대한중환자의학회지：제 26 권 제 4 호 Vol. 26, No. 4, November, 2011 / http://dx.doi.org/10.4266/kjccm.2011.26.4.217
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The S100B Protein Could Be Used as Adjuvant Diagnostic Tool in Acute Ischemic Stroke Min Hee Jung, M.D., Dong Hoon Lee, M.D., Ph.D. and Chan Woong Kim, M.D., Ph.D. Department of Emergency Medicine, Chung-Ang University Hospital, Seoul, Korea
Background: In the emergency department, the diagnosis of ischemic stroke is difficult because the diagnostic modalities are limited to non-contrast brain CT and neurologic examination. Serum S100B protein, a bio-marker for ischemic stroke, is needed as an additional diagnostic aid in acute ischemic stroke. Methods: We retrospectively reviewed 50 patients diagnosed with ischemic stroke between August 2007 and December 2008 by brain MRI after brain CT and serum S100B measurement in the emergency department. The serum levels of S100B protein were analyzed and the diagnostic sensitivity of non-contrast brain CT combined with abnormal elevation of S100B protein was compared with that of non-contrast brain CT alone. Results: The overall sensitivity of non-contrast brain CT in the diagnosis of ischemia was 54%. S100B protein in early ischemia had a sensitivity of 58%. However, combining non-contrast brain CT and S100B increased the sensitivity to 74%. Conclusions: A biomarker-based diagnostic test would not replace the necessity for CT or other early imaging studies, and before contemplating any reperfusion strategy, neuro-imaging must be performed to rule out intracranial hemorrhage. However, S100B protein, a serum bio-marker, is able to help emergency physicians evaluate patients with suspected ischemic stroke and decide on treatment. Key Words: early diagnosis, stroke, S100B protein.
but brain CT has a low sensitivity in acute ischemic stroke.
INTRODUCTION
When a patient presents with non-specific neurologic symptoms and no witnesses of the event, it is difficult for emergency
When patients with cerebral ischemia present to an emer-
physicians to diagnose and decide the disposition.
gency department (ED), they complain chiefly of neurologic deficits, such as motor weakness of extremities, sensory
Many studies have shown that serum bio-markers such as
changes, and mental changes. Fast assessment of ischemic
matrix metalloproteinase 9 (MMP-9), D-dimer, S100B, and
stroke is very important because early revascularization therapy
B-type natriuretic peptide (BNP) help to diagnosis stroke
and neurologist consultation can improve patient outcome. In
early.[1] S100B calcium-binding protein is expressed by as-
the ED, the diagnostic modalities are limited to non-contrast
trocytes in both the developing and mature nervous system. It
brain CT and neurologic examination. The definitive method of
was initially described as a neuron-specific protein, but sub-
diagnosis is brain MRI, but it is not possible to use brain
sequent characterization has indicated that S100B is localized
MRI as an emergency tool in all facilities. Emergency physi-
mainly in the glial cells in the CNS.[2,3] Because of its high
cians use non-contrast brain CT to differentiate between hem-
specificity for brain tissue, it has attracted increasing attention
orrhagic stroke and ischemic stroke during initial assessment,
as a possible tool for traumatic and ischemic brain damage. In recent studies, the level of serum S100B protein has been used to predict outcome after brain damage.[4-6]
Received on April 28, 2011, Revised on June 6, 2011 (1st), August 2, 2011 (2nd), Accepted on September 26, 2011 Correspondence to: Chan Woong Kim, Department of Emergency Medicine, Chung-Ang University Hospital, 224-1 Heukseok-dong, Dongjak-gu, Seoul 156-757, Korea Tel: 02-6299-3109, Fax: 02-6299-2558 E-mail:
[email protected]
In this study, we analyzed the diagnostic value of early serum levels of S100B protein combined with non-contrast brain CT in ischemic stroke at the ED.
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218 대한중환자의학회지：제 26 권 제 4 호 2011
sphere: the cortical and the internal. Cortical border zone areas
MATERIALS AND METHODS
are located between the cortical supply of the anterior cerebral artery (ACA) and MCA (anterior cortical border zone), and be-
The clinical setting was the emergency department of
tween the MCA and PCA (posterior cortical border zone).
Chung-Ang University Yongsan Hospital, Seoul, Korea. We ret-
Internal border zone areas are located between the ACA,
rospectively reviewed patients who were diagnosed with ische-
MCA, and PCA, and the areas supplied by the Heubner, len-
mic stroke by brain MRI between August 2007 and December
ticulostriate, and anterior choroidal arteries. The definition of a
2008. Patients who underwent brain CT and serum S100B
lacunar infarction is a small (＜1.5 cm in diameter), flu-
measurement in the ED were enrolled. Patients who visited the
id-filled cavity representing the healed stage of a small deep
ED after 24 hours of symptom onset were excluded.
infarct, which was likely due to occlusion of a single pene-
The blood samples for the S100B protein of patients were
trator artery arising from the large arteries of the circle of
analyzed using the Elecsys S100 assay (Roche Diagnostics,
Willis or from the basilar artery. According to this classi-
Indianapolis, IN, USA). The sensitivity of the assay is 0.005
fication, we compared the sensitivity of non-contrast brain CT
μg/L; however, based on the 95% CI of serum S100B con-
and serum S100B protein.
centrations in samples obtained from healthy volunteers, we used 0.1 μg/L as the cut-off.
This study was conducted with the approval of the ChungAng University Hospital Ethics Committee.
Non-contrast brain CT scans were obtained using a 16-slice
RESULTS
CT scanner (LightSpeed Pro 16, GE Healthcare, USA). The scanning parameters were 120k Vp and 200 mA, a beam width of 20 mm and reconstruction thickness of 5 mm. The
During study period, 60 patients were examined with serum
reconstructed images were directly interfaced with a picture ar-
S100 protein in diagnosis of acute ischemic stroke. But 10 pa-
chiving and communication systems (PACS) (Marosis, Infinitt,
tients were excluded because the brain CT was not performed
Korea). With a 1.5 Tesla MRI (Avanto, Siemens, Germany),
in emergency department and the time of blood sample for
MR imaging (TR7.0 msec; Field of view 260 × 260 mm; ma-
S100B was over 24 hours.
trix size, 256 × 192; flip angle 20.0; slice thickness 1.6 space) were obtained.
The mean age of the patients was 66.4 ± 12.9 years (range, 36 to 92). 33 (66.0%) patients were male and 17 (34.0%)
A radiologist reviewed the non-contrast brain CT. A positive
were female. The all patients except 3 patients were examined
result indicated suspicion of ischemic stroke and a negative re-
with brain CT and MRI. The 3 patients were not possible to
sult indicated no acute brain lesion.
be taken the brain MRI because of their medical state. The
Neurologists reviewed the MRI results and categorized the
brain CT was performed immediately in emergency department
patients into topographic classifications of MRI. The topo-
and brain MRI was done in 2 days after the onset of symp-
graphic classifications were performed by leptomeningeal artery
toms (41 patients on admission day, 5 patients on 1 day after
system.[7] In territorial anterior infarcts: large infarcts were de-
admission, and 1 patient on 2 days after admission). The time
fined as those covering at least two of the three middle cere-
of blood sample for S100B was 6.23 ± 7.47 h after the onset
bral artery (MCA) territories (deep, superficial anterior, and su-
of ischemic stroke.
perficial posterior); malignant MCA infarction referred to
The topographic findings of MRI are shown in Table 1. The
life-threatening, complete or almost complete MCA infarction;
overall sensitivity of non-contrast brain CT in the diagnosis of
and limited infarcts covered only one of the three MCA
ischemia was 54%. The level of S100B protein in malignant in-
territories. In territorial posterior infarcts: infarcts are recog-
farct of territorial anterior circulation was higher than limited in-
nized in the territory of the posterior inferior (PICA), anterior
farct of same territory, 1.116 ± 1.531 and 0.153 ± 0.148 re-
inferior (AICA), and superior (SCA) cerebellar arteries and
spectively (p = 0.006). But there was no statistical difference be-
their branches, and in the territory of the posterior cerebral
tween the positive and negative result of early brain CT in same
arteries. The small cerebellar infarcts were no more than 2 cm
topographic area.
in size. Watershed infarcts are ischemic lesions that occur at
In 28 patients, the level of S100B was above 0.1 μg/ml.
the junction between two or three arterial territories. Two types
Therefore, S100B protein in early ischemia had a sensitivity of
of vascular border zone areas exist within the cerebral hemi-
58% (Table 2). When the abnormalities of non-contrast brain CT
Min Hee Jung, et al：S100B Protein in Acute Ischemic Stroke 219
Table 1. Topographic Radiologic Pattern of Ischemic Stroke and the Sensitivity of Brain CT Compared with MRI Brain CT in ED
Topographic radiologic pattern in MRI Territorial anterior circulation infarcts
Territorial posterior circulation infarcts
Watershed infarcts
Positive
Large Malignant Limited Large Small or End zone Brainstem Cortical anterior Cortical posterior
Lacunar infarct
4 3 11 2 0 3 1 2 1
(50.0) (100.0) (57.9) (33.3) (0.0) (75.0) (100.0) (100.0) (16.7)
Negative 4 0 8 4 1 1 0 0 5
(50.0) (0.0) (42.1) (66.7) (100.0) (25.0) (0.0) (0.0) (83.3)
S100B (μg/ml) (mean ± SD) 0.178 ± 0.212 1.116 ± 1.531 0.153 ± 0.148 0.327 ± 0.261 0.011 0.178 ± 0.210 0.104 0.066 ± 0.017 0.212 ± 0.202
CT: computerized tomography; MRI: magnetic resonance imaging; SD: standard deviation.
Table 2. Comparison of Sensitivity between Brain CT and Serum S100 Protein Serum S100B protein level
Brain CT
diagnosis of stroke as well as the short treatment window, there is a clear clinical need for adjunctive diagnostic information in the acute setting. Recent studies have compared the efficacy of various serum
Abnormal (＞0.1 μg/ml)
Normal (≤0.1 μg/ml)
bio-markers in elevating the diagnostic accuracy of ischemic
18 10
9 13
specificity for brain damage than other bio-marker.[2,3] The
Positive Negative
CT: computerized tomography.
stroke.[1] The S100B protein has been found to have more serum levels of S100B protein rise within the first 3 days of acute ischemic stroke onset. Importantly, because the serum levels of S100B do not rise immediately after onset of ische-
and S100B were combined, the sensitivity was increased to 74%.
mia, early S100B levels cannot be used by themselves for the diagnosis of acute ischemic stroke.[8] However, in terms of
DISCUSSION
predicting early and long-term neurologic complications after thrombolytic treatment, S100B levels have prognostic value be-
Acute stroke is characterized clinically by neurologic deficit.
cause they rise in proportion to the size of the infarct e.g. pa-
At present, non-contrast CT constitutes the standard of care at
tients with large-artery, cortical infarcts have higher serum
most institutions in the evaluation of acute stroke to rule out
S100B levels compared to patients with lacunar infarcts.[5,9]
intracranial hemorrhage or mass lesion. But the findings of
In the ED, actually all patients undergo at least one CT or
brain CT in acute ischemic stroke are often absent or quite
one MRI scans. Reflective of current practice, acute dif-
subtle. Even the absence of evidence of hemorrhage on initial
fusion/perfusion MRI protocols are only available in select
brain CT, does not allow for diagnosis of ischemic stroke.
centers. Whilst S100B can obviously not be used on its own
Many conditions-such as headache/migraine, seizure/postictal
as a diagnostic tool in ischemic stroke, it can certainly be
state, infectious/systemic disease, cardiovascular disorders (in-
used to aid in the diagnosis of acute stroke, particularly in the
cluding syncope), no organic substrate (functional or conversion
ED setting. According to our findings, the sensitivity of a
disorder), neuromuscular disorders, mass lesions such as sub-
strategy combining this biomarker test with non-contrast CT in
dural hematoma or tumor, intoxication/metabolic disorders, ver-
the evaluation of early ischemia was significantly greater than
tigo, change in mental status unrelated to ischemia, Bell’s pal-
using CT alone. The sensitivity of the S100B level was sim-
sy, and decompensation of prior neurological deficit-can imitate
ilar to non-contrast brain CT. But when the S100B level was
the symptoms of ischemic stroke.[1] Confirmed diagnosis of is-
used as an adjuvant diagnostic tool, the sensitivity increased to
chemic stroke in the ED is based on initial non-contrast CT
74% (Table 2).
and neurologic examination and is thus very difficult and may
The goal of imaging in the acute phase of ischemic stroke
be delayed. Given the difficulties inherent in making a clinical
is to identify the location and extension of the relevant lesion
220 대한중환자의학회지：제 26 권 제 4 호 2011
and the presence of significant arterial stenosis or occlusion.
cians evaluate patients with suspected ischemic stroke and de-
The various MRI patterns of acute brain ischemia (topography,
cide on treatment.
size and multiplicity) visualized using diffusion weighted image, the pattern of vessel involvement demonstrated with MR
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