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Serum S100B, a Predictive Biomarker for Intracranial Injuries in Minor Head Injury.

Three Part Question

In [adult patients with minor head injury] is [serum S100B], [compared to head CT scan], [predictive for intracranial injuries]?

Clinical Scenario

A 50 year old male presents to the emergency department with signs of head injury, a GCS of 14 and heavily intoxicated with alcohol. He had similar presentations in the past needing a head CT scan repeatedly. His GCS is 14 after 2 hours. A CT scan is indicated and is normal. Could this CT scan have been avoided by using a serum S-100B blood biomarker test?

Search Strategy

Pubmed Medline 1949 - 2010 December
OVID Medline 1949 - 2010 December + Embase 1980 - 2010 December
CINAHL using EBSCO interface 1981 - 2010 December
TRIP database
Cochrane Library
Google search and Scholar

Pubmed Medline (All fields), CINAHL, TRIP database:
(S100 OR S-100 OR S100B OR S-100B OR S100BB OR S-100BB) AND (TBI OR mTBI OR MHI OR ((Brain OR Craniocerebral OR Head) AND (Trauma OR Injury OR Injuries))) AND (Minor OR Mild)
OVID Medline + Embase:
((S100 or S-100 or S100B or S-100B or S100BB or S-100BB) and (TBI or mTBI or MHI or ((Brain or Craniocerebral or Head) and (Trauma or Injury or Injuries))) and (Minor or Mild)).mp.
Cochrane library:
(S100 OR S-100 OR S100B OR S-100B OR S100BB OR S-100BB)

Search Outcome

Pubmed Medline: 107 articles
OVID Medline + Embase: 151 articles
CINAHL: 17 articles
TRIP Database: 37 articles
Cochrane Library: 180 articles

47 studies (all present in the Pubmed Medline search result)deemed relevant for full paper review
17 studies selected
1 additional study obtained by personal correspondence and later published in 2011 / 2012

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Ingebrigtsen, et al.
1999
Sweden
50 patients with minor head injury within 12 hours of injury. GCS 13-15. Loss of Consciousness (LOC) <20min or amnesia. Age 12-72yrs. No focal neurological deficit. No CT evident injury on initial report. CT review showed 4 abnormal CTs 4 fractures, 2 of which had contusion on CT. Index test: Serum S100B (Sangtec Medical AB, cut-off 0.20 g/L (assay lowest detection limit), taken ≤ 12 hrs from injury. Gold standard: MRI, Positive CT scan. Prospective cohortSensitivity1.00Originally designed to compare serum S100B with MRI. All patients had normal initial CT. Subsequently 4 CTs found abnormal on 2nd report. Selection bias. Neurosurgical referred population. Age 10-72 yrs. Not powered. No blinding.
Specificity0.77
PPV0.21
NPV1.00
LR+4.34
LR-0
Ingebrigtsen, et al.
2000
Sweden
182 patients with minor head injury within 12 hrs of injury. ≤10min LOC, GCS 13-15. No focal neurological deficit. Age 15-80 yrs. Index test: Serum S100B (LIA, Sangtec), cut-off 0.20 g/L (lowest detection limit), taken ≤ 12 hrs. Gold standard: Positive CT scan, within 24 hrs of injury. Prospective cohortPrevalence0.10Selection bias. Age ≥15 yrs. Small study over 28 month period. Not powered. No precision analysis. No blinding. S100B sampled within 12 hrs. Extracranial injuries not excluded
Sensitivity0.90
Specificity0.65
PPV0.13
NPV0.99
LR+2.57
LR-0.15
Biberthaler, et al.
2001
Germany
52 patients with isolated head injury GCS 13-15 + One of: Amnesia, LOC, nausea, vomiting, vertigo or severe headache. No focal neurological deficit. Control groups: +ve (severe) n=20, -ve (healthy) n=10. Index test: Serum S100B (LIA, Sangtec), cut-off 0.10 g/L, sampling time from trauma 11618 min. Gold standard: Positive CT Scan ≤ 6 hrs after injury.Prospective cohortPrevalence0.28Selection bias (high prevalence). Small study. Not powered. No precision analysis. No blinding. No age specified (adults according to personal correspondence). Convenient cut-off level taken to achieve 1.0 sensitivity. No ROC curve analysis.
Sensitivity1.000
Specificity0.405
PPV0.405
NPV1.000
LR+1.680
LR-0
Mussack, et al.
2002
Germany
139 adults with: Isolated head injury GCS 13-15 + One of: Transient LOC <5 min, Amnesia, Nausea, Vomiting, Vertigo. Index test: Serum S100B (LIAISON Sangtec)cut off 0.21 g/L Median sample time 24.3 min (IQR 18-62.5) Gold standard: Positive CT scanProspective cohortPrevalence0.137Selection bias: High prevalence, Oktoberfest population, only 19 sober patients. Consecutive sample over 18 days. Small study, not powered. No blinding mentioned. Short sampling time of 24.3 min(IQR 18-62.5 min) - difficult to replicate in practice. Limited precision analysis.
AUC (at cut-off 0.21 ug/L)0.86 (95%CI 0.78-0.94)
Sensitivity1.00
Specificity0.50 (95%CI 0.49-0.59)
PPV0.24
NPV1.00
LR+2.0 (95%CI 1.70-2.44)
LR-0
Biberthaler, et al.
2002
Germany
104 patients with: Isolated head injury within 2 hrs of injury, GCS 13-15 + One of: Transient LOC (<5 min), Amnesia, Nausea, Vomiting, Vertigo. Severe headache. Index test: Serum S100B(LIAISON Sangtec)cut-off 0.12 g/L, taken ≤2 hrs from injury. Gold standard: Positive CT Scan. Prospective CohortPrevalence0.23Selection bias. Small study over 18 months. Not powered. No blinding mentioned. Sampling time ≤2 hrs not practical. Limited precision.
AUC 0.79 (95%CI 0.70-0.89)
Sensitivity1.00
Specificity0.46
PPV0.35
NPV1.00
LR+1.85
LR-0
Biberthaler, et al.
2004
Germany
75 patients with: Isolated head injury presenting within 2 hrs of injury, GCS 13-15 + One of: Transient LOC (<5 min), Amnesia, Nausea, Vomiting, Dizziness, Severe headache. Index test: Serum S100B (Elecsys S100, cut-off 0.14 g/L, taken ≤2 hrs. Gold Standard: Positive CT Scan. Prospective cohort pilot studyPrevalence0.19Small study - not powered. Selection bias. No blinding mentioned. Sampling time ≤2 hrs not practical. Pilot study Basis for multicentre study.
AUC0.88 (95%CI 0.80-0.96)
Sensitivity1.00 (95%CI 0.75-1.00)
Specificity0.66 (95%CI 0.54-0.78)
PPV0.40 (95%CI 0.24-0.56)
NPV1.00 (95%CI 0.89-1.00)
LR+2.27
LR-0
Nygren de Boussard, et al.
2004
Sweden
66 patients with: Isolated head injury within 24 hrs of injury, Age 15-65 yrs, GCS 14-15. + One of: LOC <30 min, Amnesia <24 hrs. No other major injury. Index test: Serum S100B ≤24 hrs (LIA-mat S100 Sangtec)cut-off 0.15 g/L, 0.10 g/L using Unden meta-analysis. Gold standard: Positive CT Scan ≤24 hrs, MRI ≤7 days. Prospective cohortPrevalence0.06Small sample. Selection bias. Not powered. No blinding mentioned. Sampling up to 24 hrs. Outcome CT and/or MRI pathology (all patients had a CT scan) CT outcome measure results (without MRI) obtained only using Unden et al meta-analysis.
Sensitivity at 0.15ug/L cut-off0.80
Using Unden meta-analysisat 0.10 ug/L cut-off
Sensitivity1.00
Specificity0.47
PPV0.11
NPV1.00
LR+1.88
LR-0
Poli-de-Figueiredo et al
2006
Brazil
50 patients with: Isolated head injury GCS 13-15 + One of: Amnesia, LOC, Nausea, Vomiting, Vertigo, Severe headache, No focal neurological deficit. Index test: Serum S100B(Elecsys 2010), cut-off 0.10 g/L. Median sample time 82 min (IQR 60-110 min). Gold standard: Positive CT Scan ≤6 hrs from arrival. Prospective cohortPrevalence0.12Small sample, No age specified, (in separate study Lima et al showed 39 out of 50 cases had mean age 392.87). Selection bias. No blinding mentioned. Not powered. No precision analysis. Samples transported deep frozen for analysis in Germany.
AUC0.82 (95%CI 0.69-0.96)
Sensitivity1.00
Specificity0.20
PPV0.15
NPV1.00
LR+1.25
LR-0
Bazarian, et al.
2006
USA
96 patients with minor head injury within 4 hrs of injury + One of: LOC <30 min, Amnesia <24 hrs, Any altered mental state, GCS >13 after 30min. 86 cases (≥15 yrs) analysed by Unden et al meta-analysis. Index test: Serum S100B(Liaison Sangtec 100)cut-off 0.08 g/L, 0.10 g/L from Unden et al meta-analysis. Sampling time ≤4 hrs. Gold-standard: Positive CT Scan.Nested CohortPrevalence0.05Primary aim: Creatine kinase (CK) corrected S100B validation. Nested cohort: 96 subjects out of a larger cohort of 792 consecutive minor head injury cases participating in another study. Age 8-79 yrs. Selection bias. African-Americans excluded. Small sample. Not powered. No blinding mentioned. Extracranial injuries not excluded.
AUC0.49
At cut-off 0.08 ug/L:
Sensitivity0.8
Specificity0.04
From Unden's meta-analysis,at cut-off 0.10 ug/L:
Sensitivity0.750
Specificity0.650
PPV0.130
NPV0.900
LR+2.143
LR-0.385
Biberthaler, et al.
2006
Germany
1,309 adults with: Isolated head injury, within 3 hrs of injury, GCS 13-15 + One or more of: Brief LOC, Amnesia, Nausea, Vomiting, Severe headache, Dizziness, Vertigo, Age >60 yrs, Intoxication, Anticoagulation. Negative controls n=540 Positive controls (GCS<13) n=55 Index test: Serum S100B (Elecsys S100, Roche)at cut-off 0.10 g/L, taken ≤3 hrs from injury. Cut-off taken as 95th centile of negative control group Median sample time 60 min (IQR 40-80 min). Gold Standard: Positive CT Scan.Prospective cohortPrevalence0.071No blinding mentioned.(Study was confirmed double blinded via personal correspondence). Possible selection bias towards earlier presenting patients, as median sampling time 60 min (IQR 40-80 min) post-trauma. Roche funded study possible bias.
AUC0.80 (95%CI 0.75-0.84)
Sensitivity0.99 (95%CI 0.96-1.00)
Specificity0.30 (95%CI 0.29-0.31)
PPV0.10 (95%CI 0.07-0.13) at prevalence of 0.10
NPV0.9968 (95%CI 0.99-1.00)
LR+1.4
LR-0.03
Potential CT use reduction30%
Muller K, et al.
2007
Norway
226 adults with isolated minor head injury, within 12 hrs of injury + LOC or amnesia. GCS 13-15. No focal neurological deficit. No multiple injuries. No neurological, psychiatric, renal or liver disease. Index test: Serum S100B (LIAISON, AB Diasorin,cut-off 0.10 g/L, sample taken ≤12 hrs from injury. Gold Standard: Positive CT Scan ≤12 hrs.Prospective cohortPrevalence0.093Selection bias (high prevalence and GP referrals included). Stricter inclusion criteria: LOC or amnesia in all patients. <12 hrs inclusion but no sampling time range mentioned. Excluding cases sampled >3 hrs did not improve diagnostic properties. No blinding mentioned. Not powered enough. LR- confidence limit includes 1.
AUC0.73 (95%CI 0.62-0.84)
Sensitivity0.95 (95%CI 0.76-1.00)
Specificity0.31 (95%CI 0.25-0.38)
PPV0.12 (95%CI 0.08-0.19)
NPV0.98 (95%CI 0.92-1.00)
LR+1.39 (95%CI 1.21-1.58)
LR-0.15 (95%CI 0.02-1.04)
Unden, et al.
2009
Sweden
1,958 patients from 6 studies. Index test: Serum S100B 0.10 g/L. Gold Standard: Positive CT Scan.ReviewPrevalence0.083No effects model shown. Methodology whereby 6 heterogeneous studies data were added up not shown. No precision analysis.
Sensitivity0.981
Specificity0.346
PPV0.121
NPV0.995
LR+1.50
LR-0.05
Morochovic, et al.
2009
Slovak Republic
102 patients with minor head injury, within 6 hrs of injury, GCS 13-15, Age 12-84 yrs, + One of : LOC < 30 min, Amnesia <1 hr, Unclear history, Severe headache, Trauma above clavicles, Vomiting, Focal neurological deficit, Seizure, Coagulopathy, High energy accident, Intoxication. Index test: Serum S100B (Elecsys S100 Roche), cut-off 0.10 g/L, sample taken ≤ 6 hrs. Gold standard: Positive CT Scan (within 30 min of blood drawing). Prospective CohortPrevalence0.176Small study - not powered. Selection bias. Age range 12-84 yrs. Undens meta-analysis used for analysing cases >15 yrs. Wide inclusion criteria. Chronic intracerebral lesions & extracerebral injuries included. Sampling time ≤6 hrs no median and IQR mentioned. No blinding mentioned.
Sensitivity0.833 (95%CI 0.58-0.96)
Specificity0.298 (95%CI 0.21-0.41)
PPV0.203 (95%CI 0.12-0.32)
NPV0.893 (95%CI 0.71-0.97)
LR+1.186
LR-0.560
Using Unden's meta-analysis for >15yr olds:
Prevalence0.175
Sensitivity0.882
Specificity0.287
PPV0.208
NPV0.92
LR+1.237
LR-0.411
Bouvier, et al.
2009
France
105 adults Age >18 yrs Isolated minor head injury within 3 hrs of injury GCS 13-15 + One of: Initial LOC, Headache, Nausea, Vomiting, Amnesia, Focal neurological deficit, Convulsions, Intoxication, Signs of injury above clavicle, Age >60 yrs, Coagulopathy. Index test: Serum S100B (Elecsys Roche), 2 cut-offs: 0.10 g/L and 0.15g/L, sampled ≤ 3 hrs. Gold standard: Positive CT, Blinded.Prospective cohortPrevalence0.15Index test blinding not mentioned. Small study. Not powered. Selection bias. Masters classification rather than GCS used. No precision analysis. Roche realised study possible funding bias
AUC0.83 (95%CI 0.74-0.89)
At 0.15g/L cut-off:
Sensitivity1.0
Specificity0.5
At 0.10g/L cut-off
Sensitivity1.0
Specificity0.33
PPV0.21
NPV1.0
LR+1.51
LR-0
Kotlyar, et al.
2010
USA
158 (out of 346) adults with minor head injury, within 6 hrs of injury, GCS 13-15. Non-focal neurology exam. CT criteria: based on individual physician. No major trauma or prior intracranial pathology. Index test: Serum S100B (Can-Ag Diagnostics S100 EIA), lowest cut-off 0.24 g/L, taken ≤6 hrs from injury. Gold Standard: Positive CT, <3 hrs from arrival.Nested Case-controlPrevalence0.064Convenient design. Conveniently powered. Extracranial injury included. Criteria for CT not explained only intent of physician. Assay insensitive - poor lower detection of 0.10 g/L. Results based on analysis of ROC curve analysis rather than that of a 2x2 table.
AUC0.643 (95%CI 0.51-0.77)
Sensitivity0.96 (95%CI 0.78-1.00)
Specificity0.13 (95%CI 0.09-0.20)
PPV0.15 (95%CI 0.10-0.22)
NPV0.95 (95%CI 0.76-1.00)
LR+1.10
LR-0.31
Muller B, et al.
2010
Switzerland
233 adults with minor head injury, GCS 13-15. All patients with head injuries had CT. Exclusions: Cancer, stroke, neurological disease, coagulopathy, intoxication, late admissions, multiple injuries. Index test: Serum S100B (Elecsys S100 Roche), cut-off 0.105 g/L. Median sample time 77 min (IQR 60-120 min). Gold standard: Positive CT. Prospective cohortPrevalence0.094Selection bias. Convenience sample - late admissions excluded. All head injuries had CT (as per local protocol). No time limit for sampling. No blinding mentioned. Specificity reported as 0.122 However specificity obtained using supplied 2x2 table is 0.317.
Sensitivity0.864
Specificity0.317
PPV0.128
NPV0.857
Excluding 2 sampled >11.5 hrs:
Sensitivity0.954
Specificity0.317
PPV0.128
NPV0.986
LR+1.396
LR-0.145
Zongo, et al.
2010
France
1,559 patients, aged ≥15 yrs, with minor head injury within 6 hrs of injury, GCS 13-15 + One of: LOC, Amnesia, Nausea, Repeated vomiting, Severe headache, Dizziness, Vertigo, Alcohol poisoning, Anticoagulation, Age >65years. Exclusions: Non-head injury (AIS score >2). Non-traumatic neurological disease. Index test: Plasma S100B (Elecsys S100 Roche), Cut-off 0.14 g/L - equivalent to serum S100B cut-off 0.10 g/L. Taken ≤6 hrs . Median sample time 135 min (IQR 95-200 min) Gold Standard: Positive CT. Blinded. Prospective cohortPrevalence0.07S100B blinding not mentioned. Possible selection bias to early samples as median sampling time 135 min, IQR 95-200 min.
AUC0.76 (95%CI 0.72-0.80)
Sensitivity0.982 (95%CI 0.935-0.998)
Specificity0.268 (95%CI 0.254-0.291)
PPV0.092 (95%CI 0.076-0.110)
NPV0.995 (95%CI 0.982-0.999)
LR+1.34 (95%CI 1.29-1.40)
LR-0.07 (95%CI 0.02-0.26)
Potential CT Reduction25%

Comment(s)

Zongos and Biberthalers studies are two large good quality studies totalling 2,868 cases. Another 14 smaller studies, with mostly positive results, bring up the total to 4,506. A meta-analysis of 12 studies further underlines S100Bs diagnostic potential. In a selected adult population, S100B has a high sensitivity (0.98-0.99) and NPV (0.995), with low specificity (0.26-0.30) for CT evident intracranial injury. The poor specificity has been postulated to be due to brain injury that is not detected by head CT scans and to extracerebral sources of S100B. Serum S100B has a very low likelihood ratio negative of 0.03 to 0.07 and has the potential to reduce the number of cranial CT scan. In the UK, the population selected for CT following minor head injury is more restricted, and the results can\\\\\\\'t be readily extrapolated for use after NICE criteria. However S100B could be incorporated within NICE head injury guideline for similar inclusion criteria as Biberthaler\\\\\\\'s and Zongo\\\\\\\'s studies.

Clinical Bottom Line

A UK based derivation and validating study on S100B use in minor head injury is recommended to further assess the use of S100B with current NICE criteria, thus enabling the construction of a new clinical decision rule. However there is enough evidence to recommend incorporating serum S100B into new adult head injury guidelines. A cut-off of 0.10g/L can be used for adult patients with isolated minor head injury presenting within 3 hours of injury. The criteria for serum S100B use within NICE head injury guideline would be: GCS 13-14 2 hours after injury, >1 episode of vomiting, amnesia of events >30min before impact, amnesia or loss of consciousness + [age ≥65yrs, coagulopathy or dangerous mechanism]. A positive serum S100B would indicate the need for a CT head. A negative serum S100B result would predict a normal CT scan with high sensitivity and thus would potentially reduce CT use by 25-30%.

References

  1. Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery 1999 Sep;45(3):468-75; discussion 75-6
  2. Ingebrigtsen T, Romner B, Marup-Jensen S, Dons M, Lundqvist C, Bellner J The clinical value of serum S-100 protein measurements in minor head injury: a Scandinavian multicentre study. Brain Inj. 2000 Dec;14(12):1047-55.
  3. Biberthaler P, Mussack T, Wiedemann E, Kanz KG, Koelsch M, Gippner-Steppert C, et al Evaluation of S-100b as a specific marker for neuronal damage due to minor head trauma. World J Surg. 2001 Jan;25(1):93-7.
  4. Mussack T, Biberthaler P, Kanz KG, Heckl U, Gruber R, Linsenmaier U, et al. Immediate S-100B and neuron-specific enolase plasma measurements for rapid evaluation of primary brain damage in alcohol-intoxicated, minor head-injured patients. Shock. 2002 Nov;18(5):395-400.
  5. Biberthaler P, Mussack T, Wiedemann E, Kanz KG, Mutschler W, Linsenmaier U, et al. Rapid identification of high-risk patients after minor head trauma (MHT) by assessment of S-100B: ascertainment of a cut-off level. Eur J Med Res. 2002 Apr 30;7(4):164-70.
  6. Biberthaler P, Mussack T, Kanz KG, Linsenmaier U, Pfeifer KJ, Mutschler W, et al. Identification of high-risk patients after minor craniocerebral trauma. Measurement of nerve tissue protein S 100 Unfallchirurg. 2004 Mar;107(3):197-202.
  7. Nygren De Boussard C, Fredman P, Lundin A, Andersson K, Edman G, Borg J. S100 in mild traumatic brain injury. Brain Inj. 2004 Jul;18(7):671-83.
  8. Poli-de-Figueiredo LF, Biberthaler P, Simao Filho C, Hauser C, Mutschler W, Jochum M. Measurement of S-100B for risk classification of victims sustaining minor head injury - first pilot study in Brazil. Clinics (Sao Paulo). 2006 Feb;61(1):41-6.
  9. Bazarian JJ, Beck C, Blyth B, von Ahsen N, Hasselblatt M. Impact of creatine kinase correction on the predictive value of S-100B after mild traumatic brain injury. Restor Neurol Neurosci. 2006;24(3):163-72.
  10. Biberthaler P, Linsenmeier U, Pfeifer KJ, Kroetz M, Mussack T, Kanz KG, et al. Serum S-100B concentration provides additional information fot the indication of computed tomography in patients after minor head injury: a prospective multicenter study. Shock. 2006 May;25(5):446-53.
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  12. Unden J, Romner B. A new objective method for CT triage after minor head injury--serum S100B. Scand J Clin Lab Invest. 2009;69(1):13-7.
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  14. Bouvier D, Oddoze C, Ben Haim D, Moustafa F, Legrand A, Alazia M, et al. Interest of S100B protein blood level determination for the management of patients with minor head trauma Ann Biol Clin (Paris). 2009 Jul-Aug;67(4):425-31.
  15. Unden J, Romner B. Can low serum levels of S100B predict normal CT findings after minor head injury in adults?: an evidence-based review and meta-analysis. J Head Trauma Rehabil. 2010 Jul-Aug;25(4):228-40.
  16. Kotlyar S, Larkin GL, Moore CL, D'Onofrio G. S100b Immunoassay: An Assessment of Diagnostic Utility in Minor Head Trauma. J Emerg Med. 2010 Aug 6.
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  18. Zongo D, Ribereau-Gayon R, Masson F, Laborey M, Contrand B, Salmi LR, et al. S100-B protein as a screening tool for the early assessment of minor head injury. Ann Emerg Med. 2012 Mar;59(3):209-18.