Recent advances in traumatic brain injury Khellaf, Abdelhakim; Khan, Danyal Zaman; Helmy, Adel
Journal of neurology,
11/2019, Letnik:
266, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Traumatic brain injury (TBI) is the most common cause of death and disability in those aged under 40 years in the UK. Higher rates of morbidity and mortality are seen in low-income and middle-income ...countries making it a global health challenge. There has been a secular trend towards reduced incidence of severe TBI in the first world, driven by public health interventions such as seatbelt legislation, helmet use, and workplace health and safety regulations. This has paralleled improved outcomes following TBI delivered in a large part by the widespread establishment of specialised neurointensive care. This update will focus on three key areas of advances in TBI management and research in moderate and severe TBI: refining neurointensive care protocolized therapies, the recent evidence base for decompressive craniectomy and novel pharmacological therapies. In each section, we review the developing evidence base as well as exploring future trajectories of TBI research.
Traumatic brain injury (TBI) is a leading cause of morbidity and disability, with a considerable socioeconomic burden. Heterogeneity of pathoanatomical subtypes and diversity in the pathogenesis and ...extent of injury contribute to differences in the course and outcome of TBI. Following the primary injury, extensive and lasting damage is sustained through a complex cascade of events referred to as “secondary injury.” Neuroinflammation is proposed as an important manipulable aspect of secondary injury in animal and human studies. Because neuroinflammation can be detrimental or beneficial, before developing immunomodulatory therapies, it is necessary to better understand the timing and complexity of the immune responses that follow TBI. With a rapidly increasing body of literature, there is a need for a clear summary of TBI neuroimmunology. This review presents our current understanding of the immune response to TBI in a chronological and compartment-based manner, highlighting early changes in gene expression and initial signaling pathways that lead to activation of innate and adaptive immunity. Based on recent advances in our understanding of innate immune cell activation, we propose a new paradigm to study innate immune cells following TBI that moves away from the existing M1/M2 classification of activation states toward a stimulus- and disease-specific understanding of polarization state based on transcriptomic and proteomic profiling.
•Traumatic brain injury (TBI) is a leading cause of morbidity and disability•Neuroinflammation is an important manipulable aspect of secondary injury following TBI•A sterile immune response develops within minutes of TBI and has lasting effects•A new paradigm that moves away from the M1/M2 classification is needed
Jassam et al. review advances in the role of neuroinflammation in traumatic brain injury (TBI) in a chronological and compartment-based manner. The authors propose a new paradigm that moves away from the existing M1/M2 approach to classify microglia in TBI toward a proteomics- and transcriptomics-based approach.
The burden of traumatic brain injury (TBI) poses a large public health and societal problem, but the characteristics of patients and their care pathways in Europe are poorly understood. We aimed to ...characterise patient case-mix, care pathways, and outcomes of TBI.
CENTER-TBI is a Europe-based, observational cohort study, consisting of a core study and a registry. Inclusion criteria for the core study were a clinical diagnosis of TBI, presentation fewer than 24 h after injury, and an indication for CT. Patients were differentiated by care pathway and assigned to the emergency room (ER) stratum (patients who were discharged from an emergency room), admission stratum (patients who were admitted to a hospital ward), or intensive care unit (ICU) stratum (patients who were admitted to the ICU). Neuroimages and biospecimens were stored in repositories and outcome was assessed at 6 months after injury. We used the IMPACT core model for estimating the expected mortality and proportion with unfavourable Glasgow Outcome Scale Extended (GOSE) outcomes in patients with moderate or severe TBI (Glasgow Coma Scale GCS score ≤12). The core study was registered with ClinicalTrials.gov, number NCT02210221, and with Resource Identification Portal (RRID: SCR_015582).
Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum. In the ICU stratum, 720 (36%) patients had mild TBI (GCS score 13–15). Compared with the core cohort, the registry had a higher proportion of patients in the ER (9839 43%) and admission (8571 38%) strata, with more than 95% of patients classified as having mild TBI. Patients in the core study were older than those in previous studies (median age 50 years IQR 30–66, 1254 28% aged >65 years), 462 (11%) had serious comorbidities, 772 (18%) were taking anticoagulant or antiplatelet medication, and alcohol was contributory in 1054 (25%) TBIs. MRI and blood biomarker measurement enhanced characterisation of injury severity and type. Substantial inter-country differences existed in care pathways and practice. Incomplete recovery at 6 months (GOSE <8) was found in 207 (30%) patients in the ER stratum, 665 (53%) in the admission stratum, and 1547 (84%) in the ICU stratum. Among patients with moderate-to-severe TBI in the ICU stratum, 623 (55%) patients had unfavourable outcome at 6 months (GOSE <5), similar to the proportion predicted by the IMPACT prognostic model (observed to expected ratio 1·06 95% CI 0·97–1·14), but mortality was lower than expected (0·70 0·62–0·76).
Patients with TBI who presented to European centres in the core study were older than were those in previous observational studies and often had comorbidities. Overall, most patients presented with mild TBI. The incomplete recovery of many patients should motivate precision medicine research and the identification of best practices to improve these outcomes.
European Union 7th Framework Programme, the Hannelore Kohl Stiftung, OneMind, and Integra LifeSciences Corporation.
Summary Severe traumatic brain injury (TBI) is currently managed in the intensive care unit with a combined medical–surgical approach. Treatment aims to prevent additional brain damage and to ...optimise conditions for brain recovery. TBI is typically considered and treated as one pathological entity, although in fact it is a syndrome comprising a range of lesions that can require different therapies and physiological goals. Owing to advances in monitoring and imaging, there is now the potential to identify specific mechanisms of brain damage and to better target treatment to individuals or subsets of patients. Targeted treatment is especially relevant for elderly people—who now represent an increasing proportion of patients with TBI—as preinjury comorbidities and their therapies demand tailored management strategies. Progress in monitoring and in understanding pathophysiological mechanisms of TBI could change current management in the intensive care unit, enabling targeted interventions that could ultimately improve outcomes.
Traumatic brain injury (TBI) presents in various forms ranging from mild alterations of consciousness to an unrelenting comatose state and death. In the most severe form of TBI, the entirety of the ...brain is affected by a diffuse type of injury and swelling. Treatment modalities vary extensively based on the severity of the injury and range from daily cognitive therapy sessions to radical surgery such as bilateral decompressive craniectomies. Guidelines have been set forth regarding the optimal management of TBI, but they must be taken in context of the situation and cannot be used in every individual circumstance. In this review article, we have summarized the current status of treatment for TBI in both clinical practice and basic research. We have put forth a brief overview of the various subtypes of traumatic injuries, optimal medical management, and both the noninvasive and invasive monitoring modalities, in addition to the surgical interventions necessary in particular instances. We have overviewed the main achievements in searching for therapeutic strategies of TBI in basic science. We have also discussed the future direction for developing TBI treatment from an experimental perspective.
Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are ...emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome. Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer's disease), and as theranostic tools in pre-clinical and clinical settings. Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.
OBJECTIVETo determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) ...estimates of traumatic axonal injury (TAI).
METHODSParticipants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury.
RESULTSIn athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve AUROC 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = −0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI.
CONCLUSIONSSerum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.
OBJECTIVETo determine whether neurofilament light (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin C-terminal hydrolase-L1 (UCH-L1) measured in serum relate to traumatic brain injury ...(TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) measures of traumatic axonal injury (TAI) in patients with TBI.
METHODSPatients with TBI (n = 162) and controls (n = 68) were prospectively enrolled between 2011 and 2019. Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days, and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury.
RESULTSAt enrollment, patients with TBI had increased serum NfL compared to controls (p < 0.0001). Serum NfL decreased over the course of 5 years but remained significantly elevated compared to controls. Serum NfL at 30 days distinguished patients with mild, moderate, and severe TBI from controls with an area under the receiver-operating characteristic curve (AUROC) of 0.84, 0.92, and 0.92, respectively. At enrollment, serum GFAP was elevated in patients with TBI compared to controls (p < 0.001). GFAP showed a biphasic release in serum, with levels decreasing during the first 6 months of injury but increasing over the subsequent study visits. The highest AUROC for GFAP was measured at 30 days, distinguishing patients with moderate and severe TBI from controls (both 0.89). Serum tau and UCH-L1 showed weak associations with TBI severity and neuroimaging measures. Longitudinally, serum NfL was the only biomarker that was associated with the likely rate of MRI brain atrophy and DTI measures of progression of TAI.
CONCLUSIONSSerum NfL shows greater diagnostic and prognostic utility than GFAP, tau, and UCH-L1 for subacute and chronic TBI.
CLASSIFICATION OF EVIDENCEThis study provides Class III evidence that serum NfL distinguishes patients with mild TBI from healthy controls.
IMPORTANCE: After severe traumatic brain injury, induction of prophylactic hypothermia has been suggested to be neuroprotective and improve long-term neurologic outcomes. OBJECTIVE: To determine the ...effectiveness of early prophylactic hypothermia compared with normothermic management of patients after severe traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS: The Prophylactic Hypothermia Trial to Lessen Traumatic Brain Injury–Randomized Clinical Trial (POLAR-RCT) was a multicenter randomized trial in 6 countries that recruited 511 patients both out-of-hospital and in emergency departments after severe traumatic brain injury. The first patient was enrolled on December 5, 2010, and the last on November 10, 2017. The final date of follow-up was May 15, 2018. INTERVENTIONS: There were 266 patients randomized to the prophylactic hypothermia group and 245 to normothermic management. Prophylactic hypothermia targeted the early induction of hypothermia (33°C-35°C) for at least 72 hours and up to 7 days if intracranial pressures were elevated, followed by gradual rewarming. Normothermia targeted 37°C, using surface-cooling wraps when required. Temperature was managed in both groups for 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES: The primary outcome was favorable neurologic outcomes or independent living (Glasgow Outcome Scale–Extended score, 5-8 scale range, 1-8) obtained by blinded assessors 6 months after injury. RESULTS: Among 511 patients who were randomized, 500 provided ongoing consent (mean age, 34.5 years SD, 13.4; 402 men 80.2%) and 466 completed the primary outcome evaluation. Hypothermia was initiated rapidly after injury (median, 1.8 hours IQR, 1.0-2.7 hours) and rewarming occurred slowly (median, 22.5 hours IQR, 16-27 hours). Favorable outcomes (Glasgow Outcome Scale–Extended score, 5-8) at 6 months occurred in 117 patients (48.8%) in the hypothermia group and 111 (49.1%) in the normothermia group (risk difference, 0.4% 95% CI, –9.4% to 8.7%; relative risk with hypothermia, 0.99 95% CI, 0.82-1.19; P = .94). In the hypothermia and normothermia groups, the rates of pneumonia were 55.0% vs 51.3%, respectively, and rates of increased intracranial bleeding were 18.1% vs 15.4%, respectively. CONCLUSIONS AND RELEVANCE: Among patients with severe traumatic brain injury, early prophylactic hypothermia compared with normothermia did not improve neurologic outcomes at 6 months. These findings do not support the use of early prophylactic hypothermia for patients with severe traumatic brain injury. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00987688; Anzctr.org.au Identifier: ACTRN12609000764235
•Sex is an understudied variable in TBI research.•Sex and hormonal status at time of injury influence different outcome measures.•Female mice show a stronger brain inflammation response acutely ...post-TBI than males.•Female sex hormone treatment can improve certain TBI aspects in preclinical models.•More research into sex differences will enable better treatment strategies for TBI.
Traumatic brain injury (TBI) has historically been viewed as a primarily male problem, since men are more likely to experience a TBI because of more frequent participation in activities that increase risk of head injuries. This male bias is also reflected in preclinical research where mostly male animals have been used in basic and translational science. However, with an aging population in which TBI incidence is increasingly sex-independent due to falls, and increasing female participation in high-risk activities, the attention to potential sex differences in TBI responses and outcomes will become more important. These considerations are especially relevant in designing preclinical animal models of TBI that are more predictive of human responses and outcomes. This review characterizes sex differences following TBI with a special emphasis on the contribution of the female sex hormones, progesterone and estrogen, to these differences. This information is potentially important in developing and customizing TBI treatments.
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