Traumatic brain injury (TBI) has been described to be man’s most complex disease, in man’s most complex organ. Despite this vast complexity, variability, and individuality, we still classify the severity of TBI based on non-specific, often unreliable, and pathophysiologically poorly understood measures. Current classifications are primarily based on clinical evaluations, which are non-specific and poorly predictive of long-term disability. Brain imaging results have also been used, yet there are multiple ways of doing brain imaging, at different timepoints in this very dynamic injury. Severity itself is a vague concept. All prediction models based on combining variables that can be assessed during the acute phase have reached only modest predictive values for later outcome. Yet, these early labels of severity often determine how the patient is treated by the healthcare system at large. This opinion paper examines the problems and provides caveats regarding the use of current severity labels and the many practical and scientific issues that arise from doing so. The objective of this paper is to show the causes and consequences of current practice and propose a new approach based on risk classification. A new approach based on multimodal quantifiable data (including imaging and biomarkers) and risk-labels would be of benefit both for the patients and for TBI clinical research and should be a priority for international efforts in the field.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n=22), moderate (moTBI; n=14) or mild TBI (mTBI; n=108) according to Glasgow Coma Scale. The control group (n=28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n=23), moTBI (n=7), mTBI (n=37) patients and controls (n=27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC=0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified 'TBI metabotype' in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.

Primary objective: To evaluate the effectiveness of rivastigmine for chronic sequels of traumatic brain injury (TBI). Research design: Randomized, placebo-controlled, double-blind crossover trial. Methods and procedures: Of 772 outpatients with TBI treated during 1993–2002, all eligible patients were contacted and 102 patients volunteered. They were randomized to receive either rivastigmine (Exelon) or placebo. The study included two periods with titration to the highest tolerated or maximum dose (12 mg rivastigmine daily) and a maintenance period of 8 weeks, separated by a 4-week washout. Computerized neuropsychological testing and standardized clinical interviews were used to assess the outcome. Main outcomes and results: Sixty-nine patients completed the study and 17 withdrew because of adverse effects. In two measures of computerized testing (subtraction test, p = 0.034 and correct answers in the 10–15 minute vigilance test, p = 0.048) rivastigmine was better than placebo. The clinical interviews did not yield significant results. After the study, 45% of patients considered rivastigmine beneficial compared to 20% with placebo. Conclusions: A weak trend favouring rivastigmine for chronic symptoms of TBI was observed. The clinical significance of the results and the problems in conducting drug trials for chronic TBI symptoms are discussed.

To provide the clinician with a reasonable overview of the modern pharmacological alternatives to treat the cognitive and behavioral sequels of traumatic brain injury. Original research in this area is sparse and more than half of the articles published on the subject recently have been reviews. Of the three randomized controlled trials, one studied methylphenidate (n = 18), one methylphenidate and sertraline (n = 30) and one amantadine (n = 27). All these studies reported beneficial effects on various cognitive measures, but because of the study protocols, the evidence provided may be questioned. The various reviews, uncontrolled studies and case reports suggest that at least psychostimulants, cholinergic agents, dopaminergic agents and antidepressants may be beneficial in treating the cognitive and behavioral symptoms of traumatic brain injury. The clinician trying to ameliorate the cognitive and behavioral symptoms of traumatic brain injury has to make decisions about pharmacotherapy that are still based mainly on clinical experience. Large randomized controlled trials giving high-quality evidence are so far missing. This review discusses the problems facing both the clinician and the scientist treating the cognitive and behavioral sequels of traumatic brain injury. A symptom-based approach is suggested for current practice.

Blood-based biomarkers are promising tools to complement clinical variables and imaging findings in the diagnosis, monitoring and outcome prediction of traumatic brain injury (TBI). Several promising biomarker candidates have been found for various clinical questions, but the translation of TBI biomarkers into clinical applications has been negligible. Measured biomarker levels are influenced by patient-related variables such as age, blood-brain barrier integrity and renal and liver function. It is not yet fully understood how biomarkers enter the bloodstream from the interstitial fluid of the brain. In addition, the diagnostic performance of TBI biomarkers is affected by sampling timing and analytical methods. In this focused review, the clinical aspects of glial fibrillary acidic protein, neurofilament light, S100 calcium-binding protein B, tau and ubiquitin C-terminal hydrolase-L1 are examined. Current findings and clinical caveats are addressed.