Traumatic brain injury: assessment by biochemical serum markers Tor Ingebrigtsen 1, Bertil Romner 2

Tromso Universitas Hospital, Tromso, 2 Lund University Hospital, Lund University Hospital, Lund, Sweden

Introduction
The annual incidence rates of hospital-admitted head injuries vary between 90 and 400/100 000 population in different Western coutries [1]. Most of the patients with head injuries are fully conscious when evaluated. The management of such minor head injuries (MHI) is focused on the early detection of patients who deteriorate due to a post- traumatic intracranial haematoma. Expensive screening methods such as hospital admission for overnight observation or computed tomographic (CT) scanning are used to detect the relatively few individuals who develop this life-threaning complication [2]. After the injury, many patients experience postconcussion symptoms, even after uneventful recoveries in the acute stage. In most western countries, injuries are the leading cause of death among individuals under 45 years of age [1]. Traumatic brain injury (TBI) accounts for one half of the deaths and most cases of permanent disabibility after injury . Accurate evaluation of the primary injury and prevention of secondary ischaemic injury is assential in the clinical management. TBI is, however, difficult to assess. Clinical examination is of limited value in the first hours and days after a severe head injury (SHI). Most of the diagnostic proses in based on modern neuroimaging tecniques, such as CT or magnetic resonance imaging (MRI), but CT has a reatively low sensitivity for diffuse brain damage and the availability of MRI is limited. A biochemical marker in the seum with the ablity to both detect intracranial pathology and to predict postconcussion symtoms would be highly desirable in the management of MHI. There is also a major need for biochemical markers in the SHI, both to assess the severity of the primary TBI and to detect secondary injury. Finally , such biochemical markers may be of value as surrogate end-points in clinical trials of neuroprotective treatments.

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Biomarkers of traumatic brain Injury CT scan show increased serum S-100 level. A cut off value of about 2.0 g/1 seems

to distinguish between those patients with good and bad clinical outcomes, with a specificity of well over 90% [7,11]. MBP and GFAP MBP is found in growing oligodendroglial cell and is specific to myelin. GFAP constitutes the mojor part of the cytoskeleton of astrocytes and is found only in astrogial cell of the central nervous system. There are few studies on the serum levels of these proteins in head-injured patients. GFAP is, however, of great interest since its brain specificity may be even better than that of NSE and S- 100. Resently, missler et al. [12] reported increased serum GFAP levels in 12 of 25 head-injured patients with SHI. Hence, GFAP may be every specific marker of the primary TBI. Summary and discussion The early studies of different snzymes showed that substances may be released from the brain and detected in serum after a brain injury. Such enzyme release requires that there is cell damage with release of the enzyme into the interstitium, and that there is concomitant injury to the blood-brain barrier.this is probably the case in most brain injuries. Experimental studiesshow that even mild diffuse axonal injuryis accompanied by endothelial discruption in cerebral capillaries with astrocyte swelling. Therefore, the appearance in serum of substances releasd from damaged astrocytes and neurons would be expected in most cases of brain injury. Today, it is clear that the main drawback with the measurement of enzymes such as LDH, GPT and GOT has beeb their lack of specificity for brain injury. The studies of CK-BB showed more clearly that the amount and severity of TBI may carrelate with serum levels of substance released from the brain. The result obtained with CK-BB measurements were encouraging, probably because the barin specificity of this enzyme is better than that of the enzymes studied earlier. The specificity of this test is not, however, adequate for the accurate assessment of injury to the brain (table 39.2) [4] CK-BB and the other enzymes mentioned above are released from astroglial cell. Direct interpretation of injury to neurons by measurements of a substance released from these cell may be considered more relevant. NSE is he only marker available for such studies, but

experience eith this maeker is disappointing despite highspecificity for the brain ( Table 39.2). the reason for this may be related to difficulties in defining the optimal point of time for NSE measurements since the biological halh-life of enzyme is more than 20 hurs. This slow eliminatiaon of NSE from 400 T. Ingebrigtsen, B Romner Table 35.2 relative concentration (%) of CK-BB, NSE and S-100 in human tissues CK-BB 100 49.1 35.3 35.3 31.9 19.2 22.1 12.1 11.3 5.4 5.7 3.5 0.5 o.7 0.8 0.3 0.3 nr NSE 100 1.9 2.6 2.6 2.0 1.9 1.1 1.4 2.6 0.9 0.1 1.5 0.1 2.5 0.5 0.2 0.2 nr S-100 100 2.5 0.7 0.7 0.1 2.1 0.2 0.2 0.2 1.9 1.8 0.2 1.8 1.8 0.1 0.1 0.7 0.2

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(MDH).These early reports demonstrated increased enzyme activity in serum in many headinjured patients, but these markers did not have sufficient specificity for brain injury (4). In the 1980s, promising results were observed in studies of the creatine kinase isoenzyme BB (CK-BB). Recent research has been focused on neurone-specific enolase (NSE) and S-100 protein. These are specific markes of damage to neurons and astroglial cells, respectively. Interesting reports on two others markers of astroglial cells damage, myelin basic protein (MBP) and glial fibriallary acidic protein (GFAP), have also been published. CK-BB In the centra nervous system, CK-BB is located in the astrocytes. CK-BB is, however, also present in other organs, such as the large intestine and prostate. The concentration in these

organs is one-third to one-quarter of that found in the brain (see Table 39.2). Several reports published in the 1980s showed correlations between serum levels of CK-BB and the severity of brain injury. 401 Biomarkers of traumatic brain injury Skogseid et al.[5] performed both CK-BB measurements and CT scanning in patients with MHI, but there was no correlation between CK-BB serum levels and CT finding. Aweak tendency towards more postconcussion symptoms and mild neuropsychological dysfunction was, however, observed among patients with increased CK-BB levels, indicating more pronounced TBI in these patients. CK-BB has been extensively studied in patiens with SHI. It is clear that enzyme levels are highest on the first day after injury and that serum levels usually decline to normal levels within a few days in surviving patients [4, 5]. The levels of the enzymein serum is, however, not consistently associated with poor outcome. Thefore, Bakay and Ward [4] concluded that the sensitivity and specicificity of CK-BB is inadequate for use as an indicator of neurogical trauma. NSE At present, NSE is the only marker which specifically indicates traumatic damage to neurons. It is located in the cytoplasm of neurons and is probably involvedin creasing neuronalchloride levels during the onset of neurol activity. NSE is aslo found in peripheral neuroendocrine tissues and tumours and, thehefore,is currently used as biochemical marker of tumours such as neuroblastoma, melanoma and small cell lung cancer. The biological halflife of this protein is probably more than 20 hours. Increased serum levels of NSE have been observed in patients with head injury (5), but NSE levels are neither significantly different between MHI patients and controls nor between MHI patients and patients with SHI (6). Served studies have correlated NSE serum levels with both clinical and neuroradiological measures of injury severity and with outcome, but the results have been disappointing. Some authors have reported weak correlation between NSE and CT findings, as well as between NSE and Glasgow Coma Scale (GCS) score (5), but these findings have not been confirmed by others. No correlation has been found between serum levels of NSE and long-term outcome after SHI (7).

S-100 protein