Академический Документы
Профессиональный Документы
Культура Документы
Bandyopadhyay et al.
come Scale (GOS). The GOS score was assigned retrospectively for enrolled patients by a single investigator blinded
to NSE level. Patient outcomes were categorized as good
(GOS = 5) or poor (GOS , 5). A single radiologist reviewed
all cranial CT scans. Results: Ninety eligible subjects with
NSE levels were identified; 86 met the enrollment criteria.
Seven subjects (8%) had poor outcome. There was a significant difference in NSE levels between the poor and
good outcome groups, even within high-risk subgroups.
The area under the curve (AUC) for NSE prediction of
poor vs. good outcome was 0.83. A serum NSE level of
21.2 ng/dL was 86% sensitive and 74% specific in predicting
poor outcome. Conclusions: It appears that the serum NSE
level can be used as a predictor of global short-term physical
disability in children following cTBI. Key words: neuronspecific enolase; enolase; prediction; pediatrics; children;
disability; outcomes. ACADEMIC EMERGENCY MEDICINE 2005; 12:732738.
Approximately 85% to 95% of all cTBIs are classified as mild to moderate.3,4 Traditionally, emergency
department (ED) management has focused on stabilization, establishing the diagnosis, preventing secondary injury, and referral/disposition of children
with TBI. Over the past two decades, researchers have
focused on improving our ability to predict the need
for imaging studies, hospital admission, cost of care,
and other proximal outcome measures.513 However,
even with mild TBI, 5% to 15% may develop lasting
sequelae, generating interest in understanding longterm functional and neurocognitive outcomes in
head-injured children.6,7,10,12
There is a paucity of literature addressing our
ability to predict long-term outcome in areas of
neurocognitive and physical functioning, or the impact
of ED management on these outcomes, in children
with cTBI. Early predictors of long-term morbidity in
children with cTBI could potentially play an important
role in identifying children at risk for lasting sequelae,
and in targeting costly surveillance efforts and preventive intervention strategies to enhance functional
recovery in these children.
The brain tissue contains a unique form of a
glycolytic protein, neuron-specific enolase (NSE),
733
www.aemj.org
METHODS
Study Design. This was a retrospective analysis of
children who had been prospectively enrolled in a
separate study. The institutional review board of the
hospital approved this study.
Study Setting and Population. The study cohort
was obtained from an academic childrens hospital
emergency department (ED) head trauma study database with enrollment between December 1997 and
November 2000. This ED is located in the Childrens
Hospital of Wisconsin, in Milwaukee, and has an
annual census of 44,000. It is the only freestanding
childrens hospital in the state, and is actively serviced
by an out-of-hospital emergency medical services
system and an in-hospital transport team with access
to both air and ground transport. An annual average
of 500 patients with cTBI are seen, with approximately
5% to 10% having moderate to severe cTBI.
Study Protocol. Subjects between 0 and 18 years of
age, evaluated within 24 hours of sustaining cTBI, and
requiring a cranial computed tomography (CT) scan
in accordance with the written ED protocol were
enrolled. Blood for serum NSE assay was drawn at
the time of ED evaluation. Subjects were excluded if
they had penetrating TBIs, intentional head trauma,
multisystem injuries, pelvic or lower extremity fractures, spinal cord injuries, or bleeding disorders.
Patients who sustained injury more than 24 hours
prior to presentation or with a history of cerebral
palsy, mental retardation, developmental delay, or
ventricular shunts were also excluded.
3
4
5
Meaning
Death
Persistent vegetative state: Unresponsive and
speechless; after 23 weeks, may open eyes
and may have sleep/wake cycle
Severe disability: Conscious but disabled; dependent
for daily activities; may or may not be institutionalized
Moderate disability: disabled but independent; can
work in a structured setting
Good recovery: resumption of normal life despite
minor deficits
734
Bandyopadhyay et al.
RESULTS
Among 90 previously enrolled subjects in the head
trauma study database, 86 met enrollment criteria for
the present study. Among four ineligible subjects, two
subjects were diagnosed as having intentional head
trauma and the rest had lower extremity (pelvic and
femur) fractures. The mean (6SD) age was 8.2 6 5.5
years (range 11 months to 18 years). Approximately
two thirds were male and white. Among 86 enrolled
subjects, ten had Glasgow Coma Scale (GCS) scores ,
13 (moderate and severe cTBI). The distribution of
subjects based on GCS scores obtained in the ED is
shown in Table 2. Injury Severity Scale (ISS) score was
not recorded for the study because enrollment was
strictly restricted to subjects with isolated cTBI. From
the ED, 67% of the study population were admitted to
the hospital because of either the injury itself or its
complications. The mean time interval from the time
of reported injury and the time blood was drawn for
NSE measurement was 3.8 hours (range 0.4 to 14.8).
Seven patients (8%) had poor outcome according to
the preset criteria of GOS , 5. The mean (6SD) NSE
level was significantly higher in the subjects with poor
outcome (46.4 6 12.7 ng/mL) than those with good
outcome (19.5 6 1.4 ng/mL) (Table 3). Distribution of
NSE levels in our patient population is shown in
Figure 1. Among patients with good outcome
(GOS = 5), the admitted patients had higher mean
(6SD) NSE levels (22.4 6 2.0; 95% CI = 16.8 to 22.3
ng/mL) than the patients who were discharged from
the ED (14.4 6 0.9; 95% CI = 12.6 to 16.2 ng/mL). The
mean (6SD) NSE levels were also significantly higher
in patients who presented with abnormal GCS scores
or had abnormal cranial CT scans (Table 4).
To determine whether the NSE level adds independent predictive information, we compared NSE levels
between poor and good outcome within certain subgroups at higher risk of poor outcome: those who
were admitted in the hospital (n = 58), those with
intracranial hemorrhage (n = 32), and those with
moderate to severe cTBI (GCS , 13, n = 10) (Table
5). Even within each of these high-risk subgroups, the
Frequency (n)
1
1
1
1
2
2
2
16
14
46
NSE Level
(ng/mL; mean 6 SE)
Poor (GOS , 5) (n = 7)
Good (GOS = 5) (n = 79)
46.4 6 12.7
19.5 6 1.4
95% CI
(ng/mL)
15, 77
17, 22
DISCUSSION
Results from our study clearly indicate that a plausible association exists between cTBI outcome and the
serum level of NSE, a marker for cTBI. Previous adult
and pediatric studies have suggested a clear rise in
serum NSE level following cTBI, and our findings
suggest that this rise in posttraumatic serum NSE titer
is associated with short-term outcome. NSE levels
are significantly higher among children with poor
outcome, even within various high-risk subgroups,
suggesting that the NSE level may serve as an independent and useful early predictor of disability in
children following cTBI.
Several biochemical markers have been associated
with ischemic or traumatic insults to the brain.20,26,3143
The association of such biochemical markers with
hypoxemia, ischemia, stroke, and hypothermia is
already established in studies of adult patients.
Only in the last several years, interest has grown to
explore the association of these markers with TBI in
children. Berger et al. reported increased titers of
NSE and S100B in the cerebrospinal fluid (CSF)
following both intentional and unintentional cTBI
in children.44 Peak CSF NSE concentration was
reached as early as five hours (median 11, range 5
to 20) following cTBI. A recent study in adult
patients suggested that determination of serum
levels of glial and neuronal proteins may add to
the clinical assessment of the primary damage and
prediction of outcome after severe TBI.45
However, we know of no prior studies in children
with cTBI that have tried to correlate poor outcome
with biochemical markers. Our results show that
children with poor outcomes following cTBI (GOS
, 5) had nearly threefold higher NSE concentrations
following cTBI than children with good outcomes
(GOS = 5). Although there was an overlap in NSE
www.aemj.org
735
Figure 1. Distribution of neuron-specific enolase (NSE) titer among the study population. (Arrow at NSE titer 15 ng/mL = upper limit of
normal.) GOS = Glasgow Outcome Scale.
CT scan
GCS score*
Normal
Abnormal
p-value
16.8 6 1.1
[14.6, 19]
16.7 6 1.2
[14.3, 19.1]
26.9 6 3.0
[20.8, 33]
31.1 6 3.6
[23.5, 38.7]
0.003
0.001
736
Bandyopadhyay et al.
NSE Level in
Poor Outcome
(ng/mL)
46.4
50.4
53.7
57.2
6
6
6
6
12.7
14.2
19.2
15.3
NSE Level in
Good Outcome
(ng/mL)
22.4
23.1
23.2
18.4
6
6
6
6
1.9
2.9
3.0
2.0
Mean Difference D
in NSE Level
(ng/mL)
24.0
27.2
30.5
38.7
6
6
6
6
6.9
8.4
10.5
15.4
95% CI of D
10.0,
10.2,
8.9,
3.1,
37.9
41.1
52.0
74.3
LIMITATIONS
The major limitation of our study is the paucity of
subjects with poor outcomes. We believe the overlap in
NSE concentrations seen between the poor and good
Figure 2. Receiver-operating characteristic (ROC) curves with discriminative abilities of neuron-specific enolase (NSE) for predicting
outcome and abnormal computed tomography (CT) scan.
www.aemj.org
CONCLUSIONS
Neuron-specific enolase can be used as a predictor of
poor functional outcome in children with closed TBI.
Future studies are needed to explore the association
between other biochemical markers of brain injury
and areas of longer-term cognitive, behavioral, physical, and social functioning following cTBI in children.
References
1. Rivara FP. Childhood injuries. III: Epidemiology of non-motor
vehicle head trauma. Dev Med Child Neurol. 1984; 26:817.
2. Jennett B. Epidemiology of head injury. Arch Dis Child. 1998;
78:4036.
3. Sosin DM, Sniezek JE, Thurman DJ. Incidence of mild and
moderate brain injury in the United States, 1991. Brain Inj.
1996; 10:4754.
4. Miller JD. Minor, moderate, and severe head injury. Neurosurg
Rev. 1986; 9:1359.
5. Goldstein FC, Levin HS. Cognitive outcome after mild and
moderate traumatic brain injury in older adults. J Clin Exp
Neuropsychol. 2001; 23:73953.
6. Fann JR, Uomoto JM, Katon WJ. Cognitive improvement with
treatment of depression following mild traumatic brain injury.
Psychosomatics. 2001; 42:4854.
7. Ponsford J, Willmott C, Rothwell A, et al. Cognitive and
behavioral outcome following mild traumatic head injury in
children. J Head Trauma Rehabil. 1999; 14:36072.
8. Taylor AE, Cox CA, Mailis A. Persistent neuropsychological
deficits following whiplash: evidence for chronic mild traumatic
brain injury? Arch Phys Med Rehabil. 1996; 77:52935.
9. Ponsford J, Willmott C, Rothwell A, et al. Impact of early
intervention on outcome after mild traumatic brain injury in
children. Pediatrics. 2001; 108:1297303.
10. Light R, Asarnow R, Satz P, Zaucha K, McCleary C, Lewis R.
Mild closed-head injury in children and adolescents: behavior
problems and academic outcomes. J Consult Clin Psychol.
1998; 66:10239.
11. Kriel RL, Krach LE, Sheehan M. Pediatric closed head injury:
outcome following prolonged unconsciousness. Arch Phys
Med Rehabil. 1988; 69:67881.
12. Ponsford J, Willmott C, Rothwell, et al. Factors influencing
outcome following mild traumatic brain injury in adults.
J Int Neuropsychol Soc. 2000; 6:56879.
13. Kieslich M, Marquardt G, Galow G, Lorenz R, Jacobit G.
Neurological and mental outcome after severe head injury in
childhood: a long-term follow-up of 318 children. Disabil
Rehabil. 2001; 23:6659.
14. Woertgen C, Rothoerl RD, Holzschuh M, Metz C, Brawanski A.
Comparison of serial S-100 and NSE serum measurements
after severe head injury. Acta Neurochir. 1997; 139:11614.
15. Rosen H, Sunnerhagen KS, Herlitz J, Blomstrand C, Rosengren
L. Serum levels of the brain-derived proteins S-100 and NSE
predict long-term outcome after cardiac arrest. Resuscitation.
2001; 49:18391.
16. Fridriksson T, Kini N, Walsh-Kelly C, Hennes H. Serum
neuron-specific enolase as a predictor of intracranial lesions in
children with head trauma: a pilot study. Acad Emerg Med.
2000; 7:81620.
737
17. Ergun R, Bostanci U, Akdemir G, et al. Prognostic value of
serum neuron-specific enolase levels after head injury. Neurol
Res. 1998; 20:41820.
18. Yamazaki Y, Yada K, Morii S, Kitahara T, Ohwada T. Diagnostic
significance of serum neuron-specific enolase and myelin basic
protein assay in patients with acute head injury. Surg Neurol.
1995; 43:26770.
19. Mussack T, Biberthaler P, Kanz KG, 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; 18:395400.
20. Ogata M, Tsuganezawa O. Neuron-specific enolase as an
effective immunohistochemical marker for injured axons after
fatal brain injury. Int J Leg Med. 1999; 113:1925.
21. Ross SA, Cunningham RT, Johnston CF, Rowlands BJ. Neuronspecific enolase as an aid to outcome prediction in head injury.
Br J Neurosurg. 1996; 10:4716.
22. Uzan M, Hanci M, Guzel O, et al. The significance of neuron
specific enolase levels in cerebrospinal fluid and serum after
experimental traumatic brain damage. Acta Neurochir. 1995;
135:1413.
23. Persson L, Hardemark HG, Gustafsson J, et al. S-100 protein
and neuron-specific enolase in cerebrospinal fluid and serum:
markers of cell damage in human central nervous system.
Stroke. 1987; 18:9118.
24. Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F. Increased
serum creatine kinase BB and neuron specific enolase
following head injury indicates brain damage. Acta Neurochir.
1992; 115:10611.
25. Kruse A, Cesarini KG, Bach FW, Persson L. Increases of
neuron-specific enolase, S-100 protein, creatine kinase and
creatine kinase BB isoenzyme in CSF following intraventricular
catheter implantation. Acta Neurochir. 1991; 110:1069.
26. De Kruijk JR, Leffers P, Menheere PP, Meerhoff S, Twijnstra A.
S-100B and neuron-specific enolase in serum of mild traumatic
brain injury patients. A comparison with healthy controls. Acta
Neurol Scand. 2001; 103:1759.
27. Hellawell DJ, Signorini DF, Pentland B. Simple assessment of
outcome after acute brain injury using the Glasgow Outcome
Scale. Scand J Rehabil Med. 2000; 32:257.
28. Pettigrew LE, Wilson JT, Teasdale GM. Assessing disability
after head injury: improved use of the Glasgow Outcome Scale.
J Neurosurg. 1998; 89:93943.
29. Woischneck D, Firsching R. Efficiency of the Glasgow
Outcome Scale (GOS)-score for the long-term follow-up
after severe brain injuries. Acta Neurochir Suppl. 1998;
71:13841.
30. Anderson SI, Housley AM, Jones PA, Slattery J, Miller JD.
Glasgow Outcome Scale: an inter-rater reliability study. Brain
Inj. 1993; 7:30917.
31. Biberthaler P, Mussack T, Wiedemann E, et al. Evaluation of
S-100b as a specific marker for neuronal damage due to minor
head trauma. World J Surg. 2001; 25:937.
32. 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 as
demonstrated in cranial computerized tomography.
J Neurotrauma. 2000; 17:11322.
33. Beaudeux J, Dequen L, Foglietti M. [Pathophysiologic
aspects of S-100beta protein: a new biological marker
of brain pathology]. [French]. Ann Biol Clin. 1999; 57:
26172.
34. Ingebrigtsen T, Romner B. Biochemical serum markers for
brain damage: a short review with emphasis on clinical
utility in mild head injury. Restor Neurol Neurosci. 2003;
21:1716.
35. Linstedt U, Kropp P, Moller C, Zenz M. [Diagnostic value of
s-100 protein and neuron-specific enolase as serum markers for
cerebral deficiency after general anesthesia. Study in patient
738
36.
37.
38.
39.
40.
41.
42.
Bandyopadhyay et al.
with hip or knee replacement]. [German]. Anaesthesist. 2000;
49:88792.
Raabe A, Grolms C, Seifert V. Serum markers of brain damage
and outcome prediction in patients after severe head injury.
Br J Neurosurg. 1999; 13:569.
Hans P, Bonhomme V, Collette J, Moonen G. Neuron-specific
enolase as a marker of in vitro neuronal damage. Part I:
assessment of neuron-specific enolase as a quantitative and
specific marker of neuronal damage. J Neurosurg Anesthesiol.
1993; 5:1116.
Abdul-Khaliq H, Schubert S, Fischer T, et al. The effect of
continuous treatment with sodium nitroprusside on the serum
kinetics of the brain marker protein S-100beta in neonates
undergoing corrective cardiac surgery by means of hypothermic
cardiopulmonary bypass. Clin Chem Lab Med. 2000; 38:11735.
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; 70:95100.
Khan NE, De Souza AC, Pepper JR. S100 protein: its use as a
marker of cerebral damage in cardiac operations. Ann Thorac
Surg. 2001; 72:6667.
Raabe A, Kopetsch O, Woszczyk A, et al. Serum S-100B protein
as a molecular marker in severe traumatic brain injury. Restor
Neurol Neurosci. 2003; 21:15969.
Al Samsam RH, Alessandri B, Bullock R. Extracellular
N-acetyl-aspartate as a biochemical marker of the severity of
43.
44.
45.
46.
47.
48.
49.
50.