Annals of Emergency Medicine
Volume 39, Issue 3 , Pages 342-343, March 2002

Rule out TBI? Serum markers for traumatic brain injury☆

Department of Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA

Article Outline

Abstract 

Neumar RW. Rule out TBI? Serum markers for traumatic brain injury. Ann Emerg Med. March 2002;39:342-343.

 

See related article, p. 254 .

Emergency department evaluation of patients with closed head injury has traditionally focused on ruling out pathology that either requires acute intervention or has the potential to cause rapid deterioration. In this regard, the ED workup is aimed at detecting intracranial hemorrhage, brain edema, and impending herniation with an armamentarium predominantly limited to clinical evaluation (eg, symptoms, Glasgow Coma Scale [GCS], neurologic examination) and computed tomography (CT). Spurred by the low incidence of CT scan abnormalities in patients with minor closed head injury, clinical decision rules have been developed to identify patients in whom head CT scan can be safely deferred.1, 2 In contrast, many patients without CT scan evidence of intracranial injury have long-term neuropsychological dysfunction.3, 4 Therefore, our current model appears to both overevaluate and underdiagnose traumatic brain injury. Even an objective criterion standard for minor traumatic brain injury remains elusive.5 These limitations have fueled the search for more sensitive and specific tests to establish the diagnosis of traumatic brain injury and predict outcome.

In this issue of Annals, Shaw et al6 report on a newly developed serum marker for traumatic brain injury, cleaved tau protein (τc). In this pilot study, serum τc was detected in 9 of 17 patients with an intracranial injury (ICI) documented by CT scan and in 7 of 11 patients with poor outcome after closed head injury. Detection of serum τc within the first 10 hours after head injury was associated with an increased risk of ICI on head CT scan (odds ratio [OR] 11.2; 95% confidence interval [CI] 1.2 to 108) and an increased risk of poor outcome (OR 8.2; 95% CI 1.42 to 47). However, the clinical utility of serum τc as screening test for ICI appears to be limited, with a sensitivity of only 53% (95% CI 36% to 59%). This lack of sensitivity could be explained by the fact that τ protein is localized in neuronal axons. It is reasonable to postulate that τc is more likely to be released after diffuse axonal injury (DAI) than after injuries that cause extraaxial hemorrhage without DAI. The slightly better sensitivity of serum τc in predicting poor outcome (64% sensitivity; 95% CI 37% to 82%) may be related to the generally poorer prognosis of patients suffering DAI. The diagnostic utility of serum τc reported in this study may also be limited by variability in the timing of the assay and lack of serial measurements. As we have learned from the use of serum markers in myocardial injury, optimizing diagnostic utility requires a detailed understanding of each marker's pharmacokinetic properties. Finally, without directly comparing the prognostic value with that of GCS score and head CT scanning, it is unclear whether this assay would actually enhance our current ability to predict outcome. Hopefully, these issues will be addressed in future large-scale studies.

The diagnostic and prognostic utility of serum markers for traumatic brain injury has been intensely studied. Other markers that have been evaluated include both neuronal (neurons specific enolase, creatine kinase-BB) and glial (myelin basic protein, S-100B) cell proteins. S-100B has thus far emerged as the serum marker with the greatest diagnostic utility.7, 8 Serum S-100B is reported to have 90% sensitivity and 99% negative predictive value for intracranial pathology on head CT scans.9 In patients with moderate to severe head injury, serum S-100B levels greater than 2.0 μg/L predicted unfavorable outcome with an overall accuracy (83%) that surpassed both initial GCS score (66%) and Marshall CT score (71%).10 In mild head injury, detection of serum S-100B (>0.2 μg/L) within 6 hours of injury predicted long-term neuropsychological dysfunction, even in cases in which CT and magnetic resonance imaging (MRI) abnormalities were absent.11

The potential utility of serum markers may exceed simply enhancing the diagnostic and prognostic accuracy of our standard evaluation. Sustained or secondary release of serum markers may prove useful in detecting secondary injury or even titrating therapy.12, 13, 14 Furthermore, secondary injury in the gray and white matter may have different molecular mechanisms and therefore require distinct therapies that could be guided by serum markers specific to those regions. Perhaps most exciting is the potential for serum markers to objectively diagnose traumatic brain injury in symptomatic patients with normal head CT scan findings.

Rather than focusing on ruling out intracranial hemorrhage or impending herniation, ED evaluation of patients with closed head injury may soon focus on actually ruling out traumatic brain injury. Although MRI can detect diffuse axonal injury and cerebral contusion not evident on CT scan, its sensitivity is limited in the first 24 hours after injury.15 Furthermore, when availability and cost are considered, MRI is an inefficient screening tool. Alternatively, the potential exists to develop a battery of serum markers to supplement clinical parameters and head CT scanning in the workup of head injured patients, similar to the way that serum markers are used to supplement clinical parameters and ECG in the workup of patients with chest pain. Early identification of patients at high risk for long-term neuropsychological dysfunction could greatly facilitate the development of effective therapeutic interventions for all severities of traumatic brain injury.

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References 

  1. Haydel MJ, Preston CA, Mills TJ, et al.  Indications for computed tomography in patients with minor head injury. N Engl J Med. 2000;343:100–105
  2. Stiell IG, Wells GA, Vandemheen K, et al.  The Canadian CT Head Rule for patients with minor head injury. Lancet. 2001;357:1391–1396
  3. Ingebrigtsen T, Waterloo K, Marup-Jensen S, et al.  Quantification of post-concussion symptoms 3 months after minor head injury in 100 consecutive patients. J Neurol. 1998;245:609–612
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  6. Shaw GJ, Jauch EC, Zelman FP. Serum cleaved tau protein levels and clinical outcome in adult patients with closed head injury. Ann Emerg Med. 2002;39:254–257
  7. Raabe A, Grolms C, Seifert V. Serum markers of brain damage and outcome prediction in patients after severe head injury. Br J Neurosurg. 1999;13:56–59
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  9. Ingebrigtsen T, Romner B, Marup-Jensen S, et al.  The clinical value of serum S-100 protein measurements in minor head injury: a Scandinavian multicentre study. Brain Injury. 2000;14:1047–1055
  10. Woertgen C, Rothoerl RD, Metz C, et al.  Comparison of clinical, radiologic, and serum marker as prognostic factors after severe head injury. J Trauma. 1999;47:1126–1130
  11. Ingebrigtsen T, Waterloo K, Jacobsen EA, et al.  Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery. 1999;45:468–476
  12. Raabe A, Grolms C, Sorge O, et al.  Serum S-100B protein in severe head injury. Neurosurgery. 1999;45:477–483
  13. Herrmann M, Jost S, Kutz S, et al.  Temporal profile of release of neurobiochemical markers of brain damage after traumatic brain injury is associated with intracranial pathology demonstrated by cranial computerized tomography. J Neurotrauma. 2000;17:113–121
  14. Herrmann M, Curio N, Jost S, et al.  Release of biochemical markers of damage to neuronal and glial brain tissue is associated with short and long term neuropsychological outcome after traumatic brain injury. J Neurol Neurosurg Psychiatry. 2001;70:95–100
  15. Voller B, Auff E, Schnider P, et al.  To do or not to do? Magnetic resonance imaging in mild traumatic brain injury. Brain Injury. 2001;15:107–115

☆ Reprints not available from the author. Address for correspondence: Robert W. Neumar, MD, PhD, Department of Emergency Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; 215-898-4960, fax 215-573-5140; E-mail: rneumar@mail.med.upenn.edu.

PII: S0196-0644(02)70703-8

doi:10.1067/mem.2002.122007

Refers to article:

  • Serum cleaved tau protein levels and clinical outcome in adult patients with closed head injury

    George J. Shaw, Edward C. Jauch, Frank P. Zemlan
    Annals of Emergency Medicine March 2002 (Vol. 39, Issue 3, Pages 254-257)

Annals of Emergency Medicine
Volume 39, Issue 3 , Pages 342-343, March 2002

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