Metabolomics Profiling As a Diagnostic Tool in Severe Traumatic Brain Injury

Traumatic brain injury (TBI) is a complex disease with a multifaceted pathophysiology. Impairment of energy metabolism is a key component of secondary insults. This phenomenon is a consequence of multiple potential mechanisms including diffusion hypoxia, mitochondrial failure, and increased energy needs due to systemic trauma responses, seizures, or spreading depolarization. The degree of disturbance in brain metabolism is affected by treatment interventions and reflected in clinical patient outcome. Hence, monitoring of these secondary events in peripheral blood will provide a window into the pathophysiological course of severe TBI. New methods for assessing perturbation of brain metabolism are needed in order to monitor on-going pathophysiological processes and thus facilitate targeted interventions and predict outcome. Circulating metabolites in peripheral blood may serve as sensitive markers of pathological processes in TBI. The levels of these small molecules in blood are less dependent on the integrity of the blood–brain barrier as compared to protein biomarkers. We have recently characterized a specific metabolic profile in serum that is associated with both initial severity and patient outcome of TBI. We found that two medium-chain fatty acids, octanoic and decanoic acids, as well as several sugar derivatives are significantly associated with the severity of TBI. The top ranking peripheral blood metabolites were also highly correlated with their levels in cerebral microdialyzates. Based on the metabolite profile upon admission, we have been able to develop a model that accurately predicts patient outcome. Moreover, metabolomics profiling improved the performance of the well-established clinical prognostication model. In this review, we discuss metabolomics profiling in patients with severe TBI. We present arguments in support of the need for further development and validation of circulating biomarkers of cerebral metabolism and for their use in assessing patients with severe TBI

Tau as a fluid biomarker of concussion and neurodegeneration

Concussion is predominant among the vast number of traumatic brain injuries that occur worldwide. Difficulties in timely identification, whether concussion led to neuronal injury or not, diagnosis and the lack of prognostic tools for adequate management could lead this type of brain injury to progressive neurodegenerative diseases. Tau has been extensively studied in recent years, particularly in repetitive mild traumatic brain injuries and sports-related concussions. Tauopathies, the group of neurodegenerative diseases, have also been studied with advanced functional imaging. Nevertheless, neurodegenerative diseases, such as chronic traumatic encephalopathy, are still conclusively diagnosed at autopsy. Here, we discuss the diagnostic dilemma and the relationship between concussion and neurodegenerative diseases and review the literature on tau as a promising biomarker for concussion

How do we identify the crashing traumatic brain injury patient : the neurosurgeon's view

PURPOSE OF REVIEW: To provide an overview on recent advances in the field of assessment and monitoring of patients with severe traumatic brain injury (sTBI) in neurocritical care from a neurosurgical point of view. RECENT FINDINGS: In high-income countries, monitoring of patients with sTBI heavily relies on multimodal neurocritical parameters, nonetheless clinical assessment still has a solid role in decision-making. There are guidelines and consensus-based treatment algorithms that can be employed in both absence and presence of multimodal monitoring in the management of patients with sTBI. Additionally, novel dynamic monitoring options and machine learning-based prognostic models are introduced. Currently, the acute management and treatment of secondary injury/insults is focused on dealing with the objective evident pathology. An ongoing paradigm shift is emerging towards more proactive treatment of neuroworsening as soon as premonitory signs of deterioration are detected. SUMMARY: Based on the current evidence, serial clinical assessment, neuroimaging, intracranial and cerebral perfusion pressure and brain tissue oxygen monitoring are key components of sTBI care. Clinical assessment has a crucial role in identifying the crashing patient with sTBI, especially from a neurosurgical standpoint. Multimodal monitoring and clinical assessment should be seen as complementary evaluation methods that support one another.acceptedVersionPeer reviewe

GFAP and S100B: What You Always Wanted to Know and Never Dared to Ask

Traumatic brain injury (TBI) is a major global health issue, with outcomes spanning from intracranial bleeding, debilitating sequelae, and invalidity with consequences for individuals, families, and healthcare systems. Early diagnosis of TBI by testing peripheral fluids such as blood or saliva has been the focus of many research efforts, leading to FDA approval for a bench-top assay for blood GFAP and UCH-L1 and a plasma point-of-care test for GFAP. The biomarker S100B has been included in clinical guidelines for mTBI (mTBI) in Europe. Despite these successes, several unresolved issues have been recognized, including the robustness of prior data, the presence of biomarkers in tissues beyond the central nervous system, and the time course of biomarkers in peripheral body fluids. In this review article, we present some of these issues and provide a viewpoint derived from an analysis of existing literature. We focus on two astrocytic proteins, S100B and GFAP, the most commonly employed biomarkers used in mTBI. We also offer recommendations that may translate into a broader acceptance of these clinical tools

Changing epidemiology of traumatic brain injury among the working-aged in Finland : Admissions and neurosurgical operations

Background: Recent studies from Finland have highlighted an increase in the incidence of traumatic brain injuries (TBI) in older age groups and high overall mortality. We performed a comprehensive study on the changing epidemiology of TBI focusing on the acute events in the Finnish working-age population. Methods: Nationwide databases were searched for all emergency ward admissions with a TBI diagnosis for persons of 16–69 years of age during 2004–2018. Results: In the Finnish working-age population, there were 52,487,099 person-years, 38,810 TBI-related hospital admissions, 4664 acute neurosurgical operations (ANO), and 2247 cases of in-hospital mortality (IHM). The TBI-related hospital admission incidence was 94/100,000 person-years in men, 44/100,000 in women, and 69/100,000 overall. The incidence rate of admissions increased in women, while in men and overall, the rate decreased. The incidence rate increased in the group of 60–69 years in both genders. Lowest incidence rates were observed in the age group of 30–39 years. Occurrence risk for TBI admission was higher in men in all age groups. Trends of ANOs decreased overall, while decompressive craniectomy was the only operation type in which a rise in incidence was found. Evacuation of acute subdural hematoma was the most common ANO. Mean length of stay and IHM rate halved during the study years. Conclusions: In Finland, the epidemiology of acute working-aged TBI has significantly changed. The rates of admission incidences, ANOs, and IHM nowadays represent the lower end of the range of these acute events reported in the western world.acceptedVersionPeer reviewe

High-Risk Periods for Adult Traumatic Brain Injuries : A Nationwide Population-Based Study

Introduction: There is minimal existing available information on nationwide seasonal peaks in traumatic brain injuries (TBIs). This lack of information is an impediment to the effective development of prevention programs, societal policies, and hinders the resourcing of medical emergency services. Our current aim is to study nationwide population-based high-risk periods TBI over a 15-year study period in Finland. Methods: Nationwide databases were searched for all admissions with a TBI diagnosis and later for deaths of persons ≥16 years of age during 2004-2018. The search included all hospitals that provide acute TBI care in Finland. Results: The study period included 69,231 TBI-related hospital admissions (men = 62%). We found that for men, the highest rate of TBIs occurred on Saturdays, whereas women experience the highest rate of TBIs on Mondays. The highest rate of TBIs in men occurred in July, while women experienced the highest rate of TBIs in January. TBI-related hospital admissions (incidence risk ratio [IRR] 1.090, 95% CI 1.07-1.11, p < 0.0001) and mortality within 30 days after TBI (hazard ratio [HR] 1.057, 95% CI 1.001-1.116, p = 0.0455) were more common on public holidays and weekends than on weekdays. There was an increasing trend in the proportion of TBI-related hospital admissions occurring on public holidays and weekends from 2004 (31.5%) to 2018 (33.4%) (p = 0.0007). In summer months, TBI-related hospital admissions (IRR 1.10, 95% CI 1.08-1.12, p < 0.0001) and 30-day mortality (HR 1.069, 95% CI 1.010-1.131, p = 0.0211) were more common than in other months. TBIs occurred more often in younger and healthier individuals on these index days and times. In terms of specific public holidays, the TBI risk was overall higher on New Year's Eves and Days (IRR 1.40, 95% CI 1.25-1.58, p < 0.0001) and Midsummer's Eves and Days (IRR 1.36, 95% CI 1.20-1.54, p < 0.0001), compared to nonworking days. This finding was significant in both genders. Conclusions: TBI-related hospital admissions and mortality were more common on public holidays, weekends, and in summer months in Finland. People who sustained TBIs on these days were on average younger and healthier. The occurrence of TBIs on public holidays and weekends is increasing at an alarming rate.acceptedVersionPeer reviewe

Prognosis of patients with operated chronic subdural hematoma

Chronic subdural hematoma (cSDH), previously considered fairly benign and easy to treat, is now viewed a possible sign of incipient clinical decline. We investigated case-fatality, excess fatality and need for reoperations following operated cSDH in a nationwide setting focusing on patient-related characteristics. Finnish nationwide databases were searched for all admissions with operated cSDH as well as later deaths in adults (≥ 16 years) during 2004–2017. There were 8539 patients with an evacuated cSDH (68% men) with a mean age of 73.0 (± 12.8) years. During the follow-up, 3805 (45%) patients died. In-hospital case-fatality was 0.7% (n = 60) and 30-day case-fatality 4.2% (n = 358). The 1-year case-fatality was 14.3% (95% CI = 13.4–15.2%) among men and 15.3% (95% CI = 14.0–16.7%) among women. Comorbidity burden, older age, and alcoholism were significantly associated with fatality. One-year excess fatality rate compared to general Finnish population was 9.1% (95% CI = 8.4–9.9) among men and 10.3% (95% CI = 9.1–11.4) among women. Highest excess fatality was observed in the oldest age group in both genders. Reoperation was needed in 19.4% (n = 1588) of patients. Older age but not comorbidity burden or other patient-related characteristics were associated with increased risk for reoperation. The overall case-fatality and need for reoperations declined during the study era. Comorbidities should be considered when care and follow-up are planned in patients with cSDH. Our findings underpin the perception that the disease is more dangerous than previously thought and causes mortality in all exposed age groups: even a minor burden of comorbidities can be fatal in the post-operative period.publishedVersionPeer reviewe

Extension of Public Smoking Ban Was Not Associated with Any Immediate Effect on Stroke Occurrence in Finland

We investigated the association between the widening of a nationwide restaurant smoking ban, enacted on 1 June 2007, and stroke admissions. All acute stroke admissions between 1 May 2005 and 30 June 2009 were retrieved from a mandatory registry covering mainland Finland. Patients aged >= 18 years were included. One annual admission per patient was included. Negative binomial regression accounting for the at-risk population was applied. We found no difference in stroke occurrence before and after the smoking ban within 7 days (p = 0.217), 30 days (p = 0.176), or the whole study period (p = 0.998). Results were comparable for all stroke subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage). There was no sign of decreased occurrence in June 2007 compared to June in 2005-2006, and all subtypes of stroke occurred at least as frequently in both May and June of 2008 as in May and June of 2007. In conclusion, the nationwide restaurant smoking ban Finland enacted in June 2007 was not associated with any immediate reduction in stroke occurrence

Stroke hospitalization trends of the working-aged in Finland

BackgroundThe age-standardized incidence of stroke has decreased globally but, for reasons unknown, conflicting results have been observed regarding trend in incidence of major stroke subtypes in young adults. We studied these trends among people of working age in a population-based setting in Finland, where cardiovascular risk factor profiles have developed favorably.MethodsAll hospitalizations for stroke in 2004-2005 and 2013-2014 for persons 18-64 years of age were identified from a national register. The search included all hospitals that provide acute stroke care on mainland Finland.ResultsHospitalizations for both intracerebral hemorrhage (ICH; -15.2%; p = 0.0008) and subarachnoid hemorrhage (SAH; -26.5%; p<0.0001) decreased overall and for both sexes separately. Concerning IS, hospitalizations decreased only for men (-6.3%; p = 0.0190) but not for women or overall. However, there was an increase in IS hospitalizations in men 35-44 years of age (+37.5%; p = 0.0019). The length of stay (LOS) of IS patients declined in nearly all subgroups (overall -20.8%, p<0.0001) whereas no change in LOS was observed for patients with ICH or SAH. In-hospital mortality decreased in patients with IS (-42.8%; p = 0.0092) but remained unchanged in patients with ICH or SAH.ConclusionsStroke hospitalizations of young people declined in Finland, except for men 35-44 years of age for whom IS hospitalizations increased. Declining LOS and in-hospital mortality of IS patients suggests admission of less severe cases, improved care or both

Prognosis of patients with operated chronic subdural hematoma

Chronic subdural hematoma (cSDH), previously considered fairly benign and easy to treat, is now viewed a possible sign of incipient clinical decline. We investigated case-fatality, excess fatality and need for reoperations following operated cSDH in a nationwide setting focusing on patient-related characteristics. Finnish nationwide databases were searched for all admissions with operated cSDH as well as later deaths in adults (>= 16 years) during 2004-2017. There were 8539 patients with an evacuated cSDH (68% men) with a mean age of 73.0 (+/- 12.8) years. During the follow-up, 3805 (45%) patients died. In-hospital case-fatality was 0.7% (n = 60) and 30-day case-fatality 4.2% (n = 358). The 1-year case-fatality was 14.3% (95% CI = 13.4-15.2%) among men and 15.3% (95% CI = 14.0-16.7%) among women. Comorbidity burden, older age, and alcoholism were significantly associated with fatality. One-year excess fatality rate compared to general Finnish population was 9.1% (95% CI = 8.4-9.9) among men and 10.3% (95% CI = 9.1-11.4) among women. Highest excess fatality was observed in the oldest age group in both genders. Reoperation was needed in 19.4% (n = 1588) of patients. Older age but not comorbidity burden or other patient-related characteristics were associated with increased risk for reoperation. The overall case-fatality and need for reoperations declined during the study era. Comorbidities should be considered when care and follow-up are planned in patients with cSDH. Our findings underpin the perception that the disease is more dangerous than previously thought and causes mortality in all exposed age groups: even a minor burden of comorbidities can be fatal in the post-operative period