Teuntje M. J. C. Andriessen

GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study.

Background: Biomarker levels in blood after traumatic brain injury (TBI) may offer diagnostic and prognostic tools in addition to clinical indices. This study aims to validate glial fibrillary acidic protein (GFAP) and S100B concentrations in blood as outcome predictors of TBI using cutoff levels of 1.5 μg/L for GFAP and 1.13 μg/L for S100B from a previous study. Methods: In 79 patients with TBI (Glasgow Coma Scale score [GCS] ≤12), serum, taken at hospital admission, was analyzed for GFAP and S100B. Data collected included injury mechanism, age, gender, mass lesion on CT, GCS, pupillary reactions, Injury Severity Score (ISS), presence of hypoxia, and hypotension. Outcome was assessed, using the Glasgow Outcome Scale Extended (dichotomized in death vs alive and unfavorable vs favorable), 6 months post injury. Results: In patients who died compared to alive patients, median serum levels were increased: GFAP 33.4-fold and S100B 2.1-fold. In unfavorable compared to favorable outcome, GFAP was increased 19.8-fold and S100B 2.1-fold. Univariate logistic regression analysis revealed that mass lesion, GFAP, absent pupils, age, and ISS, but not GCS, hypotension, or hypoxia, predicted death and unfavorable outcome. Multivariable analysis showed that models containing mass lesion, pupils, GFAP, and S100B were the strongest in predicting death and unfavorable outcome. S100B was the strongest single predictor of unfavorable outcome with 100% discrimination. Conclusion: This study confirms that GFAP and S100B levels in serum are adjuncts to the assessment of brain damage after TBI and may enhance prognostication when combined with clinical variables.

Clinical characteristics and pathophysiological mechanisms of focal and diffuse traumatic brain injury

•  Introduction •  Classifying TBI ‐  Clinical injury severity ‐  Focal injury or diffuse injury •  Clinical characteristics ‐  Coma, confusion and subacute impairments ‐  Imaging TBI ‐  Focal and diffuse TBI: separate entities? •  Pathophysiological mechanisms of focal injury ‐  The essentials: glutamate and Ca2+ •  Pathophysiological mechanisms of diffuse injury ‐  A heterogeneous cascade of changes ‐  After axonal disconnection •  Conclusions

Epidemiology, severity classification and outcome of moderate and severe traumatic brain injury: A prospective multicenter study

Changes in the demographics, approach, and treatment of traumatic brain injury (TBI) patients require regular evaluation of epidemiological profiles, injury severity classification, and outcomes. This prospective multicenter study provides detailed information on TBI-related variables of 508 moderate-to-severe TBI patients. Variability in epidemiology and outcome is examined by comparing our cohort with previous multicenter studies. Additionally, the relation between outcome and injury severity classification assessed at different time points is studied. Based on the emergency department Glasgow Coma Scale (GCS), 339 patients were classified as having severe and 129 as having moderate TBI. In 15%, the diagnosis differed when the accident scene GCS was used for classification. In-hospital mortality was higher if severe TBI was diagnosed at both time points (44%) compared to moderate TBI at one or both time points (7-15%, p<0.001). Furthermore, 14% changed diagnosis when a threshold (≥6 h) for impaired consciousness was used as a criterion for severe TBI: In-hospital mortality was<5% when impaired consciousness lasted for<6 h. This suggests that combining multiple clinical assessments and using a threshold for impaired consciousness may improve the classification of injury severity and prediction of outcome. Compared to earlier multicenter studies, our cohort demonstrates a different case mix that includes a higher age (mean=47.3 years), more diffuse (Traumatic Coma Databank [TCDB] I-II) injuries (58%), and more major extracranial injuries (40%), with relatively high 6 month mortality rates for both severe (46%) and moderate (21%) TBI. Our results confirm that TBI epidemiology and injury patterns have changed in recent years whereas case fatality rates remain high.

Abnormal whole-brain functional networks in homogeneous acute mild traumatic brain injury

Objectives: To evaluate the whole-brain resting-state networks in a homogeneous group of patients with acute mild traumatic brain injury (MTBI) and to identify alterations in functional connectivity induced by MTBI. Methods: Thirty-five patients with acute MTBI and 35 healthy control subjects, matched in age, gender, handedness, and education, underwent resting-state fMRI, susceptibility weighted imaging, neuropsychological, and postconcussive symptom assessments. We ensured the homogeneity of the patient group by limiting the injury mechanism to fronto-occipital impacts. Alterations in functional connectivity were analyzed by using data-driven independent component analysis, which is not biased by a priori region selection. Results: We found a decrease in functional connectivity within the motor-striatal network in the MTBI group. At the same time, patients showed deficits in psychomotor speed as well as in speed of information processing. We propose that although disorders in motor function after MTBI are rarely reported, injury still has an effect on motor functioning, which in its turn may also explain the reduction in speed of information processing. Further, we found a cluster of increased functional connectivity in the right frontoparietal network in the MTBI group. We suggest that this abnormal increased connectivity might reflect increased awareness to external environment and explain excessive cognitive fatigue reported by patients with MTBI. It might also underlie the physical postconcussive symptoms, such as headache and increased sensitivity to noise/light. Conclusions: We proved that whole-brain functional connectivity is altered early (within 4 weeks) after MTBI, suggesting that changes in functional networks underlie the cognitive deficits and postconcussive complaints reported by patients with MTBI.

The reliability of magnetic resonance imaging in traumatic brain injury lesion detection

Objective: This study compares inter-rater-reliability, lesion detection and clinical relevance of T2-weighted imaging (T2WI), Fluid Attenuated Inversion Recovery (FLAIR), T2*-gradient recalled echo (T2*-GRE) and Susceptibility Weighted Imaging (SWI) in Traumatic Brain Injury (TBI). Methods: Three raters retrospectively scored 56 TBI patients’ MR images (12–76 years old, median TBI-MRI interval 7 weeks) on number, volume, location and intensity. Punctate lesions (diameter <10 mm) were scored separately from large lesions (diameter ≥10 mm). Injury severity was assessed with the Glasgow Coma Scale (GCS), outcome with the Glasgow Outcome Scale-Extended (GOSE). Results: Inter-rater-reliability for lesion volume and punctate lesion count was good (ICC = 0.69–0.94) except for punctate lesion count on T2WI (ICC = 0.19) and FLAIR (ICC = 0.15). SWI showed the highest number of lesions (mean = 30.0), followed by T2*-GRE (mean = 15.4), FLAIR (mean = 3.1) and T2WI (mean = 2.2). Sequences did not differ in detected lesion volume. Punctate lesion count on T2*-GRE (r = −0.53) and SWI (r = −0.49) correlated with the GCS (p < 0.001). Conclusions: T2*-GRE and SWI are more sensitive than T2WI and FLAIR in detecting (haemorrhagic) traumatic punctate lesions. The correlation between number of punctate lesions on T2*-GRE/SWI and the GCS indicates that haemorrhagic lesions are clinically relevant. The considerable inter-rater-disagreement in this study advocates cautiousness in interpretation of punctate lesions using T2WI and FLAIR.

Cognitive performance after mild traumatic brain injury: the impact of poor effort on test results and its relation to distress, personality and litigation.

Primary objective: To compare consecutive Mild Traumatic Brain Injury (MTBI) patients with and without adequate effort on cognitive performance, litigation status, fatigue, distress and personality. Research design: (Neuro)psychological assessment was done 6 months post-injury in 110 patients from a cohort of 618 consecutive MTBI patients aged 18–60, who attended the emergency department of our level I trauma centre. Effort was tested with the Amsterdam Short Term Memory test. Main outcome and results: Thirty patients (27%) failed the effort test. Poor effort was associated with significantly poorer scores on seven out of eleven measures, covering all tested domains. Poor effort was associated with lower educational level and changes in work status, but not litigation. Furthermore, poor effort was related to high levels of distress, Type-D personality and fatigue. Conclusions: Even in a sample of non-referred MTBI patients, poor effort was common and was strongly associated with inferior test performance. These findings imply that effort testing should be part of all cognitive assessments, also outside mediolegal settings. Behavioural factors like distress and personality should be considered as potential threats to the validity of neuropsychological testing after MTBI.

Prognosis in moderate and severe traumatic brain injury: external validation of the IMPACT models and the role of extracranial injuries.

BACKGROUND Several prognostic models to predict outcome in traumatic brain injury (TBI) have been developed, but few are externally validated. We aimed to validate the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models in a recent unselected patient cohort and to assess the additional prognostic value of extracranial injury. METHODS The Prospective Observational COhort Neurotrauma (POCON) registry contains 508 patients with moderate or severe TBI, who were admitted in 2008 and 2009 to five trauma centers in the Netherlands. We predicted the probability of mortality and unfavorable outcome at 6 months after injury with the IMPACT prognostic models. We studied discrimination (area under the curve [AUC]) and calibration. We added the extracranial component of the Injury Severity Score (ISS) to the models and calculated the increase in AUC. RESULTS The IMPACT models had an adequate discrimination in the POCON registry, with AUCs in the external validation between 0.85 and 0.90 for mortality and between 0.82 and 0.87 for unfavorable outcome. Observed outcomes agreed well with predicted outcomes. Adding extracranial injury slightly improved predictions in the overall population (unfavorable outcome: AUC increase of 0.002, p = 0.02; mortality: AUC increase of 0.000, p = 0.37) but more clearly in patients with moderate TBI (unfavorable outcome: AUC increase of 0.008, p < 0.01, mortality: AUC increase of 0.012, p = 0.02) and patients with minor computed tomographic result abnormalities (unfavorable outcome: AUC increase of 0.013, p < 0.01; mortality: AUC increase of 0.001, p = 0.08). CONCLUSION The IMPACT models performed well in a recent series of TBI patients. We found some additional impact of extracranial injury on outcome, specifically in patients with less severe TBI or minor computed tomographic result abnormalities. LEVEL OF EVIDENCE Epidemiologic/prognostic study,

Health-related quality of life after mild, moderate and severe traumatic brain injury: Patterns and predictors of suboptimal functioning during the first year after injury

BACKGROUND The Glasgow Outcome Scale Extended (GOSE) is the established functional outcome scale to assess disability following traumatic brain injury (TBI), however does not capture the patients subjective perspective. Health-related quality of life (HRQL) does capture the individuals perception of disability after TBI, and has therefore been recognized as an important outcome in TBI. In contrast to GOSE, HRQL enables comparison of health outcome across various disease states and with healthy individuals. We aimed to assess functional outcome, HRQL, recovery, and predictors of 6 and 12-month outcome in a comprehensive sample of patients with mild, moderate or severe TBI, and to examine the relationship between functional impairment (GOSE) and HRQL. METHODS A prospective cohort study was conducted among a sample of 2066 adult TBI patients who attended the emergency department (ED). GOSE was determined through questionnaires or structured interviews. Questionnaires 6 and 12 months after ED treatment included socio-demographic information and HRQL measured with Short-Form Health Survey (SF-36; reflecting physical, mental and social functioning) and Perceived Quality of Life Scale (PQoL; measuring degree of satisfaction with functioning). RESULTS 996 TBI survivors with mild, moderate or severe TBI completed the 6-month questionnaire. Functional outcome and HRQL after moderate or severe TBI was significantly lower than after mild TBI. Patients with moderate TBI showed greatest improvement. After one year, the mild TBI group reached outcomes comparable to population norms. TBI of all severities highly affected SF-36 domains physical and social functioning, and physical and emotional role functioning. GOSE scores were highly related to all SF-36 domains and PQoL scores. Female gender, older age, co-morbidity and high ISS were strongest independent predictors of decreased HRQL at 6 and 12 months after TBI. CONCLUSIONS HRQL and recovery patterns differ for mild, moderate and severe TBI. This study indicates that GOSE, although clinically relevant, fails to capture the subjective perspective of TBI patients, which endorses the use of HRQL as valuable addition to established instruments in assessing disability following TBI. Influence of TBI severity on recovery, together with female gender, older age, co-morbidity and high ISS should be considered in long-term follow-up and intervention programs.

Factors influencing intracranial pressure monitoring guideline compliance and outcome after severe traumatic brain injury.

Objective:To determine adherence to Brain Trauma Foundation guidelines for intracranial pressure monitoring after severe traumatic brain injury, to investigate if characteristics of patients treated according to guidelines (ICP+) differ from those who were not (ICP-), and whether guideline compliance is related to 6-month outcome. Design:Observational multicenter study. Patients:Consecutive severe traumatic brain injury patients (≥16 yrs, n = 265) meeting criteria for intracranial pressure monitoring. Measurements and Main Results:Data on demographics, injury severity, computed tomography findings, and patient management were registered. The Glasgow Outcome Scale Extended was dichotomized into death (Glasgow Outcome Scale Extended = 1) and unfavorable outcome (Glasgow Outcome Scale Extended 1–4). Guideline compliance was 46%. Differences between the monitored and nonmonitored patients included a younger age (median 44 vs. 53 yrs), more abnormal pupillary reactions (52% vs. 32%), and more intracranial pathology (subarachnoid hemorrhage 62% vs. 44%; intraparenchymal lesions 65% vs. 46%) in the ICP+ group. Patients with a total intracranial lesion volume of ~150 mL and a midline shift of ~12 mm were most likely to receive an intracranial pressure monitor and probabilities decreased with smaller and larger lesions and shifts. Furthermore, compliance was low in patients with no (Traumatic Coma Databank score I −10%) visible intracranial pathology. Differences in case-mix resulted in higher a priori probabilities of dying (median 0.51 vs. 0.35, p < .001) and unfavorable outcome (median 0.79 vs. 0.63, p < .001) in the ICP+ group. After correction for baseline and clinical characteristics with a propensity score, intracranial pressure monitoring guideline compliance was not associated with mortality (odds ratio 0.93, 95% confidence interval 0.47–1.85, p = .83) nor with unfavorable outcome (odds ratio 1.81, 95% confidence interval 0.88–3.73, p = .11). Conclusions:Guideline noncompliance was most prominent in patients with minor or very large computed tomography abnormalities. Intracranial pressure monitoring was not associated with 6-month outcome, but multiple baseline differences between monitored and nonmonitored patients underline the complex nature of examining the effect of intracranial pressure monitoring in observational studies.

Multicenter Evaluation of the Course of Coagulopathy in Patients with Isolated Traumatic Brain Injury: Relation to CT Characteristics and Outcome

This prospective multicenter study investigated the association of the course of coagulation abnormalities with initial computed tomography (CT) characteristics and outcome in patients with isolated traumatic brain injury (TBI). Patient demographics, coagulation parameters, CT characteristics, and outcome data of moderate and severe TBI patients without major extracranial injuries were prospectively collected. Coagulopathy was defined as absent, early but temporary, delayed, or early and sustained. Delayed/sustained coagulopathy was associated with a higher incidence of disturbed pupillary responses (40% versus 27%; p<0.001) and higher Traumatic Coma Data Bank (TCDB) CT classification (5 (2-5) versus 2 (1-5); p=0.003) than in patients without or with early, but short-lasting coagulopathy. The initial CT of patients with delayed/sustained coagulopathy more frequently showed intracranial hemorrhage and signs of raised intracranial pressure (ICP) compared to patients with early coagulopathy only. This was paralleled by higher in-hospital mortality rates (51% versus 33%; p<0.05), and poorer 6-month functional outcome in patients with delayed/sustained coagulopathy. The relative risk for in-hospital mortality was particularly related to disturbed pupillary responses (OR 8.19; 95% CI 3.15,21.32; p<0.001), early, short-lasting coagulopathy (OR 6.70; 95% CI 1.74,25.78; p=0.006), or delayed/sustained coagulopathy (OR 5.25; 95% CI 2.06,13.40; p=0.001). Delayed/sustained coagulopathy is more frequently associated with CT abnormalities and unfavorable outcome at 6 months after TBI than early, short-lasting coagulopathy. Our finding that not only the mere presence but also the time course of coagulopathy holds predictive value for patient outcome underlines the importance of systematic hemostatic monitoring over time in TBI.