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Bandyopadhyay et al.

SERUM NEURON-SPECIFIC ENOLASE IN PEDIATRIC TBI

Serum Neuron-specific Enolase as a Predictor

of Short-term Outcome in Children with
Closed Traumatic Brain Injury
Subhankar Bandyopadhyay, MD, Halim Hennes, MD, MS, Marc H.
Gorelick, MD, MSCE, Robert G. Wells, MD, Christine M. Walsh-Kelly, MD
Abstract
Background: Closed traumatic brain injury (cTBI) is a
significant cause of mortality and morbidity in children. The
natural course and extent of recovery from cTBI in children
are poorly understood. Neuron-specific enolase (NSE), an
enzyme detected in serum following structural damage of
neuronal brain cells, appears to be a good marker for
intracranial injury. However, to the best of the authors
knowledge, the usefulness of NSE as a predictor of disability in children with cTBI has not been reported. Objectives:
To examine the association between posttraumatic serum
NSE level and short-term physical disability in children
with cTBI. Methods: This was a retrospective analysis of a
prospectively enrolled cohort of children aged 018 years
with isolated cTBI presenting to the emergency department
(ED) within 24 hours of injury, and having a cranial
computed tomography (CT) scan as part of the evaluation.
The NSE level was obtained at the time of ED evaluation.
Physical disability was measured using the Glasgow Out-

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.

Closed traumatic brain injury (cTBI) is a significant

cause of morbidity and mortality in children.1,2 Most
studies on disability following TBI in children and
youth are based on case series from selected hospitals
or rehabilitation facilities. The difficulty of measuring
the effects of the injury in the context of naturally
occurring developmental changes contributes to the
challenge of assessing outcomes of TBI in children.

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),

From the Department of Pediatrics, Emergency Medicine Division,

Emory University School of Medicine (SB), Atlanta, GA; the Medical
College of Wisconsin (HH, MHG, CMW), Milwaukee, WI; and the
Department of Radiology, Childrens Hospital of Wisconsin (RGW),
Milwaukee, WI.
Received October 28, 2004; revision received February 1, 2005;
accepted February 15, 2005.
Presented at the Pediatric Academic Society annual meeting, San
Francisco, CA, May 2004; and as a poster at the SAEM annual
meeting, Orlando, FL, May 2004.
Supported by a grant from the Medical College of Wisconsin
Clinical Research Center (Grant # 627).
Address for correspondence and reprints: Subhankar Bandyopadhyay, MD, Assistant Professor, Department of Pediatrics,
Emergency Medicine Division, Emory University School of
Medicine, 1645 Tullie Circle, Atlanta, GA 30329. Fax: 404-785-7989;
e-mail: sbandy2@emory.edu.
doi:10.1197/j.aem.2005.02.017

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which is found only in neurons of brain and other

central nervous system tissues. Structural damage of
neuronal brain cells causes leakage of NSE into the
extracellular compartment and the bloodstream. NSE
can be detected in the serum following neuronal cell
death secondary to traumatic injury or a catastrophic
vascular event. Several studies in adult patients, and
one pediatric study, have already established NSE as a
marker of intracranial injury.1426 Because NSE can be
detected in the serum within six hours of TBI, this
enzyme may be a useful early predictor of neurocognitive and/or global functional deficits following
cTBI in children. To our knowledge, no studies in the
pediatric literature have examined the NSE level as a
potential predictor of long- or short-term functional,
neurocognitive, or behavioral outcomes in children
with cTBI. The objective of this study was to examine
the association between posttraumatic serum NSE
level and the short-term outcome of physical disability measured by the Glasgow Outcome Scale (GOS),
in children with cTBI.

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.

Measurements. The primary outcome variable was

GOS score at the time of hospital discharge. The GOS
is a validated five-point ordinal scale of global physical disability following cTBI, with the lower score
indicating worse outcome (Table 1).2730 The GOS at
the time of discharge from the hospital, from either
the ED or the inpatient service, was assigned retrospectively for all enrolled patients by a single investigator blinded to the NSE level. Subjects GOS scores
were categorized as good (GOS = 5) or poor (GOS
, 5) outcome.
Data collected include demographics, mechanisms
of injury, symptoms, vital signs, and physical examination findings. The interval from time of injury to
obtaining the blood sample for NSE determination
was recorded. The NSE assays for the cohort were
done by standard radioimmunoassay (RIA) technique
by Specialty Laboratories (Santa Monica, CA) using
stored frozen serum (270C) of centrifuged 5 mL
patient blood. NSE level $ 15 ng/mL was considered
abnormal as per the test reference range of the
processing laboratory. A single radiologist reviewed
all cranial CT scans. An abnormal CT scan was
defined as a CT scan with cerebral contusions, cerebral edema, or parenchymal, subarachnoidal, subdural, or epidural bleeding. Presence of skull fracture
alone was not sufficient to classify a CT as abnormal.
Data Analysis. Group differences in mean NSE levels
were calculated with 95% confidence intervals (95%
CIs), and statistical significance was assessed using
unpaired t-tests with an a priori significance level of
p , 0.05. Logistic regression analyses (using maximum likelihood methods) were performed to construct receiver-operating characteristic (ROC) curves
for the ability of NSE to predict outcomes of interest.
A single predictor variable, NSE level, was used in
both models. For one model, the dichotomous dependent variable was good (GOS = 5) vs. poor (GOS , 5)
outcome, and for the second model it was CT scan
normal vs. abnormal. Sensitivity and specificity were
calculated at the optimal cutoff value, defined as the
point closest to the upper left corner of the graph.
Statistical software Stata version 8 was used for all
statistical analyses (StataCorp LP, College Station, TX).
TABLE 1. The Glasgow Outcome Scale
Score
1
2

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

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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

TABLE 2. Distribution of the Subjects Based on

Initial Glasgow Coma Scale (GCS) Score on
Presentation to the Emergency Department
GCS Score
3
4
7
8
9
11
12
13
14
15

Frequency (n)
1
1
1
1
2
2
2
16
14
46

SERUM NEURON-SPECIFIC ENOLASE IN PEDIATRIC TBI

TABLE 3. Neuron-specific Enolase (NSE) Levels in

the Poor and Good Outcome Groups
Outcome*

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

*GOS = Glasgow Outcome Scale score.

NSE level was significantly higher among patients

with poor outcome.
The overall ability of the NSE level to discriminate
poor versus good outcome was good, with an area
under the ROC curve (c statistic) of 0.83 (Figure 2).
The NSE level at a cutoff value of 21.2 ng/mL was
86% sensitive and 74% specific in predicting poor
outcome in our patients with cTBI. In contrast, the
NSE level was a relatively poor predictor of abnormal
CT scan, with a c statistic of 0.66.

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

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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.

levels between the poor and good outcome groups

(Figure 1), none of the subjects in the good outcome
group had an NSE level higher than the acceptable
upper limit of reference range (>15 ng/mL). The
differences in the NSE levels were also significant
between the poor and good outcome groups, even in
patients who are considered to be at higher risk of
having poor outcome (with intracranial hemorrhage,
GCS # 12, etc.). According to our results, the NSE
level for predicting poor outcome in our study population had a sensitivity and a specificity of 86% and
74%, respectively, which may be acceptable as an
early screening test for identifying children at risk of
developing significant physical disability. Our results
must be interpreted with caution, however, since we
relied on single-point NSE analysis rather than serial
estimation, and therefore may have been unsuccessful
in catching peak NSE levels in some of our patients.
However, this would not have influenced our results,
TABLE 4. Association of the Neuron-specific
Enolase (NSE) Level with Glasgow Coma Scale
(GCS) Score and Computed Tomography (CT)
Scan
NSE Levels (ng/mL; mean 6 SE) [95% CI]

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

*Abnormal GCS score = GCS , 15.

0.001

as the majority of our patients with good outcomes

had NSE levels ranging between 17 and 22 ng/mL,
and it is highly unlikely that they sustained any
further secondary brain injury, which would influence
their NSE titers. On the other hand, patients who had
a poor outcome, but whose NSE titers were determined early (1825 ng/mL), might have not yet
reached their peak.
Predicting neurologic, physical, and cognitive disability following cTBI becomes challenging in the
context of naturally occurring developmental changes
in the pediatric population. The patients age, the
mechanism of injury, the prior history of developmental or cognitive disability, any social or language
barrier, and genetic predisposition, along with the
extent of progression of TBI itself, all play significant
roles in the recovery after cTBI. Researchers have not
yet been able to identify a single factor that is directly
attributable to either deficit or complete recovery
following cTBI. Injury severity based on GCS alone
is limited in predicting outcome in children with cTBI.
Neuropsychological outcomes following cTBI are not
significantly different in children who had low GCS
scores (35) compared with children who had GCS
scores of 6 or higher.46 Subsequent studies have
established that multiple injury indices (ISS, headabbreviated ISS, and GCS at several time points),
along with GCS and physiologic reflex (oculocephalic), are suitable predictors of outcome following
cTBI, but none of these parameters has been singled
out as the most important prognostic factor.47,48 Our
study results show NSE, when added to the higher

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Bandyopadhyay et al.

SERUM NEURON-SPECIFIC ENOLASE IN PEDIATRIC TBI

TABLE 5. Neuron-specific Enolase (NSE) Levels in High-risk Subgroups of

Closed Traumatic Brain Injury (cTBI)
Risk Category:
All Patients
(N = 86)
Admitted (n = 58)
Abnormal CT scan (n = 43)
Intracranial hemorrhage (n = 32)
GCS* , 13 (n = 10)

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

*GCS = Glasgow Coma Scale score.

risk category (low GCS, intracranial bleed), clearly

distinguished subjects having poor and good outcomes based on the GOS score at the time of discharge. Further prospective studies are needed to
explore the strength of the association of these biochemical markers with outcome following cTBI in
children.
An ideal outcome scale that examines all of the
domains in daily life is nonexistent. The GOS is a
simple scale that has been used widely but has a very
limited scope. The GOS measures acceptable and
unacceptable outcomes. Furthermore, it has an excellent track record of being used retrospectively, and its
interrater reliability is also excellent. Although the
GOS was initially developed to assess outcome in
adult stroke patients, Fisher validated its utility across
all pediatric ages when he developed the Pediatric
Overall Performance Category (POPC) and Pediatric
Cerebral Performance Category (PCPC) scales based
on the GOS.49 We have converted the GOS into a

dichotomous outcome variable by grouping scores of

14 as poor versus a score of 5 corresponding to a
good recovery, for the purpose of broad classification of poor and good outcomes only. There is previously documented use of the GOS as a dichotomous
variable in children with severe cTBI,50 as we did in
our study. We were, however, limited to the documentation of the GOS at the time of discharge, and
were unable to correlate a three- or six-month postinjury outcome score with NSE. Furthermore, we
assigned a GOS score of 5 to any patients discharged
from the ED who did not have a physical/occupational or rehabilitation service consult on their chart,
and did not have any recorded limitation of activity.

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.

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outcome groups could have been addressed in depth

with a larger sample size. The retrospective nature of
our data abstraction from medical records with regard
to the GOS also has its own limitations. We dichotomized the GOS into good vs. poor outcome because of
the limited number of subjects with poor outcomes.

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.
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Where to Find AEM Instructions for Authors

For complete instructions for authors, see the January or July issue of
Academic Emergency Medicine; visit http://ees.elsevier.com/acaeme/
default.asp and click on Guide for Authors; or contact SAEM via
e-mail at aem@saem.org, via phone at 517-485-5484, or via fax at
517-485-0801.