Biomarkers of focal and diffuse traumatic brain injury

Traumatic brain injury (TBI) is a pathologically heterogeneous disease affecting people of all ages. The highest incidence of TBI occurs in young people and the average age is 30 to 40 years. Injury grading may range from mild with a low frequency (1 per 100) of life-threatening intracranial hematoma that needs immediate neurosurgical operation and very low mortality (1 per 1,000) to severe with a high likelihood of life-threatening intracranial hematoma (up to 1 per 3), a 40% case fatality rate and a high disability rate (2 per 3) in survivors. Estimation of the prognosis in severe TBI is currently based on demographic and clinical predictors, including age, Glasgow Coma Scale, pupillary reactions, extracranial injury (hypotension and hypoxia) and computed tomography indices (brain swelling, focal mass lesions, subarachnoid hemorrhage). Biomarkers reflecting damage to neurons and astrocytes may add important complementary information to clinical predictors of outcome and provide insight into the pathophysiology of TBI.


Abstract
Traumatic brain injury (TBI) is a pathologically heterogeneous disease aff ecting people of all ages. The highest incidence of TBI occurs in young people and the average age is 30 to 40 years. Injury grading may range from mild with a low frequency (1 per 100) of life-threatening intracranial hematoma that needs immediate neurosurgical operation and very low mortality (1 per 1,000) to severe with a high likelihood of life-threatening intracranial hematoma (up to 1 per 3), a 40% case fatality rate and a high disability rate (2 per 3) in survivors. Estimation of the prognosis in severe TBI is currently based on demographic and clinical predictors, including age, Glasgow Coma Scale, pupillary reactions, extracranial injury (hypotension and hypoxia) and computed tomography indices (brain swelling, focal mass lesions, subarachnoid hemorrhage). Biomarkers refl ecting damage to neurons and astrocytes may add important complementary information to clinical predictors of outcome and provide insight into the pathophysiology of TBI.
predict mortality yielded diagnostic accuracies of 0.92 for the combination of GFAP with pupillary reactions and 0.92 for the combination of GFAP with mass lesions.
Th e study by Mondello and colleagues focused on focal versus diff use injuries defi ned by computed tomography rather than magnetic resonance imaging. Th is dichotomization did not allow the levels of biomarkers in patients with mixed focal and diff use pathology to be studied. Recent magnetic resonance imaging demonstrates that focal and diff use injuries occur separately but also coexist in moderate/severe TBI. Pure forms of focal injury occur in 28% of moderate/severe TBI cases, pure diff use axonal injury in 22%, while mixed focal and diff use injuries occur in 50% [9]. Th e cohort size of 81 in this transatlantic study in four centers limits the number of potential predictors that could be assessed and only three (age, UCH-L1, GCS) were included in the fi nal model to predict mortality.
Th e investigation did not obtain other outcome measures (global or cognitive) than mortality (in hospital and at 6 months). Knowing that a biomarker predicts mortality, however, is important when treatment limitation or withdrawal is considered. In this study UCH-L1 together with age and the GCS were included in the fi nal model, suggesting that biomarker test results are specifi c for a particular outcome category (death) and may increase the confi dence with which fi nal decisions can be made.
More importantly, however, will biomarkers ultimately add to the prediction of long-term outcome of survivors to answer whether a patient will reach independency from care givers or return to work? In this respect it is promising that diff erent results were obtained for the two markers with diff use and focal injuries. Th e importance of the pathological heterogeneity of focal and diff use TBI lies in the fact that patients with the same GCS score can have markedly diff erent treatments, recovery patterns and outcomes depending on the causative lesion.
A challenging next step is to obtain cutoff levels for neuronal and glial markers of TBI with small falsepositive rates not only for death but also for global unfavorable outcome measures such as disability or cognitive dysfunction. To achieve this goal, larger (multicenter) studies are needed to establish precise threshold values and to demonstrate that information obtained from biomarkers in addition to clinical variables indeed allows for suffi ciently accurate outcome prediction in individual patients. In addition, it will be interesting if prolonged determination of biomarker levels in the acute phase can be associated with secondary complications such as increased intracranial pressure, decreased cerebral perfusion pressure and eff ects of treatment.

Competing interests
PEV serves on a scientifi c advisory board and received funding for travel and speaker honoraria from Ever Neuro Pharma; serves as a member of the editorial advisory board of The European Journal of Neurology; and has received honoraria for lectures or educational activities not funded by the industry.