Lesion Frequency Distribution Maps of Traumatic Axonal Injury on Early Magnetic Resonance Imaging After Moderate and Severe Traumatic Brain Injury and Associations to 12 Months Outcome.

Traumatic axonal injury (TAI) is a common finding on magnetic resonance imaging (MRI) in patients with moderate-severe traumatic brain injury (TBI), and the burden of TAI is associated with outcome in this patient group. Lesion mapping offers a way to combine imaging findings from numerous individual patients into common lesion maps where the findings from a whole patient cohort can be assessed. The aim of this study was to evaluate the spatial distribution of TAI lesions on different MRI sequences and its associations to outcome with use of lesion mapping. Included prospectively were 269 patients (8-70 years) with moderate or severe TBI and MRI within six weeks after injury. The TAI lesions were evaluated and manually segmented on fluid-attenuated inversed recovery (FLAIR), diffusion weighted imaging (DWI), and either T2* gradient echo (T2*GRE) or susceptibility weighted imaging (SWI). The segmentations were registered to the Montreal Neurological Institute space and combined to lesion frequency distribution maps. Outcome was assessed with Glasgow Outcome Scale Extended (GOSE) score at 12 months. The frequency and distribution of TAI was assessed qualitatively by visual reading. Univariable associations to outcome were assessed qualitatively by visual reading and also quantitatively with use of voxel-based lesion-symptom mapping (VLSM). The highest frequency of TAI was found in the posterior half of corpus callosum. The frequency of TAI was higher in the frontal and temporal lobes than in the parietal and occipital lobes, and in the upper parts of the brainstem than in the lower. At the group level, all voxels in mesencephalon had TAI on FLAIR. The patients with poorest outcome (GOSE scores ≤4) had higher frequencies of TAI. On VLSM, poor outcome was associated with TAI lesions bilaterally in the splenium, the right side of tectum, tegmental mesencephalon, and pons. In conclusion, we found higher frequency of TAI in posterior corpus callosum, and TAI in splenium, mesencephalon, and pons were associated with poor outcome. If lesion frequency distribution maps containing outcome information based on imaging findings from numerous patients in the future can be compared with the imaging findings from individual patients, it would offer a new tool in the clinical workup and outcome prediction of the patient with TBI.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI.

BACKGROUND: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury. METHODS: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers. RESULTS: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1ß and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+). CONCLUSIONS: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Frequency and predictors of headache in the first 12 months after traumatic brain injury: results from CENTER-TBI.

BACKGROUND: Headache is a prevalent and debilitating symptom following traumatic brain injury (TBI). Large-scale, prospective cohort studies are needed to establish long-term headache prevalence and associated factors after TBI. This study aimed to assess the frequency and severity of headache after TBI and determine whether sociodemographic factors, injury severity characteristics, and pre- and post-injury comorbidities predicted changes in headache frequency and severity during the first 12 months after injury. METHODS: A large patient sample from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study was used. Patients were stratified based on their clinical care pathway: admitted to an emergency room (ER), a ward (ADM) or an intensive care unit (ICU) in the acute phase. Headache was assessed using a single item from the Rivermead Post-Concussion Symptoms Questionnaire measured at baseline, 3, 6 and 12 months after injury. Mixed-effect logistic regression analyses were applied to investigate changes in headache frequency and associated predictors. RESULTS: A total of 2,291 patients responded to the headache item at baseline. At study enrolment, 59.3% of patients reported acute headache, with similar frequencies across all strata. Female patients and those aged up to 40 years reported a higher frequency of headache at baseline compared to males and older adults. The frequency of severe headache was highest in patients admitted to the ICU. The frequency of headache in the ER stratum decreased substantially from baseline to 3 months and remained from 3 to 6 months. Similar trajectory trends were observed in the ICU and ADM strata across 12 months. Younger age, more severe TBI, fatigue, neck pain and vision problems were among the predictors of more severe headache over time. More than 25% of patients experienced headache at 12 months after injury. CONCLUSIONS: Headache is a common symptom after TBI, especially in female and younger patients. It typically decreases in the first 3 months before stabilising. However, more than a quarter of patients still experienced headache at 12 months after injury. Translational research is needed to advance the clinical decision-making process and improve targeted medical treatment for headache. TRIAL REGISTRATION: ClinicalTrials.gov NCT02210221.

Improvement in Functional Outcome from 6 to 12 Months After Moderate and Severe Traumatic Brain Injury Is Frequent, But May Not Be Detected With the Glasgow Outcome Scale Extended.

The aims of this study were (1) to report outcome and change in outcome in patients with moderate and severe traumatic brain injury (mo/sTBI) between 6 and 12 months post-injury as measured by the Glasgow Outcome Scale Extended (GOSE), (2) to explore if demographic/injury-related variables can predict improvement in GOSE score, and (3) to investigate rate of improvement in Disability Rating Scale (DRS) score, in patients with a stable GOSE. All surviving patients ≥16 years of age who were admitted with mo/sTBI (Glasgow Coma Scale [GCS] score ≤13) to the regional trauma center in Central Norway between 2004 and 2019 were prospectively included (n = 439 out of 503 eligible). GOSE and DRS were used to assess outcome. Twelve-months post-injury, 13% with moTBI had severe disability (GOSE 2-4) versus 27% in sTBI, 26% had moderate disability (GOSE 5-6) versus 41% in sTBI and 62% had good recovery (GOSE 7-8) versus 31% in sTBI. From 6 to 12 months post-injury, 27% with moTBI and 32% with sTBI had an improvement, whereas 6% with moTBI and 6% with sTBI had a deterioration in GOSE score. Younger age and higher GCS score were associated with improved GOSE score. Improvement was least frequent for patients with a GOSE score of 3 at 6 months. In patients with a stable GOSE score of 3, an improvement in DRS score was observed in 22 (46%) patients. In conclusion, two thirds and one third of patients with mo/sTBI, respectively, had a good recovery. Importantly, change, mostly improvement, in GOSE score between 6 and 12 months was frequent and argues against the use of 6 months outcome as a time end-point in research. The GOSE does, however, not seem to be sensitive to actual change in function in the lower categories and a combination of outcome measures may be needed to describe the consequences after TBI.

Longitudinal Associations Between Persistent Post-Concussion Symptoms and Blood Biomarkers of Inflammation and CNS-Injury After Mild Traumatic Brain Injury.

The aim of our study was to investigate the biological underpinnings of persistent post-concussion symptoms (PPCS) at 3 months following mild traumatic brain injury (mTBI). Patients (n = 192, age 16-60 years) with mTBI, defined as Glasgow Coma Scale (GCS) score between 13 and 15, loss of consciousness (LOC) <30 min, and post-traumatic amnesia (PTA) <24 h were included. Blood samples were collected at admission (within 72 h), 2 weeks, and 3 months. Concentrations of blood biomarkers associated with central nervous system (CNS) damage (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], and tau) and inflammation (interferon gamma [IFNγ], interleukin [IL]-8, eotaxin, macrophage inflammatory protein-1-beta [MIP]-1ß, monocyte chemoattractant protein [MCP]-1, interferon-gamma-inducible protein [IP]-10, IL-17A, IL-9, tumor necrosis factor [TNF], basic fibroblast growth factor [FGF]-basic platelet-derived growth factor [PDGF], and IL-1 receptor antagonist [IL-1ra]) were obtained. Demographic and injury-related factors investigated were age, sex, GCS score, LOC, PTA duration, traumatic intracranial finding on magnetic resonance imaging (MRI; within 72 h), and extracranial injuries. Delta values, that is, time-point differences in biomarker concentrations between 2 weeks minus admission and 3 months minus admission, were also calculated. PPCS was assessed with the British Columbia Post-Concussion Symptom Inventory (BC-PSI). In single variable analyses, longer PTA duration and a higher proportion of intracranial findings on MRI were found in the PPCS group, but no single biomarker differentiated those with PPCS from those without. In multi-variable models, female sex, longer PTA duration, MRI findings, and lower GCS scores were associated with increased risk of PPCS. Inflammation markers, but not GFAP, NFL, or tau, were associated with PPCS. At admission, higher concentrations of IL-8 and IL-9 and lower concentrations of TNF, IL-17a, and MCP-1 were associated with greater likelihood of PPCS; at 2 weeks, higher IL-8 and lower IFNγ were associated with PPCS; at 3 months, higher PDGF was associated with PPCS. Higher delta values of PDGF, IL-17A, and FGF-basic at 2 weeks compared with admission, MCP-1 at 3 months compared with admission, and TNF at 2 weeks and 3 months compared with admission were associated with greater likelihood of PPCS. Higher IL-9 delta values at both time-point comparisons were negatively associated with PPCS. Discriminability of individual CNS-injury and inflammation biomarkers for PPCS was around chance level, whereas the optimal combination of biomarkers yielded areas under the curve (AUCs) between 0.62 and 0.73. We demonstrate a role of biological factors on PPCS, including both positive and negative effects of inflammation biomarkers that differed based on sampling time-point after mTBI. PPCS was associated more with acute inflammatory processes, rather than ongoing inflammation or CNS-injury biomarkers. However, the modest discriminative ability of the models suggests other factors are more important in the development of PPCS.

The Epidemiology of Moderate and Severe Traumatic Brain Injury in Central Norway.

INTRODUCTION: Few studies account for prehospital deaths when estimating incidence and mortality rates of moderate and severe traumatic brain injury (msTBI). In a population-based study, covering both urban and rural areas, including also prehospital deaths, the aim was to estimate incidence and mortality rates of msTBI. Further, we studied the 30-day and 6-month case-fatality proportion of severe TBI in relation to age. METHODS: All patients aged ≥17 years who sustained an msTBI in Central Norway were identified by three sources: (1) the regional trauma center, (2) the general hospitals, and (3) the Norwegian Cause of Death Registry. Incidence and mortality rates were standardized according to the World Health Organization's world standard population. Case-fatality proportions were calculated by the number of deaths from severe TBI at 30 days and 6 months, divided by all patients with severe TBI. RESULTS: The overall incidence rates of moderate and severe TBI were 4.9 and 6.7 per 100,000 person-years, respectively, increasing from age 70 years. The overall mortality rate was 3.4 per 100,000 person-years, also increasing from age 70 years. Incidence and mortality rates were highest in men. The case-fatality proportion in people with severe TBI was 49% in people aged 60-69 years and 81% in people aged 70-79 years. CONCLUSION: The overall incidence and mortality rates for msTBI in Central Norway were low but increased from age 70 years, and among those ≥80 years of age with severe TBI, nearly all died. Overall estimates are strongly influenced by high incidence and mortality rates in the elderly, and studies should therefore report age-specific estimates, for better comparison of incidence and mortality rates.

Diffusion Tensor and Kurtosis Imaging Findings the First Year following Mild Traumatic Brain Injury.

Despite enormous research interest in diffusion tensor imaging and diffusion kurtosis imaging (DTI; DKI) following mild traumatic brain injury (MTBI), it remains unknown how diffusion in white matter evolves post-injury and relates to acute MTBI characteristics. This prospective cohort study aimed to characterize diffusion changes in white matter the first year after MTBI. Patients with MTBI (n = 193) and matched controls (n = 83) underwent 3T magnetic resonance imaging (MRI) within 72 h and 3- and 12-months post-injury. Diffusion data were analyzed in three steps: 1) voxel-wise comparisons between the MTBI and control group were performed with tract-based spatial statistics at each time-point; 2) clusters of significant voxels identified in step 1 above were evaluated longitudinally with mixed-effect models; 3) the MTBI group was divided into: (A) complicated (with macrostructural findings on MRI) and uncomplicated MTBI; (B) long (1-24 h) and short (< 1 h) post-traumatic amnesia (PTA); and (C) other and no other concurrent injuries to investigate if findings in step 1 were driven mainly by aberrant diffusion in patients with a more severe injury. At 72 h, voxel-wise comparisons revealed significantly lower fractional anisotropy (FA) in one tract and significantly lower mean kurtosis (Kmean) in 11 tracts in the MTBI compared with control group. At 3 months, the MTBI group had significantly higher mean diffusivity in eight tracts compared with controls. At 12 months, FA was significantly lower in four tracts and Kmean in 10 tracts in patients with MTBI compared with controls. There was considerable overlap in affected tracts across time, including the corpus callosum, corona radiata, internal and external capsule, and cerebellar peduncles. Longitudinal analyses revealed that the diffusion metrics remained relatively stable throughout the first year after MTBI. The significant group*time interactions identified were driven by changes in the control rather than the MTBI group. Further, differences identified in step 1 did not result from greater diffusion abnormalities in patients with complicated MTBI, long PTA, or other concurrent injuries, as standardized mean differences in diffusion metrics between the groups were small (0.07 ± 0.11) and non-significant. However, follow-up voxel-wise analyses revealed that other concurrent injuries had effects on diffusion metrics, but predominantly in other metrics and at other time-points than the effects observed in the MTBI versus control group analysis. In conclusion, patients with MTBI differed from controls in white matter integrity already 72 h after injury. Diffusion metrics remained relatively stable throughout the first year after MTBI and were not driven by deviating diffusion in patients with a more severe MTBI.

Moderate and severe traumatic brain injury in general hospitals: a ten-year population-based retrospective cohort study in central Norway.

BACKGROUND: Patients with moderate and severe traumatic brain injury (TBI) are admitted to general hospitals (GHs) without neurosurgical services, but few studies have addressed the management of these patients. This study aimed to describe these patients, the rate of and reasons for managing patients entirely at the GH, and differences between patients managed entirely at the GH (GH group) and patients transferred to the regional trauma centre (RTC group). We specifically examined the characteristics of elderly patients. METHODS: Patients with moderate (Glasgow Coma Scale score 9-13) and severe (score ≤ 8) TBIs who were admitted to one of the seven GHs without neurosurgical services in central Norway between 01.10.2004 and 01.10.2014 were retrospectively identified. Demographic, injury-related and outcome data were collected from medical records. Head CT scans were reviewed. RESULTS: Among 274 patients admitted to GHs, 137 (50%) were in the GH group. The transferral rate was 58% for severe TBI and 40% for moderate TBI. Compared to the RTC group, patients in the GH group were older (median age: 78 years vs. 54 years, p < 0.001), more often had a preinjury disability (50% vs. 39%, p = 0.037), and more often had moderate TBI (52% vs. 35%, p = 0.005). The six-month case fatality rate was low (8%) in the GH group when transferral was considered unnecessary due to a low risk of further deterioration and high (90%, median age: 87 years) when neurosurgical intervention was considered nonbeneficial. Only 16% of patients ≥ 80 years old were transferred to the RTC. For this age group, the in-hospital case fatality rate was 67% in the GH group and 36% in the RTC group and 84% and 73%, respectively, at 6 months. CONCLUSIONS: Half of the patients were managed entirely at a GH, and these were mainly patients considered to have a low risk of further deterioration, patients with moderate TBI, and elderly patients. Less than two of ten patients ≥ 80 years old were transferred, and survival was poor regardless of the transferral status.

Long-term post-concussion symptoms. / Langvarige plager etter hjernerystelse.

Concussion is common and usually resolves without complications. However, persistent symptoms occur in 10-15 % of patients. These post-concussion symptoms are predominantly somatic, cognitive and emotional. The condition is most common in those with previous somatic and mental health issues. The causes underlying long-term post-concussion symptoms are unclear, but a biopsychosocial explanatory model is currently regarded as the most appropriate basis for diagnosis and treatment. This clinical review article is based on key literature and our own clinical experiences with patients who have these long-term post-concussion symptoms.

A population-based study of global outcome after moderate to severe traumatic brain injury in children and adolescents.

OBJECTIVE: The primary aim of this study was to evaluate the global outcome longitudinally over 5 years in children and adolescents surviving moderate to severe traumatic brain injury (msTBI) to investigate changes in outcome over time. The secondary aim was to explore how age at the time of injury affected outcome. METHODS: All children and adolescents (aged 0-17 years; subdivided into children aged 0-10 years and adolescents aged 11-17 years) with moderate (Glasgow Coma Scale [GCS] score 9-13) or severe (GCS score ≤ 8) TBI who were admitted to a level I trauma center in Norway over a 10-year period (2004-2014) were prospectively included. In addition, young adults (aged 18-24 years) with msTBI were included for comparison. Outcome was assessed with the Glasgow Outcome Scale-Extended (GOS-E) at 6 months, 12 months, and 5 years after injury. The effect of time since injury and age at injury on the probability of good outcome was estimated by the method of generalized estimating equations. RESULTS: A total of 30 children, 39 adolescents, and 97 young adults were included, among which 24 children, 38 adolescents, and 76 young adults survived and were planned for follow-up. In-hospital mortality from TBI was 7% for children, 3% for adolescents, and 18% for young adults. In surviving patients at the 5-year follow-up, good recovery (GOS-E score 7 or 8) was observed in 87% of children and all adolescents with moderate TBI, as well as in 44% of children and 59% of adolescents with severe TBI. No patient remained in a persistent vegetative state. For all patients, the odds for good recovery increased from 6 to 12 months (OR 1.79, 95% CI 1.15-2.80; p = 0.010), although not from 12 months to 5 years (OR 0.98, 95% CI 0.62-1.55; p = 0.940). Children/adolescents (aged 0-17 years) had higher odds for good recovery than young adults (OR 2.86, 95% CI 1.26-6.48; p = 0.012). CONCLUSIONS: In this population-based study of pediatric msTBI, surprisingly high rates of good recovery over 5 years were found, including good recovery for a large majority of children and all adolescents with moderate TBI. Less than half of the children and more than half of the adolescents with severe TBI had good outcomes. The odds for good recovery increased from 6 to 12 months and were higher in children/adolescents (aged 0-17 years) than in young adults.

Trajectories of Persistent Postconcussion Symptoms and Factors Associated With Symptom Reporting After Mild Traumatic Brain Injury.

OBJECTIVE: To examine the trajectories of persistent postconcussion symptoms (PPCS) after mild traumatic brain injury (MTBI) and to investigate which injury-related and personal factors are associated with symptom reporting. DESIGN: Prospective longitudinal cohort study. Follow-up at 3 and 12 months postinjury. SETTING: A level 1 trauma center and an emergency outpatient clinic. PARTICIPANTS: Patients with MTBI (n=358), trauma controls (n=75), and community controls (n=78). MAIN OUTCOME MEASURES: Symptoms were assessed with the British Columbia Postconcussion Symptom Inventory (BC-PSI). Participants were categorized as having moderate to severe PPCS (msPPCS) when reporting ≥3 moderate/severe symptoms or a BC-PSI total score of ≥13. BC-PSI total scores were compared between the groups and were further used to create cutoffs for reliable change by identifying uncommon and very uncommon change in symptoms in the community control group. Associations between symptom reporting and 25 injury-related and personal factors were examined. RESULTS: The MTBI group had a similar prevalence of msPPCS at 3 and 12 months (21%) and reported more symptoms than the control groups. Analyses of individual trajectories, however, revealed considerable change in both msPPCS and BC-PSI total scores in the MTBI group, where both worsening and improvement was common. Intracranial lesions on computed tomography were associated with a greater likelihood of improving from 3 to 12 months. Those with msPPCS at both assessments were more likely to be women and to have these personal preinjury factors: reduced employment, pain, poor sleep, low resilience, high neuroticism and pessimism, and a psychiatric history. CONCLUSIONS: Group analyses suggest a stable prevalence of msPPCS the first year postinjury. However, there was considerable intraindividual change. Several personal factors were associated with maintaining symptoms throughout the first year.

Examining 3-month test-retest reliability and reliable change using the Cambridge Neuropsychological Test Automated Battery.

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a battery of computerized neuropsychological tests commonly used in Europe in neurology and psychiatry studies, including clinical trials. The purpose of this study was to investigate test-retest reliability and to develop reliable change indices and regression-based change formulas for using the CANTAB in research and practice involving repeated measurement. A sample of 75 healthy adults completed nine CANTAB tests, assessing three domains (i.e., visual learning and memory, executive function, and visual attention) twice over a 3-month period. Wilcoxon signed-rank tests showed significant practice effects for 6 of 14 outcome measures with effect sizes ranging from negligible to medium (Hedge's g: .15-.40; Cliff's delta: .09-.39). The Spatial Working Memory test, Attention Switching Task, and Rapid Visual Processing test were the only tests with scores of adequate test-retest reliability. For all outcome measures, Pearson's and Spearman's correlation coefficients ranged from .39 to .79. The measurement error surrounding difference scores was large, thus requiring large changes in performance (i.e., 1-2 SDs) in order to interpret a change score as reliable. In the regression equations, test scores from initial testing significantly predicted retest scores for all outcome measures. Age was a significant predictor in several of the equations, while education was a significant predictor in only two of the equations. The adjusted R2 values ranged between .19 and .67. The present study provides results enabling clinicians to make probabilistic statements about change in cognitive functions based on CANTAB test performances.

Poor sleep quality is associated with greater negative consequences for cognitive control function and psychological health after mild traumatic brain injury than after orthopedic injury.

OBJECTIVE: To test the hypothesis that poor sleep quality has a stronger negative effect on cognitive control function and psychological health after mild traumatic brain injury (mTBI) than after orthopedic injury. METHOD: Patients with mTBI (n = 197) and trauma controls with orthopedic injuries (n = 82) were included in this prospective longitudinal study. The participants (age 16-60) completed three computerized neurocognitive tests assessing response speed and accuracy at 2 weeks and 3 months after injury, as well as questionnaires and interviews assessing sleep quality and psychological distress at 2 weeks, 3 months, and 12 months after injury. Separate Linear Mixed Models (LMMs) for each of the outcome measures (response speed, response accuracy, psychological distress) were performed. RESULTS: We observed a significant interaction effect between poor sleep quality and group (mTBI vs. trauma controls) in the response speed (p = .028) and psychological distress (p = .001) models, driven by a greater negative impact of poor sleep quality on response speed and psychological distress in the mTBI group. We found no such interaction effect for response accuracy (p = .825), and poor sleep quality was associated with worse accuracy to a similar extent for both groups. CONCLUSIONS: Our findings show that poor sleep quality has a more negative impact on cognitive control function and psychological outcome in patients with mTBI, compared to trauma controls. This indicates an increased vulnerability to poor sleep quality in patients who have suffered an mTBI. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

One-Year Prospective Study of Plasma Biomarkers From CNS in Patients With Mild Traumatic Brain Injury.

Objective: To investigate the longitudinal evolution of three blood biomarkers: neurofilament light (NFL), glial fibrillary acidic protein (GFAP) and tau, in out-patients and hospitalized patients with mild traumatic brain injury (mTBI) compared to controls, along with their associations-in patients-with clinical injury characteristics and demographic variables, and ability to discriminate patients with mTBI from controls. Methods: A longitudinal observation study including 207 patients with mTBI, 84 age and sex-matched community controls (CCs) and 52 trauma controls (TCs). Blood samples were collected at 5 timepoints: acute (<24 h), 72 h (24-72 h post-injury), 2 weeks, 3 and 12 months. Injury-related, clinical and demographic variables were obtained at inclusion and brain MRI within 72 h. Results: Plasma GFAP and tau were most elevated acutely and NFL at 2 weeks and 3 months. The group of patients with mTBI and concurrent other somatic injuries (mTBI+) had the highest elevation in all biomarkers across time points, and were more likely to be victims of traffic accidents and violence. All biomarkers were positively associated with traumatic intracranial findings on MRI obtained within 72 h. Glial fibrillary acidic protein and NFL levels were associated with Glasgow Coma Scale (GCS) score and presence of other somatic injuries. Acute GFAP concentrations showed the highest discriminability between patients and controls with an Area Under the Curve (AUC) of 0.92. Acute tau and 2-week NFL concentrations showed moderate discriminability (AUC = 0.70 and AUC = 0.75, respectively). Tau showed high discriminability between mTBI+ and TCs (AUC = 0.80). Conclusions: The association of plasma NFL with traumatic intracranial MRI findings, together with its later peak, could reflect ongoing secondary injury or repair mechanisms, allowing for a protracted diagnostic time window. Patients experiencing both mTBI and other injuries appear to be a subgroup with greater neural injury, differing from both the mTBI without other injuries and from both control groups. Acute GFAP concentrations showed the highest discriminability between patients and controls, were highly associated with intracranial traumatic injury, and showed the largest elevations compared to controls at the acute timepoint, suggesting it to be the most clinically useful plasma biomarker of primary CNS injury in mTBI.

Acute Diffusion Tensor and Kurtosis Imaging and Outcome following Mild Traumatic Brain Injury.

In this prospective cohort study, we investigated associations between acute diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) metrics and persistent post-concussion symptoms (PPCS) 3 months after mild traumatic brain injury (mTBI). Adult patients with mTBI (n = 176) and community controls (n = 78) underwent 3 Tesla magnetic resonance imaging (MRI) within 72 h post-injury, estimation of cognitive reserve at 2 weeks, and PPCS assessment at 3 months. Eight DTI and DKI metrics were examined with Tract-Based Spatial Statistics. Analyses were performed in the total sample in uncomplicated mTBI only (i.e., without lesions on clinical MRI), and with cognitive reserve both controlled for and not. Patients with PPCS (n = 35) had lower fractional anisotropy (in 2.7% of all voxels) and kurtosis fractional anisotropy (in 6.9% of all voxels), and higher radial diffusivity (in 0.3% of all voxels), than patients without PPCS (n = 141). In uncomplicated mTBI, only fractional anisotropy was significantly lower in patients with PPCS. Compared with controls, patients with PPCS had widespread deviations in all diffusion metrics. When including cognitive reserve as a covariate, no significant differences in diffusion metrics between patients with and without PPCS were present, but patients with PPCS still had significantly higher mean, radial, and axial diffusivity than controls. In conclusion, patients who developed PPCS had poorer white matter microstructural integrity acutely after the injury, compared with patients who recovered and healthy controls. Differences became less pronounced when cognitive reserve was controlled for, suggesting that pre-existing individual differences in axonal integrity accounted for some of the observed differences.

Methodology Matters: Comparing Approaches for Defining Persistent Symptoms after Mild Traumatic Brain Injury.

Some people experience persistent post-concussion symptoms (PPCS) after mild traumatic brain injury (mTBI). A meaningful clinical classification and scientific progress are hampered by a lack of consensus regarding the phenomenology, assessment, and operationalization of PPCS. Here we demonstrate and evaluate how the methodology used to assess and define persistent symptoms after mTBI influences PPCS as a binary outcome. We present empirical data from 15 classification methods reflecting procedures found in the literature and clinical practice. In total, 221 patients with mTBI, 73 patients with orthopedic injuries, and 77 community controls were included in the study. The prevalence rate of PPCS in the mTBI group varied between 10% and 47%, depending on the method used to assess and define unfavorable outcome. There was generally low positive agreement between the different methods; even the two methods yielding the most similar prevalence rates (89.2% overall proportion agreement) agreed on less than half (45.5% positive agreement) of the PPCS cases. Using a liberal but not uncommon threshold for symptom severity, there was a considerable misclassification rate of PPCS in both comparison groups. Our results highlight the importance for researchers to be aware of the limitations of using binary approaches for classification of PPCS. The poor agreement between methods should be considered when (1) interpreting the heterogeneity in the existing PPCS literature and (2) developing new improved methods. An empirically informed consensus regarding classification of PPCS should be a priority for the research community.

Personal Factors Associated With Postconcussion Symptoms 3 Months After Mild Traumatic Brain Injury.

OBJECTIVE: To describe personal factors in patients with mild traumatic brain injury (MTBI) and 2 control groups and to explore how such factors were associated with postconcussion symptoms (PCSs). DESIGN: Prospective cohort study. SETTING: Level 1 trauma center and outpatient clinic. PARTICIPANTS: Participants (N=541) included patients with MTBI (n=378), trauma controls (n=82), and community controls (n=81). MAIN OUTCOME MEASURES: Data on preinjury health and work status, personality, resilience, attention deficit/hyperactivity, and substance use. Computed tomography (CT) findings and posttraumatic amnesia were recorded. Symptoms were assessed at 3 months with the British Columbia Postconcussion Symptom Inventory and labeled as PCS+ if ≥3 symptoms were reported or the total score was ≥13. Predictive models were fitted with penalized logistic regression using the least absolute shrinkage and selection operator (lasso) in the MTBI group, and model fit was assessed with optimism-corrected area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: There were few differences in personal factors between the MTBI group and the 2 control groups without MTBI. Rates of PCS+ were 20.8% for the MTBI group, 8.0% for trauma controls, and 1.3% for community controls. In the MTBI group, there were differences between the PCS+ and PCS- group on most personal factors and injury-related variables in univariable comparisons. In the lasso models, the optimism-corrected AUC for the full model was 0.79, 0.73 for the model only including personal factors, and 0.63 for the model only including injury variables. Working less than full time before injury, having preinjury pain and poor sleep quality, and being female were among the selected predictors, but also resilience and some personality traits contributed in the model. Intracranial abnormalities on CT were also a risk factor for PCS. CONCLUSIONS: Personal factors convey important prognostic information in patients with MTBI. A vulnerable work status and preinjury health problems might indicate a need for follow-up and targeted interventions.

Examining the Subacute Effects of Mild Traumatic Brain Injury Using a Traditional and Computerized Neuropsychological Test Battery.

This study investigates subacute cognitive effects of mild traumatic brain injury (MTBI) in the Trondheim Mild TBI Study, as measured, in part, by the neuropsychological test battery of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) program, including computerized tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and traditional paper-and-pencil tests. We investigated whether cognitive function was associated with injury severity: intracranial traumatic lesions on neuroimaging, witnessed loss of consciousness (LOC), or post-traumatic amnesia (PTA) >1 h. Further, we explored which of the tests in the CENTER-TBI battery might be associated with the largest subacute effects of MTBI (i.e., at 2 weeks post-injury). We recruited 177 patients with MTBI (16-59 years of age) from a regional trauma center and an outpatient clinic,79 trauma control participants, and 81 community control participants. The MTBI group differed from community controls only on one traditional test of processing speed (coding; p = 0.009, Cliff's delta [Δ] = 0.20). Patients with intracranial abnormalities performed worse than those without on a traditional test (phonemic verbal fluency; p = 0.043, Δ = 0.27), and patients with LOC performed differently on the Attention Switching Task from the CANTAB (p = 0.020, Δ = -0.20). Patients with PTA >1 h performed worse than those with <1 h on 10 measures, from traditional tests and the CANTAB (Δ = 0.33-0.20), likely attributable, at least in part, to pre-existing differences in intellectual functioning between groups. In general, those with MTBI had good neuropsychological outcome 2 weeks after injury and no particular CENTER-TBI computerized or traditional tests seemed to be more sensitive to subtle cognitive deficits.

Examining Test-Retest Reliability and Reliable Change for Cognition Endpoints for the CENTER-TBI Neuropsychological Test Battery.

Objective: Seven candidate cognition composite scores have been developed and evaluated as part of a research program designed to validate a cognition endpoint for traumatic brain injury (TBI) research and clinical trials, but these composites have yet to be examined longitudinally. This study examined test-retest reliability and methods for determining reliable change for these seven candidate composite scores, using the neuropsychological test battery from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Methods: Participants (18-59 years-old) with mild TBI (n = 124), orthopedic trauma without head injury (n = 67), and healthy community controls (n = 63) from the Trondheim MTBI follow-up study completed the CENTER-TBI neuropsychological test battery at 2 weeks and 3 months after injury. The battery included both traditional paper-and-pencil tests and computerized tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Seven composite scores were calculated for the paper-and-pencil tests, the CANTAB tests, and all tests combined (i.e., 21 composites in total on each assessment): the overall test battery mean (OTBM); global deficit score (GDS); neuropsychological deficit score-weighted (NDS-W); low score composite (LSC); and the number of scores ≤5th percentile, ≤16th percentile, or <50th percentile. The OTBM was calculated by averaging T scores for all tests. The other composite scores were deficit-based scores, assigning different weights to low scores. Results: All composites revealed better cognitive performance at the 3-month assessment compared to the 2-week assessment and the magnitude of improvement was similar across groups. Differences, in terms of effect sizes, were largest on the OTBMs. In the combined composites, the test-retest correlation was highest for the OTBM (Spearman's rho = 0.87, in the community control group) and lowest for the number of scores ≤5th percentile (rho = 0.41). Conclusion: The high test-retest reliability of the OTBM appears to favor its use in TBI research; however, future studies are needed to examine these candidate composite scores in participants with more severe TBIs and cognitive deficits and the association of the composites with functional outcomes.