By: Juan Jose Egea-Guerrero, MD, PhD; Francisco Murillo-Cabezas, MD, PhD; José León-Carrión, PhD
Traumatic Brain Injury (TBI) has a tremendous impact on public health and social-sanitary resources. It remains the primary cause of death and disability among young adults. In the United States alone, 50,000 people die annually from TBI side effects, and among those who survive, over 80,000 suffer long term sequelae. In Europe, TBI has an annual incidence rate of approximately 235 per 100,000 and a mortality rate of 2.7%. Hospital admissions due to TBI reach one million per year in the European Union.  Mild TBI constitutes one of the most frequent motives for emergency hospital care, and the first among neurological illnesses.   In contrast, severe TBI is one of the main causes of trauma-related mortality. An unfavourable prognosis, such as death, vegetative state or severe disability could be the case in over 20% of these patients. 
S100β is a 21 kDa calcium-binding protein (Ca2+), found mainly in the cytosol of astroglial cells and Schwann cells. The intracellular functions of this protein are radically different from its extracellular effects. At the intracellular level, S100β functions as a Ca2+, regulating multiple functions, including protein phosphorylation and degradation, cell motility and form, cellular proliferation and differentiation, Ca2+ homeostasis, and receptor transcription and regulation. At the extracellular level, S100β functions as a neuromodulatory signal, exhibiting concentration-dependent characteristics. Under physiological conditions, it acts as a neurotrophic factor, nearing nanomolar. In the presence of astrocyte damage or necrosis, however, its concentration increases to micromolar or sub-micromolar due to the passive release of intracellular S100β, and its effects become neurotoxic, directly provoking neuronal apoptosis, or indirectly stimulating the astrocytic release of nitric oxide. 
The S100β protein, eliminated by renal excretion, has a biological half-life of 30 minutes to 2 hours.    It can be found in serum, cerebrospinal fluid or urine. Its values are not affected by haemolysis. Currently, two tests provide measurements of S100β levels in serum: the Elecsys®S100 test (Roche Diagnostics, Mannheim, Germany) and the Liaison Sangtec®100 system (DiaSorin S.p.A. Saluggia, VC, Italy). However, studies have shown that these assays do not concur when analyzing serum S100β concentration levels, making their results incomparable. This divergence in measurement also complicates efforts to compare different TBI-related studies.     
Detection of post-TBI intracranial lesion using the S100β protein
The S100β protein is a biomarker for brain injury which could aid in the management of patients who sustain a mild TBI. Its inclusion in emergency unit protocols helps streamline patient priority, reduce waiting periods, and determine which patients require emergency testing (CT scan) due to high risk of intracranial lesion (IL). Studies on the utility of S100β have focused on mild TBI patients, including a wide range of TBI patients, with Glasgow Coma Scale (GCS) scores of 13 –15, and determinations from the first three hours post-injury.    Their results have demonstrated the S100β protein’s high sensibility in detecting IL and its severity. However, its specificity remains low, even at a cut-off value of 0.10 mcg/L.  Our studies on patients with unaltered consciousness after TBI, showed that inclusion periods inferior to 6-hr and an increased cut-off value (0.130 mcg/L), did not alter the diagnostic properties of the protein. This provides an opportunity to improve and extend the utility of S100β to a greater number of patients.  Its utility has recently been tested in patients with TBI and alcohol intoxication. 
S100β serum levels have also been found to correlate with severity of the head injury, based on Traumatic Coma Data Bank classification, regardless of TBI type.   Furthermore, factors associated with more severe brain injury, including higher intracranial pressure, disruption of the blood–brain barrier, or invasive neurosurgical procedures have also been linked to increased S100β protein levels. 
Prognostic capacity of the S100β protein post-acute TBI
S100β protein levels reflect IL and its severity on the one hand, and on the other predict the development of long term sequelae and a patient’s quality of life post-TBI. Studies show that S100β serum levels at admission after a mild TBI correlate with returning to work and the reappearance of residual symptoms six months post-injury. 
Different studies have explored the prognostic capacity of the S100β protein after severe TBI. While they all concur that S100β levels in these patients are related to clinical outcome, and certain elevations may be a predictive factor for mortality  , they do not agree on the time frame for the prognostic evaluation. Testing can range from ER or hospital discharge to one month, three months, six months or one year post-TBI.      Moreover, given the heterogeneous design of these studies, there is no general consensus on what would be the ideal moment for S100β protein extraction, which could predict prognosis after severe TBI. Some authors support extraction at 24h post-injury, predicting short term prognosis at 3 months post-injury.   . Others rely on later determinations (72h) to provide long term prognostic predictions (1 year post-injury). 
Authors who study S100β serum levels during the first days post-injury report progressively dropping concentrations, with a maximum at admission followed by a rapid decrease during the next 24-48h. At 72h post-injury, the protein levels stabilize.  There seems to be wide agreement that early determinations--within the first 12h post-trauma--could lead to false positive results. This is due to the effect of reanimation efforts, which generally occur at this time period, and lead to S100β serum concentrations which reflect tissue damage, blood-brain barrier disruption and the presence of secondary injury more precisely.
The S100β protein was originally measured in cerebrospinal fluid, yet most studies focus on its prognostic capacity in serum after TBI. Its determination in urine has received comparatively little research, with most studies focusing on paediatric populations and the role of S100β in infant hypoxic encephalopathy and traumatic pathologies.   In adults, S100β levels in urine were found to correlate with mortality, although its predictive capacity did not surpass plasma concentrations. 
Extracranial interference in S100β levels
In the 80s, S100β protein was classified as extracranial in origin, found in skeletal muscle, skin, fat and melanoma tumours.  This extracranial location is a widely disputed limitation, given its potential interference in S100β levels and their subsequent interpretation. However, recent research has demonstrated that S100β protein values are not affected, or barely so, by the presence of other traumatic injuries associated with head insult. A higher Injury Severity Score at admission due to non-CNS injury did not correlate with increased levels of S100β. Results from previous studies on patients with different types of TBI have confirmed the absence of interference in serum S100β levels in victims of polytrauma and TBI without associated injury.    
Application in the Health Care System
TBI is a leading factor in mortality and morbidity associated with trauma. Its personal, social and economic consequences have a devastating effect on the lives of patients and their families. Most victims are healthy young individuals. On occasion, the lack of tools which clarify or aid correct decision-making is a real set-back for health care and society as a whole.
The inclusion of biomarkers prognostic model development could help determine which patients have a high risk of mortality during the post-TBI acute phase, which show unrecoverable sequelae, and which could benefit from acute and post-acute rehabilitation in specialized treatment centres. This comprehensive treatment helps patients maximize their functional recovery and improve their overall outcome through personalized rehabilitation programs.
The utility of the S100β protein in TBI management is clearly promising for a wide range of health care professionals, including specialized physicians in the emergency department and ICU, neurosurgeons, rehabilitation and neurorehabilitation specialists, and other professional health care workers.
The S100β protein is a promising candidate as biochemical marker for the diagnosis, monitoring, and prognosis of traumatic brain injury severity.
Declaration of Interest:
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
1. Hyder AA, Wunderlich CA, Puvanachandra P, et al. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 2007;22:341–53.
2. Haydel MJ. Clinical Decision Instruments for CT Scanning in Minor Head Injury. JAMA 2005; 28 : 1551-53
3. Tagliaferri F, Compagnone C, Korsic M, Servadei F, Kraus J A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 2006;148:255–268.
4. Donato R, Heizmann CW. S100Β Protein in the Nervous System and Cardiovascular Apparatus in Normal and Pathological Conditions. Cardiovasc Psychiatry Neurol. 2010;2010:929712.
5. Rodríguez-Rodríguez A, Egea-Guerrero JJ, León-Justel A, et al. Role of S100Β protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults. Clinica Chimica Acta 2012; 414: 228–33.
6. Egea-Guerrero JJ, Revuelto-Rey J,Murillo-Cabezas F, et al. Accuracy of the S100Β protein as a marker of brain damage in traumatic brain injury. Brain Inj 2012;26:76-82.
7. Townend W, Dibble C, Abid K, Vail A, Sherwood R, Lecky F. Rapid elimination of protein S-100B from serum after minor head trauma. J Neurotrauma 2006;23:149–55.
8. Müller K, Elverland A, Romner B, Waterloo K, Langbakk B, Undén J, Ingebrigtsen T. Analysis of protein S-100B in serum: a methodological study. Clin Chem Lab Med. 2006;44:1111-4.
9. Rainey T, Lesko M, Sacho R, Lecky F, Childs C. Predicting outcome after severe traumatic brain injury using the serum S100Β biomarker: results using a single (24h) time-point. Resuscitation. 2009;80:341-5.
10. Dimopoulou I, Korfias S, Dafni U, et al. Protein S-100b serum levels in trauma induced brain death. Neurology 2003;60:947–51.
11. Murillo-Cabezas F, Muñoz-Sánchez MA, Rincón-Ferrari MD, et al. The prognostic value of the temporal course of S100Β protein in the post-acute severe brain injury: a prospective and observational study. Brain Inj 2010;24:609-19.
12. Lange RT, Iverson GL, Brubacher JR Clinical Utility of the protein S100B to evaluate traumatic brain injury in the presence of acute alcohol intoxication. J Head Trauma Rehabil. 2012; 27: 123-34
13. Biberthaler P, Linsenmeier U, Pfeifer KJ, et al. Serum S-100B concentration provides additional information for the indication of Computed tomography in patients after minor head injury: a prospective multicenter study. Shock 2006; 25:446-53.
14. Müller K, Townend W, Biasca N, Undén J, Waterloo K, Romner B, Ingebrigtsen T. S100Β serum level predicts computed tomography findings after minor head injury. J Trauma 2007; 62:1452-6.
15. Bloomfield SM, McKinney J, Smith L, et al. Reliability of S100Β in predicting severity of central nervous system injury. Neurocrit Care 2007; 6:121-138.
16. Petzold A, Green AJ, Keir G, et al. Role of serum S100Β as an early predictor of high intracranial pressure and mortality in brain injury: a pilot study. Crit Care Med 2002; 30:2705-2710.
17. Stranjalis G, Korfias S, Papapetrou C, et al. Elevated serum S-100B protein as a predictor of failure to short-term return to work or activities after mild head injury. J Neurotrauma 2004;21:1070 –1075.
18. Berger RP, Kochanek PM. Urinary S100Β concentrations are increased after brain injury in children: a preliminary study. Pediatr Crit Care Med 2006;7:557-61.
Dr. Juan José Egea-Guerrero, MD, PhD
NeuroCritical Care Unit. Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville
Avda. Manuel Siurot s/n. PC 41013 Seville. Spain.
Ph. + 34 955 012582 // +34 686638646. Fax + 34 955012582.