c 2010 wolters kluwer health lippincott williams & … low serum levels of s100b predict normal...

J Head Trauma RehabilVol. 25, No. 4, pp. 228–240Copyright c© 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Can Low Serum Levels of S100BPredict Normal CT Findings AfterMinor Head Injury in Adults?:An Evidence-Based Review andMeta-Analysis

Johan Unden, MD, PhD; Bertil Romner, MD, PhD

Objective: To determine whether low levels of S100B in serum can predict normal computed tomography (CT)findings after minor head injury (MHI) in adults. Participants: Not applicable. Design: Systematic evidence-basedreview of the peer-reviewed literature with meta-analytical interpretation. Primary Measures: Not applicable. Results:We identified 12 eligible articles that specifically studied adult MHI patients with S100B and cranial CT scans in theacute phase after injury, comprising a total of 2466 separate patients. Individual negative predictive values of 90%to 100% were found for the ability of a negative (under cutoff) S100B level to predict a normal CT scan. A total of6 patients included in the studies had low S100B levels and positive CT scans (0.26%) and only 1 of these patients(0.04%) had a clinically relevant CT finding. The pooled negative predictive value for all studies was more than 99%(95% CI 98%–100%), with an average prevalence for any CT finding at 8%. The studies are consistently classed aslevel 2 and level 3 grades of evidence, suggesting a grade B recommendation. Conclusion: Low serum S100B levelsaccurately predict normal CT findings after MHI in adults. S100B sampling should be considered in MHI patientswith no focal neurological deficit, an absence of significant extracerebral injury, should be taken within 3 hours ofinjury, and the cutoff for omitting CT set at less than 0.10 μg/L. Care givers should also be aware of other clinicalfactors predictive of intracranial complications after MHI. Keywords: evidence, guidelines, head injury, management,meta-analysis, MHI, mild, minor, TBI, S100/S-100/S100B

TRAUMATIC HEAD INJURY is a significant causeof mortality and morbidity in adults1 and is the

leading cause of death in childhood.2 Minor head injury(MHI) represents up to 95% of head injuries3 and man-agement today involves computed tomography (CT)or in-hospital observation, although neither of theseoptions are ideal. In-hospital observation is not cost-effective4,5 and CT is sometimes impractical, not alwaysavailable, involves potentially harmful ionizing radia-tion, and is also relatively costly.6,7 Furthermore, onlya small proportion of patients with MHI have intracra-nial injuries (ICI) and even fewer require neurosurgical

Author Affiliations: Department of Anaesthesia and Intensive Care,Halmstad Regional Hospital, Halmstad, Sweden (Dr Unden); Departmentof Neurosurgery, Rigshospitalet, Copenhagen, Denmark (Dr Romner).

JU has received funding from the following noncommercial sources:Vetenskapliga Radet/Landstinget i Halland, Region Skane and SodraSjukvardsregionen.

Corresponding Author: Johan Unden, MD, PhD, Department of Anaesthesiaand Intensive Care, Halmstad Regional Hospital, 30185 Halmstad, Sweden([email protected]).

intervention.8,9 Several rules have been published aimedat identifying patients with higher risks for CT find-ings and/or neurosurgical intervention. These are basedon patient history and clinical examination such as theCanadian CT Head Rule, the New Orleans Criteria, CTin Head Injury, the Scandinavian Neurotrauma Com-mittee guidelines, and the National Institute for Clin-ical Excellence guidelines.9–13 These guidelines could,in theory, safely identify patients with intracranial com-plications after MHI and reduce CT usage by 12% to46% with very high sensitivities for ICI.14 However,in a recent evaluation, approximately 10% of physi-cians reported that Canadian CT Head Rule and NewOrleans Criteria guidelines were uncomfortable to ap-ply and approximately 5% of physicians misinterpretedthe guidelines and did not order a CT when one wasrequired.15 Furthermore, 30% to 50% of MHI patientsare intoxicated,16 which may confound several of theclinical predictors included in these decision rules.

Over the past 15 years, levels of protein S100B in bio-logical fluids have been shown to be correlated with the

Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

228

Can Low Serum Levels of S100B Predict Normal CT Findings? 229

presence and severity of neurological disorders. S100Bwas originally thought to be specific to astroglia inthe central nervous system, but further studies haveshown the protein in neurons17 and in extracerebraltissues such as adipocytes, chondrocytes, lymphocytes,and bone marrow cells.18 The biological function ofS100B is still somewhat unclear, but it seems to haveboth toxic/degenerative and trophic/reparative roles de-pending on the concentration of the protein.19 S100B isfound in low, but measurable, levels in healthy individu-als, rises rapidly in blood after head injury and has a shorthalf-life of about 30 to 90 minutes.20,21 The possibilityof using serum S100B in patients with MHI was first re-ported in 1995.22 It was first thought that S100B releasewas a biomarker of subtle brain damage after MHI, al-though data suggest that an equally relevant mechanismmay involve the release of extracellular S100B througha disrupted blood-brain barrier, without necessarily in-volving actual cellular damage.19,23,24 Since the origi-nal studies from the mid-1990s, several studies from dif-ferent research groups have explored the ability of thisbiomarker to aid in decision making in the initial phasesof MHI management. These efforts concentrate on thehigh sensitivity of S100B for CT-evident injury, ratherthan specificity, as several studies have shown clear ex-tracerebral sources of the protein.25,26

This report will summarize and analyze the evidencecurrently available to attempt to answer the followingkey clinical question: Can low serum levels of S100Bpredict normal CT findings after minor head injury inadults?

METHODS

Definition of minor head injury

There exist several different definitions of MHI, butall have the common goal to classify patients accordingto the risk of developing acute intracranial complica-tions, such as intracranial hemorrhage and brain con-tusions. Most definitions of MHI include a short pe-riod of unconsciousness or amnesia and grading accord-ing to Glasgow Coma Scale (GCS). In 1995, Stein andSpettell presented their definition based on 25 000 pa-tients where patients with MHI are graded as GCS 14to 15.27 Patients with a GCS score of 13 are sometimesincluded in the MHI group despite the increased in-cidence of intracranial lesions in this group.28 In con-trast, including only patients with a GCS score of 15results in a patient group with a very low risk of clin-ically important complications.29 Mild traumatic braininjury (mTBI) is a term also used in the literature, essen-tially referring to an injury to the brain itself, rather thanthe process and presentation of the injury. This defini-tion is, however, problematic in the sense that it impliesa diagnosis of brain injury without the actual diagnostic

process being completed. Without elaborating furtheron nomenclature issues, MHI will be defined as followsfor the purpose of this review: History of nonpenetrat-ing head injury, GCS score 13 to 15 at admission, lossof consciousness (LOC) or amnesia. This wide defini-tion includes typical aspects from different MHI andmTBI definitions while still focusing on the process andpresentation of the head trauma, rather than the finaldiagnosis after neuroradiology or hospital stay. Studiesof patients presenting with GCS scores of 12 or less werenot included in the analysis.

Index test

The analysis of S100B in serum has been achievedthrough several different techniques, including im-munoradiometric assays, immunoluminometric assays,enzyme-linked immunosorbent assays, and electro-chemiluminescence immunoassays. These are avail-able from several commercial sources and differ inperformance.19 For the purpose of simplicity in this re-port, no distinction will be made between different as-says despite the fact that discrepancies in analytical per-formance may be of importance.30

Reference test

CT is not 100% sensitive for intracranial complica-tions after MHI.31–33 However, cranial CT is widely ac-cepted as the gold standard in detection of intracraniallesions after MHI and evidence shows that patients witha normal CT scan after MHI have a minimal risk of de-veloping an intracranial lesion.8 Cranial CT will there-fore be considered as the reference test in this report.

Search strategy and identification of relevant studies

To adequately answer the key question, we performeda Medline search for studies between 1983 (when CTbecame clinically available) to the present day using ap-propriate combinations of MeSH terms and key words;head injury, TBI, mTBI, MHI, minor, mild, mini-mal, serum, biomarkers, S-100, S100, S-100B, S100B, S-100BB, S100BB, computed tomography, CT, CCT, andmanagement. A less comprehensive TripDataBase andClinical Queries search using these keywords was alsoconducted. We performed this relatively wide search toinclude the maximum number of relevant patients. Thesearch was complemented by examining the bibliogra-phies of identified relevant studies.

Study eligibility

Studies containing adult patients with nonpenetrat-ing head injury with an admission/initial GCS scoreof 13 or more, S100B levels in serum and cranial CTwithin 24 hours of injury and possibilities for extraction


www.headtraumarehab.com

230 JOURNAL OF HEAD TRAUMA REHABILITATION/JULY–AUGUST 2010

of relevant data (sensitivities, specificities, positive pre-dictive values [PPV], negative predictive values [NPV],and prevalence) for the relevant patient group were in-cluded. Studies concerning children were excluded.

Data extraction

The eligible studies were examined and relevant datarecorded including; first author, year of publication,study design, patient group and inclusion criteria, char-acteristics of the index test including cutoff used, rele-vant results with respect to the key question includingpredictive statistics, and study limitations. If certain keyfactors or data were missing from the studies, authorswere contacted for clarification. In the case of multiplestudies from the same research group, authors were alsocontacted to ensure unique patients. Because a cutoff of0.10 μg/L has independently been reported from differ-ent research groups,21,34 results in relation to this levelwere extracted, if possible, to attempt an interpretationof data using the same cutoff.

Quality assessment

Studies were graded and assigned a quality rating withrespect to the key question according to the Centre ofEvidence Based Medicine (CEBM) criteria.35 Studieswere graded from 1 (strongest evidence, for instancereports of clinical decision rules and high quality val-idating study) to level 5 (weakest evidence, often expertopinion). Following this, the 14 Quality Assessment ofDiagnostic Accuracy Studies (QUADAS) criteria36 wereapplied. Studies receive scores from 1 (lowest quality) to14 (highest quality) based on 14 separate criteria relevantto diagnostic studies accounting for bias (items 3–7, 10–12), variability (items 1–2), and reporting (items 8–9, 13);1 point was given for each criteria satisfied. Studies with3 or more missing points (ie, 11 points or less in total)were downgraded one level. Studies therefore receiveda final evidence level accounting for both criteria. Thisapproach was used to account for classical features ofstudies (CEBM) including specific details related to di-agnostic studies (QUADAS). The final recommendation(A to D) is based on CEBM criteria; grade A referringto consistent class 1 studies, grade B for consistent level2 or 3 studies (or extrapolations from level 1 studies),grade C for level 4 studies (or extrapolations from level2 or 3 studies), and grade D for level 5 studies.

Data presentation and analysis

Studies are briefly presented in evidentiary tables.Data are presented in table form with correspondingnumber of patients with true positives (TPs), false pos-itives (FPs), false negatives (FNs), and true negatives(TNs) for each study along with relevant comments con-cerning FN patients. We explored heterogeneity using

a using a Chi-squared test. Because of heterogeneity,weighted pooled sensitivity and specificity were calcu-lated with a random effects model. We calculated likeli-hood ratios and predictive values from the pooled sen-sitivities and specificities derived from the random ef-fects model. This approach also eliminates differencesin prevalence from the studies and allows for calculationof predictive values corresponding to typical prevalencelevels for this patient group.

RESULTS

A total of 272 abstracts were examined independentlyby the authors and 49 full manuscripts were chosen andstudied in detail. Twelve studies were found eligible forthe current review and data analysis,21,34,37–46 consistingof 2466 separate patients. These studies are presented inthe evidentiary table, Table 1. The number of patientsincluded in the cohorts range from 50 to 1309 patients(average 206 patients). Time from injury to S100B sam-pling ranged from less than 3 hours to less than 24 hoursaccording to inclusion criteria (with all but one studysampling patients within 12 hours). The settings for allstudies were emergency departments in the followingcountries; Sweden, Norway, Germany, France, Slovenia,Brazil, and the United States. In 6 of the studies, dataconcerning a cutoff of 0.10μg/L could be analyzed, insome instances after contact with authors.

Table 2 presents studies with accompanying TP, FP,FN, and TN results, also including pathological radio-logical data from patients with S100B under the cutofflevel.

The 12 eligible studies show similar results with highindividual sensitivities (75%–100%). More importantly,they show very high individual NPVs (90%–100%) forthe ability of a negative (under cutoff level) S100B levelto predict a normal CT scan. Six FNs (low S100B, butpositive CT scans) were found in the total patient groupof 2264 patients (0.26%). These diagnoses were 2 smalltraumatic subarachnoid hemorrhages, 2 skull fractures,1 patient with a small cerebral contusion, and 1 patientwith an acute subdural hematoma. Only the latter pa-tient needed surgical intervention (1 patient from thetotal of 2264, 0.04%), 17 days after the trauma, fromneurological deterioration.

Meta-analysis

Sensitivities were only borderline homogenous(Q = 19, degrees of freedom = 11, P = 0.054) but speci-ficities were clearly heterogeneous (Q = 168, P < .001).Considering only those studies in which a cutoff of 0.10μg/L could be evaluated did not eliminate heterogeneity(Q = 15, degrees of freedom 7, P = .042 for sensitivity andQ = 27, degrees of freedom 7, P < .001 for specificity).Because of this heterogeneity, a random effects model



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TABLE 2 Table showing the 12 eligible studies with true positives (S100+, CT+), falsepositives (S100+, CT−), false negatives (S100−, CT+), true negatives (S100−, CT−)and brief information concerning false negatives

CT+ Patientswith S100

Study, year S100+, CT+ S100+, CT− S100−, CT+ S100−, CT− Total Below Cutoff

Ingebrigtsen et al38 9 60 1 112 182 tSAH, S100B 7 hafter injury, notreatment

Bazarian et al44 3 73 1 9 86 Skull fractureNygren de Boussard et al43 4 33 0 29 66Poli-de-Figueiredo et al39 6 35 0 9 50Muller et al, 2007 20 141 1 64 226 Small brain

contusion, nobrain injury ortreatment

Ingebrigtsen et al37 3 11 0 36 50Biberthaler et al21 92 855 1 361 1309 Skull fracture, no

brain injury ortreatment

Biberthaler et al41 24 43 0 37 104Biberthaler et al42 15 22 0 15 52Mussack et al40 19 60 0 60 139Bouvier et al46 16 60 0 29 105Morochovic et al45 15 57 2 23 97 tSAH and SDH

(83 y of age,GCS score 15,surgery after17 d)

Total 226 1450 6 784 2466

Abbreviations: CT, computed tomography; GCS, Glasgow Coma Scale; tSAH, traumatic subarachnoid hemorrhage; SDH, subduralhematoma.

was utilized. Figures 1 and 2 show graphical presenta-tions of sensitivities and specificities from the studies,and Figure 3 shows a summary receiver operating char-acteristic curve based on the same data. Table 3 presentsthe weighted pooled statistical data from the 12 stud-ies. The pooled sensitivity for all studies was 97% (95%CI 91%–99%) and the pooled specificity 40% (95% CI30%–51%). Considering the 6 studies where a cutoff of0.10 μg/L could be evaluated, sensitivities and specifici-ties were 96% (95% CI 85%–99%) and 30% (95% CI23%–38%), respectively.

The prevalence of intracranial findings after MHIhas been reported to be in the ranges of 1% to10%.8,9

Corresponding NPVs for prevalence levels of 1%, 5%,10%, and 20% are 100% (95% CI 100%–100%), 100%(95% CI 99%–100%), 99% (95% CI 97%–100%), and98% (95% CI 94%–99%), respectively. PPVs consider-ing prevalence levels of 1%, 5%, 10%, and 20% are 2%(95% CI 1%–2%), 8% (95% CI 7%–9%), 15% (95% CI13%–18%), and 29% (95% CI 25%–33%), respectively.The average prevalence from the included studies in this

article was 8%, giving a NPV of more than 99% (95%CI 98%–100%).

The studies are consistently classed as level 2 and level3 grades of evidence, which suggests a grade B recom-mendation according the CEBM criteria.

DISCUSSION

Limitations

The included studies use different assays for detec-tion of S100B in serum, which is a potential sourceof error. Different assays may report different levels ofS100B from the same sample from differences in per-formance characteristics.30 Four studies used the LIAI-SON assay from Sangtec (total number of patients 555),2 used the Elecsys assay from Roche (total number of pa-tients 1359), 2 used immunoluminometric assays fromSangtec (total number of patients 118), 1 used immuno-radiometric assays from Sangtec (total number of pa-tients 50), and the final study used a Sangtec 100 (to-tal number of patients 182). Hence, the Elecsys assay



Figure 1. Figure showing individual and pooled sensitivity ofS100B for computed tomography findings in 12 studies. Sizesof bold markers proportional to logarithms of number of pa-tients in the studies; horizontal lines represent 95% confidenceintervals computed according to Agresti and Coull.

accounts for 60% of the patients and the LIAISON ac-counts for 25%. Because the LIAISON assay reportshigher values of S100B than the Elecsys assay,30 it isunlikely that the pooled sensitivity would be decreasedif differences in assay performance were corrected. Ulti-mately, it is most correct to apply evidence from a cer-tain assay to only those patients measured with the sameassay. This approach is unpractical however, because dif-

Figure 2. Figure showing individual and pooled specificity ofS100B for computed tomography findings in 12 studies. Sizesof bold markers proportional to logarithms of number of pa-tients in the studies; horizontal lines represent 95% confidenceintervals computed according to Agresti and Coull.

Figure 3. sROC (summary receiver operating characteristic)curve from all 12 studies showing the relationship of sensitivityvs 1-specificity.

ferent assays will always exist and new assays with newtechnologies will replace older versions. This problem istherefore not unique to S100B and difficult to accountfor.

Because S100B is also produced by melanocytes, dif-ferent races could have different basal levels of S100B.This aspect has not been examined in these studies andshould be considered in future studies.

According to the QUADAS tool, the included pa-tients are judged relatively representative for the tar-get population for the test. Despite this, the prevalenceof intracranial complication differs between the stud-ies, generally being higher than values reported in theliterature.8,9 In particular, 2 of the studies had a preva-lence of CT findings over 20%, yet both these alsoshowed NPVs of 100%.41,42 These aspects, together withthe observed heterogeneity, are worrying and suggestbias but cannot be penetrated further in this report.However, consideration for this was achieved through

TABLE 3 Data showing pooled statisticsfor all patients from the 12 studies

Lower 95% Upper 95%CI CI

Sensitivity 97 91 99Specificity 40 30 51Positive 1.6 1.3 1.9

likelihood ratioNegative 0.080 0.025 0.25

likelihood ratioTheoretical 32%

computedtomographyreduction

Abbreviation: CI, confidence interval.




the use of a random effects model for the statistical anal-ysis and calculating predictive values based on typicalprevalence values for this patient group.

Detection of CT findings versus surgical intervention

Studies concerning the early diagnostic managementof head injury usually report both CT findings andneurosurgical intervention (alternatively clinically im-portant brain injury) as endpoints.9–11,13 In this report,we focus only on CT findings. However, it is obvious,without statistical analysis, that the sensitivity of S100Bfor surgical intervention (or clinically important braininjury) would be even higher because only 1 patient(subdural hematoma) would be included in this group.Because the prevalence of surgical intervention and clini-cally important brain injury is very low after MHI (0.1%–1%),8,9 the NPV based on the data would be 100% withvery narrow CIs.

Can S100B be used in other severities of head injury?

The predictive performance of S100B will depend onwhich patients are considered for testing. This is relatedto the pretest probability (prevalence) of the relevant out-come; in this case, CT findings or clinically relevant in-tracranial complication. A lower pretest probability willresult in an increased NPV and a decreased PPV andvice versa. This also stresses that S100B can initially beapplied only to similar patient cohorts as those reportedin the studies examined within this report. ApplyingS100B to other patients will result in different posttestprobabilities, which may cause a diagnostic imbalancetoward false negatives (missed patients) or false positives(unnecessary CT scans). Oh et al found a sensitivity of97%, a specificity of 54%, an NPV of 88%, and a PPVof 84% for CT or magnetic resonance imaging findingsusing a cutoff of 0.105 μg/L in a cohort of 45 patientswith mild, moderate, and severe head injury.47 In fact,only 1 patient with radiological findings showed a S100Bbelow the reference limit, despite the high prevalenceof complications and the use of MRI as the referencetest.

The emergence of new decision rules for CT scan-ning has further complicated this issue. Ideally, S100Bcould be used in conjunction with these rules. Becauseof the very high sensitivity of S100B, the test should bemade before applying the decision rule when the pretestprobability is low. Applying S100B to patients selectedfor CT (via the decision rule) would lead to a lower nega-tive prediction because of a higher pretest probability. Itmust be remembered that, in contrast to the clinical deci-sion rules, S100B is an objective measurement and is notaffected by intoxication in MHI. Studies of CT predic-tion combining S100B with recently presented clinicaldecision rules are welcomed.

Is S100B influenced by alcohol intoxication?

Clinical parameters included in existing and proposedmanagement guidelines may be difficult to interpret inintoxicated patients, and some of these guidelines in-clude intoxication as a indicator for CT scanning.9,48 Inaddition, CT scanning or hospital observation may bepractically difficult in these patients. Because between30% and 50% of patients with MHI are intoxicated,49,50

this presents a practical management problem. Small el-evations of S100B after moderate alcohol intake in non–head-injured subjects has been reported,51 althoughS100B does not seem to be affected by alcohol intoxi-cation in head-injured patients.40,51,52 This is confirmedby unpublished data from our clinic where intoxicatedpatients show similar levels of S100B compared withsober patients.

What is the evidence for S100B use in children withhead injury?

The management of children with traumatic head in-jury is more complicated than in adults, because pa-tient history may be unreliable and physical exami-nation can be practically difficult. Also, CT scans ofchildren should be minimized because of potentialhealth risks.7 Despite recent impressive reports of pre-diction rules,53 a biomarker is welcomed in this patientcategory. Reference levels for healthy children are higherthan in adults.54–56 Berger and colleagues have publishedseveral studies concerning S100B levels in children afterTBI,57–60 showing promising results. These studies alsohighlight the diagnostic problem of inflicted TBI, an areawhere a reliable biomarker may have considerable clini-cal impact. Bechtel et al61 recently reported a study withS100B levels in serum after closed head injury in chil-dren younger than 18 years. They found that S100B wasa poor predictor of intracranial injury at a cutoff of 0.5μg/L with a PPV of only 20%, but found a high NPVof 90% at the same cutoff. They also investigated theimpact of bone fractures on S100B levels and, similar toresults in adult studies,25 found that these extracranialinjuries may be responsible for the poor specificity ofS100B in trauma. Castellani et al present a study of 109children with MHI in which they found a sensitivity andNPV of 100%, a specificity of 42%, and a PPV of 46%for CT findings using a cutoff of 0.16 μg/L derived fromanalysis of healthy children.62

Venous cannulation is not always performed afterMHI in children, especially in asymptomatic cases. Re-ports considering urine measurements of S100B in chil-dren showed initial promise.63,64 However, in a case-control pilot study, Pickering et al concluded that early(<12 hours after injury) urinary levels of S100B arenot useful in pediatric head injury.65 A recent study bySchultke et al confirmed these findings.66 Measurements



of capillary S100B would be a suitable option becausethis sampling method is often used for children in theemergency department. Unpublished results from an on-going study in Sweden show that capillary S100B is sig-nificantly correlated to, but not interchangeable with,venous samples. Therefore, separate reference and in-jury values must be studied before this method can beconsidered. Summarizing, although reports are gener-ally promising, the evidence for S100B in pediatric TBIis insufficient and must be expanded before it can beconsidered for clinical utility.

What is the evidence for other biomarkersin MHI management?

Because S100B is not specific to the brain, othermore specific biomarkers are needed to obtain a clin-ically useful specificity and PPV for brain injury afterMHI. Several other biomarkers have been studied inhead injury, including glial fibrillary acidic protein,67–69

brain- and heart- fatty acid-binding proteins,70 myelinbasic protein,71 neuron-specific enolase,72 and alpha II-spectrin breakdown products.73 Of these, glial fibrillaryacidic protein seems most interesting with a much betterclinical specificity than S100B.74 However, these mark-ers have not been sufficiently investigated in MHI andfurther studies are needed before any conclusions canbe made.

Will S100B miss important CT complications?Comparison with other clinical tests

S100B used in the proposed setting is not 100% sen-sitive. It is unreasonable to expect an actual 100% sen-sitivity or NPV from a diagnostic test. In this clinicalsituation, a very high sensitivity and even higher NPV isacceptable if combined with other diagnostic variables.It is important that clinicians are aware that neither de-cision rules nor recommendations are completely reli-able but merely based on the best available evidence.75

If S100B was to be used alone as a diagnostic tool af-ter MHI, without considering other clinical aspects, thiswill eventually lead to a false negative result (ie, a caseof ICI after MHI will be missed). Parallels can be madewith other diagnostic tests in potentially serious clinicalconditions.

Pulmonary embolism (PE) is a feared clinical con-dition with relatively high morbidity and mortality.Diagnostic problems with PE show several parallels withintracranial complications after MHI. The blood testD-dimer has been used for many years for the purposeof selecting patients who do not need radiological in-vestigation. Despite many years of experience with thetest and multiple efforts of refining assays and guide-lines, the sensitivity and NPV of D-dimer for PE has

recently been reported to be 95% (95% CI, 73.1%–99.7%) and 99% (95% CI, 96.2%–99.9%), respectively,with low specificity and PPV.76 This is inferior to the per-formance of S100B. The performance of D-dimer is evenpoorer when referring to deep vein thrombosis insteadof PE with sensitivities/NPVs of 88%/99%, 90%/96%,and 92%/84% in low-, moderate-, and high-prevalencegroups, respectively.77

Myoglobin, troponin I, and troponin T have largelyreplaced the rather unspecific creatine kinase MB asa heart-specific biomarker used in the diagnostics ofacute myocardial infarction. In a recent large multi-center study, Keller et al found sensitivities/NPVs foracute myocardial infarction of 61%/87% for myoglobin,91%/96% for troponin , and 73%/91% for troponin T.78

Epidural hematoma is a feared complication to MHI.Initially, before clinical manifestation, this conditionmay not be associated with any actual brain damage, butis rather an expanding extradural mass with a risk of fu-ture brain damage if left untreated. Hence, a biomarkerof brain damage may be insensitive of this condition.However, all epidural hematomas reported in the litera-ture have shown S100B levels over 0.10 μg/L, althoughthe values are often relatively low,34,79 which supportsthe idea that S100B is also a biomarker of blood-brainbarrier disruption23,24 as well as a marker of actual celldamage. Six patients from this report had pathologicalCT findings and a S100B level below cutoff. Only 1 ofthese patients required surgical treatment and would beclassified as clinically important brain injury accordingto the Canadian CT Head Rule decision rule.10 This pa-tient (an 83-year-old female with cardiopulmonary dis-ease) had an admission GCS score of 15 with risk fac-tors of headache and vomiting and would therefore bemissed by several of the existing clinical guidelines. Also,this patient was first surgically treated after 17 days post-trauma for neurological deterioration (presumably thena chronic subdural hematoma and hence likely to beeventually detected by clinical means).45

The half-life of S100B has been shown to be as shortas 25 minutes,20 although a recent study in patients withMHI has shown a half-life of 97 minutes.80 This impliesthat the timing of S100B sampling is important to avoidmissing patients with CT pathologies. If considered forclinical use, S100B should therefore be taken within 3hours of injury until more data are available.

Certain clinical risk factors have shown strong associ-ations with intracranial injury. In our opinion, patientswith special risk factors, particularly clinical signs of skullfracture, posttraumatic seizures, certain anticoagulationtherapies, and shunt-treated hydrocephalus should notundergo S100B sampling, but should receive a CT ac-cording to normal practice,12 because these factors havenot been properly addressed in the literature.




Future aspects

Serum S100B levels show a high sensitivity and NPVfor intracranial complications after MHI. The speci-ficity is poor, mostly from contamination of extracere-bral S100B,25 although it is also possible that S100Bmay be more sensitive for certain trauma-induced le-sions than CT81 and elevated levels may, in some cases,be reflecting subtle brain damage. It is also possible thatextracranial trauma may release cytokines that can dis-rupt the blood-brain barrier and allow extracellular cere-bral S100B to enter the bloodstream. The developmentand validation of other, more specific brain biomarkers,should address these aspects. Specificity issues aside, thisobjective biochemical tool may reduce the frequency ofCT scanning after MHI by as much as 30%. Incorpo-rating methods of correction to account for extracere-bral contamination may further improve this figure.44

These are, however, only theoretical values of CT reduc-tion and the health economics of S100B implementa-tion remain to be elucidated. An interesting report fromRuan et al addresses this aspect and the authors concludethat S100B can be cost saving, depending on the clin-ical utility and setting.82 Preliminary data from an on-going study in a level III trauma hospital in Halmstad,Sweden, indicate that S100B has reduced CT scans after

MHI by approximately 15% and is cost effective. Dur-ing 3 years of clinical application, no patients have beenmissed by S100B, currently used as a clinical decisionrule in conjunction with the Scandinavian NeurotraumaCommittee guidelines. Several studies concerning theuse of brain biomarkers, including S100B, in pediatrichead injury are underway.

Serum levels of S100B are used in MHI managementin several European countries, including Sweden andGermany, in conjunction with existing guidelines, al-though none of these has been published or validated.

CONCLUSION

Low serum S100B levels accurately predict normal CTfindings after MHI in adults. The evidence in this reportsupports a grade B recommendation. S100B samplingshould be considered in MHI patients with no focalneurological deficit, an absence of significant extracere-bral injury, should be taken within 3 hours of injury andthe cutoff for omitting CT set at less than 0.10 μg/L.Approximately one third of CT scans may be omit-ted using this approach in the defined patient group,although care givers should be aware of other clini-cal factors predictive of intracranial complications afterMHI.

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