitoring of intracranial pressure and cerebral perfusion pressure (CPP, defined as the difference between the mean arterial pressure and intracranial pressure) is routine. In this article we present an overview on different types of TBI, and describe the treatment of patients in the acute setting.

Importance: The effect of a physical property of irrigation fluid (at body vs room temperature) on recurrence rate in the evacuation of chronic subdural hematoma (cSDH) needs further study., Objective: To explore whether irrigation fluid temperature has an influence on cSDH recurrence., Design, Setting, and Participants: This was a multicenter randomized clinical trial performed between March 16, 2016, and May 30, 2020. The follow-up period was 6 months. The study was conducted at 3 neurosurgical departments in Sweden. All patients older than 18 years undergoing cSDH evacuation during the study period were screened for eligibility in the study., Interventions: The study participants were randomly assigned by 1:1 block randomization to the cSDH evacuation procedure with irrigation fluid at room temperature (RT group) or at body temperature (BT group)., Main Outcomes and Measures: The primary end point was recurrence requiring reoperation within 6 months. Secondary end points were mortality, health-related quality of life, and complication frequency., Results: At 6 months after surgery, 541 patients (mean [SD] age, 75.8 [9.8] years; 395 men [73%]) had a complete follow-up according to protocol. There were 39 of 277 recurrences (14%) requiring reoperation in the RT group, compared with 16 of 264 recurrences (6%) in the BT group (odds ratio, 2.56; 95% CI, 1.38-4.66; P < .001). There were no significant differences in mortality, health-related quality of life, or complication frequency., Conclusions and Relevance: In this study, irrigation at body temperature was superior to irrigation at room temperature in terms of fewer recurrences. This is a simple, safe, and readily available technique to optimize outcome in patients with cSDH. When irrigation is used in cSDH surgery, irrigation fluid at body temperature should be considered standard of care., Trial Registration: ClincalTrials.gov Identifier: NCT02757235.

Background: Chronic subdural hematoma (cSDH) is one of the most common neurosurgical disorders and the incidence is rising. The routine treatment is neurosurgical hematoma evacuation, which is associated with recurrence rates up to 10-25%. In recent years, endovascular embolization of the middle meningeal artery (eMMA) has garnered much attention due to recurrence rates as low as < 5%. Several randomized controlled trials are planned or ongoing. In most of these trials, conventional neurosurgical treatment with or without adjunctive endovascular embolization is compared. The proposed trial aims to conduct a head-to-head comparison between neurosurgical and endovascular treatment as stand-alone treatments., Methods: The trial is academically driven and funded within existing public healthcare systems and infrastructure. Patients with uni- or bilateral cSDH, presenting with mild-to moderate symptoms, and admitted to neurosurgery on clinical grounds will be offered participation. Subjects are randomized 1:1 between conventional neurosurgical treatment (control) and endovascular embolization of the middle meningeal artery (intervention). Primary endpoint is reoperation due to clinically and/or radiologically significant recurrence within 3 months. Secondary endpoints include safety, technical success rate, neurological disability, and quality of life., Discussion: There are mounting retrospective data suggesting eMMA, as sole treatment or as an adjunctive to neurosurgery for cSDH, is safe and effective with a reoperation rate lower than neurosurgical hematoma evacuation alone. If randomized controlled trials confirm these findings, there is a potential for a paradigm shift in the treatment of cSDH where a minimally invasive procedure can replace open surgery in a large and oftentimes old and fragile patient cohort., Trial Registration: ClinicalTrials.gov, ClinicalTrials.gov Identifier NCT05267184 . Registered March 4, 2022., (© 2022. The Author(s).)

Background Context: Degenerative cervical spondylotic myelopathy (DCM) is the commonest form of spinal cord injury in adults. However, a limited number of clinical reports have assessed the role of biomarkers in DCM., Purpose: We evaluated cerebrospinal fluid (CSF) biomarkers in patients scheduled for DCM surgery and hypothesized that CSF biomarkers levels (1) would reflect the severity of preoperative neurological status; and (2) correlate with radiological appearance; and (3) correlate with clinical outcome., Study Design/setting: Prospective clinical and laboratory study., Patient Sample: Twenty-three DCM patients, aged 66.4±12.8 years and seven controls aged 45.4±5.3 years were included., Outcome Measures: The American Spinal Injury Association Impairment Scale, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire and EuroQol 5-dimensions were assessed preoperatively and at 3 months post-surgery., Methods: We measured preoperative biomarkers (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], phosphorylated neurofilament-H [pNF-H] and Ubiquitin C-terminal hydrolase L1) in CSF samples collected from patients with progressive clinical DCM who underwent surgical treatment. Biomarker concentrations in DCM patients were compared with those of cervical radiculopathy controls., Results: The median symptom duration was 10 (interquartile range 6) months. The levels of GFAP, NFL, pNF-H, Ubiquitin C-terminal hydrolase L1 were significantly higher in the DCM group compared to controls (p=.044, p=.002, p=.016, and p=.006, respectively). Higher pNF-H levels were found in patients with low signal on T1 Magnetic Resonance Imaging sequence compared to those without (p=.022, area under the receiver operating characteristic curve [AUC] 0.780, 95% Confidence Interval: 0.59-0.98). Clinical improvement following surgery correlated mainly with NFL and GFAP levels (p<.05)., Conclusions: Our results suggest that CSF biomarkers of white matter injury and astrogliosis may be a useful tool to assess myelopathy severity and predict outcome after surgery, while providing valuable information on the underlying pathophysiology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Traumas to the head and neck are common in sports and often affects otherwise healthy young individuals. Sports-related concussions (SRC), defined as a mild traumatic brain injury (mTBI), may inflict persistent neck and shoulder pain, and headache, but also more complex symptoms, such as imbalance, dizziness, and visual disturbances. These more complex symptoms are difficult to identify with standard health care diagnostic procedures., Objective: To investigate postural control in a group of former elite athletes with persistent post-concussive symptoms (PPCS) at least 6 months after the incident., Method: Postural control was examined using posturography during quiet stance and randomized balance perturbations with eyes open and eyes closed. Randomized balance perturbations were used to examine motor learning through sensorimotor adaptation. Force platform recordings were converted to reflect the energy used to maintain balance and spectrally categorized into total energy used, energy used for smooth corrective changes of posture (i.e., <0.1 Hz), and energy used for fast corrective movements to maintain balance (i.e., >0.1 Hz)., Results: The mTBI group included 20 (13 males, mean age 26.6 years) elite athletes with PPCS and the control group included 12 athletes (9 males, mean age 26.4 years) with no history of SRC. The mTBI group used significantly more energy during balance perturbations than controls: +143% total energy, p = 0.004; +122% low frequency energy, p = 0.007; and +162% high frequency energy, p = 0.004. The mTBI subjects also adapted less to the balance perturbations than controls in total (18% mTBI vs. 37% controls, p = 0.042), low frequency (24% mTBI vs. 42% controls, p = 0.046), and high frequency (6% mTBI vs. 28% controls, p = 0.040). The mTBI subjects used significantly more energy during quiet stance than controls: +128% total energy, p = 0.034; +136% low-frequency energy, p = 0.048; and +109% high-frequency energy, p = 0.015., Conclusion: Athletes with previous mTBI and PPCS used more energy to stand compared to controls during balance perturbations and quiet stance and had diminished sensorimotor adaptation. Sports-related concussions are able to affect postural control and motor learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al-Husseini, Gard, Fransson, Tegner, Magnusson, Marklund and Tjernström.)

Cerebellar dysfunction is commonly observed following traumatic brain injury (TBI). While direct impact to the cerebellum by TBI is rare, cerebellar pathology may be caused by indirect injury via cortico-cerebellar pathways. To address the hypothesis that degeneration of Purkinje cells (PCs), which constitute the sole output from the cerebellum, is linked to long-range axonal injury and demyelination, we used the central fluid percussion injury (cFPI) model of widespread traumatic axonal injury in mice. Compared to controls, TBI resulted in early PC loss accompanied by alterations in the size of pinceau synapses and levels of non-phosphorylated neurofilament in PCs. A combination of vDISCO tissue clearing technique and immunohistochemistry for vesicular glutamate transporter type 2 show that diffuse TBI decreased mossy and climbing fiber synapses on PCs. At 2 days post-injury, numerous axonal varicosities were found in the cerebellum supported by fractional anisotropy measurements using 9.4 T MRI. The disruption and demyelination of the cortico-cerebellar circuits was associated with poor performance of brain-injured mice in the beam-walk test. Despite a lack of direct input from the injury site to the cerebellum, these findings argue for novel long-range mechanisms causing Purkinje cell injury that likely contribute to cerebellar dysfunction after TBI., (© 2022. The Author(s).)

Background: Delayed cerebral ischemia (DCI), a complication of subarachnoid hemorrhage (SAH), is linked to cerebral vasospasm and associated with poor long-term outcome. We implemented a structured cerebral microdialysis (CMD) based protocol using the lactate/pyruvate ratio (LPR) as an indicator of the cerebral energy metabolic status in the neurocritical care decision making, using an LPR ≥ 30 as a cutoff suggesting an energy metabolic disturbance. We hypothesized that CMD monitoring could contribute to active, protocol-driven therapeutic interventions that may lead to the improved management of patients with SAH., Methods: Between 2018 and 2020, 49 invasively monitored patients with SAH, median Glasgow Coma Scale 11 (range 3-15), and World Federation of Neurosurgical Societies scale 4 (range 1-5) on admission receiving CMD were included. We defined a major CMD event as an LPR ≥ 40 for ≥ 2 h and a minor CMD event as an LPR ≥ 30 for ≥ 2 h., Results: We analyzed 7,223 CMD samples over a median of 6 days (5-8). Eight patients had no CMD events. In 41 patients, 113 minor events were recorded, and in 23 patients 42 major events were recorded. Our local protocols were adhered to in 40 major (95%) and 98 minor events (87%), with an active intervention in 32 (76%) and 71 (63%), respectively. Normalization of energy metabolic status (defined as four consecutive samples with LPR < 30 for minor and LPR < 40 for major events) was seen after 69% of major and 59% of minor events. The incidence of DCI-related infarcts was 10% (five patients), with only two observed in a CMD-monitored brain region., Conclusions: Active interventions were initiated in a majority of LPR events based on CMD monitoring. A low DCI incidence was observed, which may be associated with the active interventions. The potential aid of CMD in the clinical decision-making targeting DCI needs confirmation in additional SAH studies., (© 2022. The Author(s).)

Primary Objective: Traumatic brain injury (TBI) and sports-related concussion (SRC) may result in chronic functional and neuroanatomical changes. We tested the hypothesis that neuroimaging findings (cerebral blood flow (CBF), cortical thickness, and 1 H-magnetic resonance (MR) spectroscopy (MRS)) were associated to cognitive function, TBI severity, and sex., Research Design: Eleven controls, 12 athletes symptomatic following ≥3SRCs and 6 patients with moderate-severe TBI underwent MR scanning for evaluation of cortical thickness, brain metabolites (MRS), and CBF using pseudo-continuous arterial spin labeling (ASL). Cognitive screening was performed using the RBANS cognitive test battery., Main Outcomes and Results: RBANS-index was impaired in both injury groups and correlated with the injury severity, although not with any neuroimaging parameter. Cortical thickness correlated with injury severity (p = 0.02), while neuronal density, using the MRS marker ((NAA+NAAG)/Cr, did not. On multivariate analysis, injury severity (p = 0.0003) and sex (p = 0.002) were associated with CBF. Patients with TBI had decreased gray (p = 0.02) and white matter (p = 0.02) CBF compared to controls. CBF was significantly lower in total gray, white matter and in 16 of the 20 gray matter brain regions in female but not male athletes when compared to female and male controls, respectively., Conclusions: Injury severity correlated with CBF, cognitive function, and cortical thickness. CBF also correlated with sex and was reduced in female, not male, athletes. Chronic CBF changes may contribute to the persistent injury mechanisms in TBI and rSRC.

Background: Treatment options for spontaneous intracerebral hemorrhage (ICH) are limited. A possible inflammatory response in the brain tissue surrounding an ICH may exacerbate the initial injury and could be a target for treatment of subsequent secondary brain injury. The study objective was to compare levels of inflammatory mediators in the interstitial fluid of the perihemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) in the acute phase after surgical evacuation of ICH, with the hypothesis being that a difference could be demonstrated between the PHZ and the SNX., Methods: In this observational study, ten patients needing surgical evacuation of supratentorial ICH received two cerebral microdialysis catheters: one in the PHZ and one in the SNX that is remote from the ICH. The microdialysate was analyzed for energy metabolites (including lactate pyruvate ratio and glucose) and for inflammatory mediators by using a multiplex immunoassay of 27 cytokines and chemokines at 6-10 h, 20-26 h, and 44-50 h after surgery., Results: A metabolic crisis, indicated by altered energy metabolic markers, that persisted throughout the observation period was observed in the PHZ when compared with the SNX. Proinflammatory cytokines interleukin (IL) 8, tumor necrosis factor α, IL-2, IL-1β, IL-6 and interferon γ, anti-inflammatory cytokine IL-13, IL-4, and vascular endothelial growth factor A were significantly higher in PHZ compared with SNX and were most prominent at 20-26 h following ICH evacuation., Conclusions: Higher levels of both proinflammatory and anti-inflammatory cytokines in the perihemorrhagic brain tissue implies a complex role for inflammatory mediators in the secondary injury cascades following ICH surgery, suggesting a need for targeted pharmacological interventions., (© 2021. The Author(s).)

Background: Neurological and psychiatric manifestations related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are widely recognised. Standard magnetic resonance imaging (MRI) investigations are normal in 40-80% of symptomatic patients, eventually delaying appropriate treatment when MRI is unrevealing any structural changes. The aim of this study is to investigate white matter abnormalities during an early stage of post-COVID-19 (coronavirus disease 2019) encephalitis while conventional MRI was normal., Methods: A patient with post-COVID-19 autoimmune encephalitis was investigated by serial MRIs and diffusion tensor imaging (DTI). Ten healthy control individuals (HC) were utilised as a control group for the DTI analysis. Major projection, commissural and association white matter pathways were reconstructed, and multiple diffusion parameters were analysed and then compared to the HC average using a z-test for serial examinations., Results: Eleven days after the onset of neurological symptoms, DTI revealed early white matter changes, compared with HC, when standard MRI was normal. On day 68, DTI showed multiple white matter lesions compared with HC, visible at this time also by the MRI images, indicating inflammatory changes in different association and projection white matter pathways., Conclusion: We confirm a limitation in the sensitivity of conventional MRI at the acute setting of post-COVID-19 autoimmune encephalitis. A complementary DTI investigation could be a valuable diagnostic tool in early therapeutic decisions concerning COVID-19-related neurological symptoms., Competing Interests: The authors report no conflict of interest., (© 2022 The Author(s). Published by Upsala Medical Society.)

Symptoms of vestibular dysfunction such as dizziness and vertigo are common after sports-related concussions (SRC) and associated with a worse outcome and a prolonged recovery. Vestibular dysfunction after SRC can be because of an impairment of the peripheral or central neural parts of the vestibular system. The aim of the present study was to establish the cause of vestibular impairment in athletes with SRC who have persisting post-concussive symptoms (PPCS). We recruited 42 participants-21 athletes with previous SRCs and PPCS ≥6 months and 21 healthy athletic age- and sex-matched controls-who underwent symptom rating, a detailed test battery of vestibular function and 7T magnetic resonance imaging with diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) of cerebellar white matter tracts, and T1-weighted imaging for cerebellar volumetrics. Vestibular dysfunction was observed in 13 SRC athletes and three controls ( p  = 0.001). Athletes with vestibular dysfunction reported more pronounced symptoms on the Dizziness Handicap Inventory (DHI; p  < 0.001) and the Hospital Anxiety and Depression Scale (HADS; p  < 0.001). No significant differences in DTI metrics were found, while in DKI two metrics were observed in the superior and/or inferior cerebellar tracts. Cerebellar gray and white matter volumes were similar in athletes with SRC and controls. Compared with controls, pathological video head impulse test results (vHIT; p  < 0.001) and cervical vestibular evoked myogenic potentials (cVEMP; p  = 0.002) were observed in athletes with SRC, indicating peripheral vestibular dysfunction and specifically suggesting injury to the inferior vestibular nerve. In athletes with persisting symptoms after SRC, vestibular dysfunction is associated with injury to the inferior vestibular nerve.

Cerebellar dysfunction after traumatic brain injury (TBI) is commonly suspected based on clinical symptoms, although cerebellar pathology has rarely been investigated. To address the hypothesis that the cerebellar axon-myelin unit is altered by diffuse TBI, we used the central fluid percussion injury (cFPI) model in adult mice to create widespread axonal injury by delivering the impact to the forebrain. We specifically focused on changes in myelin components (myelin basic protein [MBP], 2',3'-cyclic nucleotide 3'-phosphodiesterase [CNPase], nodal/paranodal domains [neurofascin (Nfasc), ankyrin-G], and phosphorylated neurofilaments [SMI-31, SMI-312]) in the cerebellum, remote from the impact, at two, seven, and 30 days post-injury (dpi). When compared with sham-injured controls, cerebellar MBP and CNPase protein levels were decreased at 2 dpi that remained reduced up to 30 dpi. Diffuse TBI induced different effects on neuronal (Nfasc 186, Nfasc 140) and glial (Nfasc 155) neurofascin isoforms that play a key role in the assembly of the nodes of Ranvier. Expression of Nfasc 140 in the cerebellum increased at 7 dpi, in contrast to Nfasc 155 levels, which were decreased. Although neurofascin binding partner ankyrin-G protein levels decreased acutely after cFPI, its expression levels increased at 7 dpi and remained unchanged up to 30 dpi. The TBI-induced reduction in neurofilament phosphorylation (SMI-31) observed in the cerebellum was closely associated with decreased levels of the myelin proteins MBP and CNPase. This is the first evidence of temporal and spatial structural changes in the axon-myelin unit in the cerebellum, remote from the location of the impact site, in a diffuse TBI model in mice.

Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC ( p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC ( p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

Introduction: Ischemic spinal cord injury (SCI) is a serious complication of complex aortic repair. Prophylactic cerebrospinal fluid (CSF) drainage, used to decrease lumbar cerebrospinal fluid (CSF) pressure, enables monitoring of CSF biomarkers that may aid in detecting impending SCI. We hypothesized that biomarkers, previously evaluated in traumatic SCI and brain injury, would be altered in CSF over time following complex endovascular aortic repair (cEVAR)., Objectives: To examine if a chosen cohort of CSF biomarker correlates to SCI and warrants further research., Methods: A prospective observational study on patients undergoing cEVAR with extensive aortic coverage. Vital parameters and CSF samples were collected on ten occasions during 72 hours post-surgery. A panel of ten biomarkers were analyzed (Neurofilament Light Polypeptide (NFL), Tau, Glial Fibrillary Acidic Protein (GFAP), Soluble Amyloid Precursos Protein (APP) α and β, Amyloid β 38, 40 and 42 (Aβ38, 40 and 42), Chitinase-3-like protein 1 (CHI3LI or YKL-40), Heart-type fatty acid binding protein (H-FABP).)., Results: Nine patients (mean age 69, 7 males) were included. Median total aortic coverage was 68% [33, 98]. One patient died during the 30-day post-operative period. After an initial stable phase for the first few postoperative hours, most biomarkers showed an upward trend compared with baseline in all patients with >50% increase in value for NFL in 5/9 patients, in 7/9 patients for Tau and in 5/9 patients for GFAP. One patient developed spinal cord and supratentorial brain ischemia, confirmed with MRI. In this case, NF-L, GFAP and tau were markedly elevated compared with non-SCI patients (maximum increase compared with baseline in the SCI patient versus mean value of the maximal increase for all other patients: NF-L 367% vs 79%%, GFAP 95608% versus 3433%, tau 1020% vs 192%)., Conclusion: This study suggests an increase in all ten studied CSF biomarkers after coverage of spinal arteries during endovascular aortic repair. However, the pilot study was not able to establish a specific correlation between spinal fluid biomarker elevation and clinical symptoms of SCI due to small sample size and event rate., (Copyright © 2021. Published by Elsevier Inc.)

Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral artery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ischemia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals without treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.

Background: To date, there is neither any pharmacological treatment with efficacy in traumatic brain injury (TBI) nor any method to halt the disease progress. This is due to an incomplete understanding of the vast complexity of the biological cascades and failure to appreciate the diversity of secondary injury mechanisms in TBI. In recent years, techniques for high-throughput characterization and quantification of biological molecules that include genomics, proteomics, and metabolomics have evolved and referred to as omics., Methods: In this narrative review, we highlight how omics technology can be applied to potentiate diagnostics and prognostication as well as to advance our understanding of injury mechanisms in TBI., Results: The omics platforms provide possibilities to study function, dynamics, and alterations of molecular pathways of normal and TBI disease states. Through advanced bioinformatics, large datasets of molecular information from small biological samples can be analyzed in detail and provide valuable knowledge of pathophysiological mechanisms, to include in prognostic modeling when connected to clinically relevant data. In such a complex disease as TBI, omics enables broad categories of studies from gene compositions associated with susceptibility to secondary injury or poor outcome, to potential alterations in metabolites following TBI., Conclusion: The field of omics in TBI research is rapidly evolving. The recent data and novel methods reviewed herein may form the basis for improved precision medicine approaches, development of pharmacological approaches, and individualization of therapeutic efforts by implementing mathematical "big data" predictive modeling in the near future., (© 2021. The Author(s).)

Background: Compression of the greater occipital nerve (GON) may contribute to chronic headache, neck pain, and migraine in a subset of patients. We aimed to evaluate whether GON decompression could reduce pain and improve quality of life in patients with occipital neuralgia and chronic headache and neck pain., Methods: In this retrospective cohort study, selected patients with neck pain and headache referred to a single neurosurgical center were analyzed. Patients (n = 22) with suspected GON neuralgia based on nerve block or clinical criteria were included. All patients presented with occipital pain spreading frontally and to the neck in various degree. Surgical decompression was performed under local anesthesia. Follow-up was made by an assessor not involved in the treatment of the patients, by telephone 2-5 years after the surgical procedure and an interview protocol was used to collect information. The data from the follow-up protocols were then analyzed and reported., Results: When analyzing the follow-up protocols, decreased headache/migraine was reported in 77% and neck pain was reduced in 55% of the patients., Conclusions: Decompression of GON(s) may reduce neck pain and headache in selected patients with persistent headache, neck pain, and clinical signs of GON neuralgia. Based on the limitations of the present retrospective study, the results should be considered with caution., (© 2021. The Author(s).)

Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aβ) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aβ40 were lower, and tau higher when compared to the NCX. Altered levels of Aβ peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients., (© 2021. The Author(s).)

Background: Visual snow syndrome (VSS) is a neurological condition characterized by flickering dots throughout the entire visual field. Both the pathophysiology and possible location of VSS are still under debate. White matter abnormalities were investigated using diffusion tensor imaging (DTI) in a patient with VSS., Methods: A 28-year-old patient with VSS and 10 healthy controls were investigated with DTI. Diffusion parametric maps were calculated and reconstructed using q-space diffeomorphic reconstruction. White matter pathways of the dorsal, ventral, integrative visual streams and thalamic connectivity were tracked. Then, they were applied to each subject's parameter map, stretched to the same length, and sampled along the tracts for regional analyses of DTI parameters., Results: Compared with healthy controls, our patient displayed higher axial diffusivity (AD) and radial diffusivity (RD) in the dorsal visual stream (cingulum, arcuate fasciculus, horizontal indirect anterior segment of the superior longitudinal fasciculus), in the ventral visual stream (fronto-occipital fasciculus, inferior longitudinal fasciculus) and in the integrative visual stream (indirect posterior component of the superior longitudinal fasciculus, vertical occipital fasciculus). Higher AD and RD were also detected in acoustic and optic radiations, and in thalamic radiations distal to the thalamus., Conclusion: This VSS patient displayed multiple, bilateral white matter changes in the temporo-parieto-occipital junction in white matter pathways related to vision. We encourage the study of white matter pathology using DTI in complex neurological syndromes including VSS., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Traumatic brain injury and stroke result in hemiplegia, hemiparesis, and asymmetry in posture. The effects are mostly contralateral; however, ipsilesional deficits may also develop. We here examined whether ablation brain injury and controlled cortical impact (CCI), a rat model of clinical focal traumatic brain injury, both centered over the left or right sensorimotor cortex, induced hindlimb postural asymmetry (HL-PA) with contralesional or ipsilesional limb flexion. The contralesional hindlimb was flexed after left or right side ablation injury. In contrast, both the left and right CCI unexpectedly produced HL-PA with flexion on left side. The flexion persisted after complete spinal cord transection suggesting that CCI triggered neuroplastic processes in lumbar neural circuits enabling asymmetric muscle contraction. Left limb flexion was exhibited under pentobarbital anesthesia. However, under ketamine anesthesia, the body of the left and right CCI rats bent laterally in the coronal plane to the ipsilesional side suggesting that the left and right injury engaged mirror-symmetrical motor pathways. Thus, the effects of the left and right CCI on HL-PA were not mirror-symmetrical in contrast to those of the ablation brain injury, and to the left and right CCI produced body bending. Ipsilateral effects of the left CCI on HL-PA may be mediated by a lateralized motor pathway that is not affected by the left ablation injury. Alternatively, the left-side-specific neurohormonal mechanism that signals from injured brain to spinal cord may be activated by both the left and right CCI but not by ablation injury., (© 2021. The Author(s).)

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein ( APP ), microtubule associated protein tau ( MAPT ), neurofilament heavy ( NEFH ), neurofilament medium ( NEFM ), and neurofilament light ( NEFL ), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP , MAPT , NEFH , and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.

We aimed to investigate whether selective head-neck cooling could shorten recovery after sports-related concussions (SRCs). In a nonrandomized study of 15 Swedish professional ice hockey teams, 29 concussed players received immediate head and neck cooling for ≥30 min (initiated at 12.3 ± 9.2 min post-SRC by a portable cooling system), and 52 SRC controls received standard management. Players receiving head-neck cooling had shorter time to return-to-play than controls (7 vs 12.5 days, p < 0.0001), and 7% in the intervention group versus 25% in the control group were out of play for ≥3 weeks (p = 0.07). Immediate selective head-neck cooling is a promising option in the acute management of SRC that should be addressed in larger cohorts., Competing Interests: Financial & competing interests disclosure Centrum för idrottsforskning, 2020-0116. Regional funds from the Skåne University Hospital, 2018-Projekt0081. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2021 Niklas Marklund and co authors.)

Objective: Degenerative cervical spondylotic myelopathy (CSM) is a major cause of spinal cord dysfunction with an unpredictable prognosis. Βiomarkers reflecting pathophysiological processes in CSM have been insufficiently investigated. It was hypothesized that preoperative cerebrospinal fluid (CSF) biomarker levels are altered in patients with CSM and correlate with neurological status and outcome., Methods: CSF biomarkers from patients with CSM and controls were analyzed with immunoassays. Spinal cord changes were evaluated with MRI. The American Spinal Cord Injury Association Impairment Scale, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), and the EQ-5D questionnaire were applied prior to and 3 months after surgery. A p value < 0.05 was considered statistically significant., Results: Twenty consecutive CSM patients with a mean age of 67.7 ± 13 years and 63 controls with a mean age of 65.2 ± 14.5 years (p > 0.05) were included in the study. In the CSM subjects, CSF neurofilament light subunit (NF-L) and glial fibrillary acidic protein (GFAP) concentrations were higher (p < 0.05), whereas fatty acid-binding protein 3 (FABP3), soluble amyloid precursor proteins (sAPPα and sAPPβ), and amyloid β (Aβ) peptide (Aβ38, Aβ40, and Aβ42) concentrations were lower than in controls (p < 0.05). Aβ peptide levels correlated positively with symptom duration. Preoperative JOACMEQ lower extremity function and CSF NF-L levels correlated positively, and the JOACMEQ bladder function correlated negatively with sAPPα and sAPPβ (p < 0.05). CSF NF-L and FABP3 levels were higher in patients with improved outcome (EQ-5D visual analog scale difference > 20)., Conclusions: CSF biomarkers of glial and axonal damage, inflammation, and synaptic changes are altered in symptomatic CSM patients, indicating that axonal injury, astroglial activation, and Aβ dysmetabolism may be present in these individuals. These findings reflect CSM pathophysiology and may aid in prognostication. However, future studies including larger patient cohorts, postoperative biomarker data and imaging, and longer follow-up times are required to validate the present findings.