Journal of Neurology

https://doi.org/10.1007/s00415-018-9026-1

ORIGINAL COMMUNICATION

Effect of anti-seizure drugs on serum S100B in patients with focal

seizure: a randomized controlled trial
Rituparna Maiti1 · Biswa Ranjan Mishra2 · Monalisa Jena1 · Archana Mishra1 · Santanu Nath2 · Anand Srinivasan1

Received: 26 June 2018 / Revised: 13 August 2018 / Accepted: 17 August 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose  S100B, a cytokine produced by astrocytes, has been studied as a biomarker of glial and neuronal damage in epi-
lepsy. The present study investigated the reliability of serum S100B as a biomarker and the effect of carbamazepine and
oxcarbazepine on serum S100B in patients with focal seizure.
Methods  The present randomized, open-label, active-controlled, parallel design clinical trial (NCT02705768) conducted on
60 patients with focal seizure. After recruitment, clinical evaluations were performed including Chalfont-National Hospital
seizure severity scale (NHS3), Quality of Life in Epilepsy Inventory (QOLIE-31) and serum S100B was estimated. Thirty
healthy individuals were recruited for evaluation of serum S100B at baseline only. After randomization, the study groups
received either tablet oxcarbazepine or tablet carbamazepine. At follow-up after 2 weeks, clinical status was checked and at
4 weeks, NHS3 and QOLIE-31 were scored along with serum S100B level estimation.
Results  Serum S100B level in patients with focal seizure increased significantly in comparison to healthy volunteers. The
decrease in serum S100B was significantly higher with carbamazepine group (0.004; 95% CI 0.001–0.006; p = 0.01) over
oxcarbazepine group. In logistic regression analysis, there was an increase in the log odds of 0.17 for focal seizure positivity
against healthy controls if S100B level increases by 1 pg and area under curve obtained by ROC analysis was 0.96 (p < 0.001).
Conclusion  Serum S100B increases in the patients with focal seizure and therapy with carbamazepine can decrease serum
S100B level significantly over oxcarbazepine. Serum S100B can be used as a prognostic biomarker in a focal seizure.

Keywords  Focal seizure · S100B · Carbamazepine · Oxcarbazepine

Introduction

Epilepsy is a neurological disorder where reactive astrocy-

* Biswa Ranjan Mishra tosis induces local synaptic dysfunction and leads to deficits
brm1678@gmail.com in neuronal inhibition [1]. S100B is and a calcium-binding
Rituparna Maiti cytokine produced primarily by astrocytes that shows auto-
rituparnamaiti@gmail.com crine and paracrine effects on neurons and glial cells [2].
Monalisa Jena At nanomolar concentrations, S100B stimulates the growth
drmonalisajena@gmail.com of neurites, the proliferation of astrocyte, and increases the
Archana Mishra free calcium concentration in both neurons and astrocytes
archanapmv@gmail.com [2, 3]. Increase in S100B may be due to either damage to
Santanu Nath glial cells or astrocytic reactions to neuronal injury [2, 4, 5].
beta.santanu@gmail.com The elevated S100B level is used as a marker of injury to the
Anand Srinivasan astrocytes and is also associated with a number of diseases
pharm_anand@aiimsbhubaneswar.edu.in including epilepsy [6–12].
Role of S100B in epilepsy is controversial and contra-
1
Department of Pharmacology, All India Institute of Medical dictory in the previous studies and literature. According to
Sciences (AIIMS), Bhubaneswar, Odisha, India
Steinhoff et al., interictal dysfunction of temporal lobe cor-
2
Department of Psychiatry, All India Institute of Medical responds to the elevation of neuronal and glial biomarkers in
Sciences (AIIMS), Bhubaneswar, Odisha, India

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 Journal of Neurology

the extracellular fluid and site-specific elevations may indi- were excluded from the study. Patients on anti-seizure
cate the site of origin of seizure [13]. Kaciñski et al. found drugs, psychoactive or central nervous system depressant
that the serum 100B is significantly elevated in children with drugs and pregnant/lactating mothers were also excluded
epilepsy and clinical seizure attacks [14]. Chang et al. con- from the study.
cluded that increased serum S100B level was predictive of
higher frequencies of seizures in the temporal lobe epilepsy
Study design
[15]. Lu et al. found elevated plasma S100B concentration
in mesial temporal lobe epilepsy [16]. Mikkonen et al. also
This is a randomized, open-label, active-controlled, parallel
concluded that S100B proteins may generate a signal of a
design clinical trial. After obtaining an informed consent,
continuing pathological process in the brain in the context
patients with focal seizure were screened and 60 patients
of febrile seizures and the probability of their recurrence
were recruited following inclusion and exclusion criteria. A
[17]. But Leutmezer et al. could not observe any significant
detailed history was taken and clinical evaluations were per-
change in serum S100 protein concentrations after a single
formed including Chalfont-National Hospital seizure sever-
episode of focal to bilateral tonic–clonic seizure in patients
ity scale (NHS3).Serum S100B was estimated at baseline
with mesial temporal lobe epilepsy or after convulsive status
and at the end of follow-up. Thirty healthy individuals aged
epilepticus [18]. Similarly, Portela et al. found normal serum
18–45 of either sex were recruited for evaluation of serum
S100B level in patients with focal epilepsy [19].
S100B at baseline only. After baseline assessment, patients
The literature review reveals that there is a paucity of
were randomized (allocation ratio 1:1) by simple randomiza-
data on serum S100B in focal seizures and there is no study
tion to either carbamazepine of oxcarbazepine group using
on the effect of carbamazepine and oxcarbazepine on serum
computer-generated random codes. The random allocation
S100B level. Hence, the present randomized, controlled trial
codes of the participants were generated by an investigator
has been outlined to evaluate the levels of serum S100B in
who was not involved in the patient recruitment. The codes
focal seizures and its changes (if any) after treatment with
were assigned to a sequence of numbers which was given to
carbamazepine or oxcarbazepine. The primary objective of
another investigator who was responsible for patient recruit-
this study was to evaluate and compare the change in serum
ment. This process ensured allocation concealment. Carba-
S100B levels with carbamazepine and oxcarbazepine mono-
mazepine was started with a dose of 200 mg/day in divided
therapy over a period of 4 weeks.
doses for the first week, 400 mg/day for the second week
and then increased to 600 mg/day for third and fourth weeks.
Oxcarbazepine was started with 10 mg/kg daily divided dose
Materials and methods for the first week followed by 15 mg/kg daily for the second
week and then was increased to 20 mg/kg for 3rd and 4th
The present study was conducted following ICMR’s ethical
weeks. All patients were followed up at 2 and 4 weeks after
guidelines for biomedical research on human subjects (2006)
randomization. At 2 weeks, clinical status was checked and
after getting the approval of the institutional ethics commit-
at 4 weeks, NHS3 and QOLIE-31 were scored along with
tee. The data presented in this publication are a part of the
serum S100B level estimation.
clinical trial registered with ClinicalTrials.gov (Identifier:
NCT02705768).
Outcome measures
Study population and eligibility
• Serum S100B
Patients aged 18–45 years, of either sex attending Epilepsy
clinic of AIIMS, Bhubaneswar, with focal motor seizure Serum S100B was estimated by ELISA using human
were screened for the study and recruitment was done S100B ELISA kit from DiaMetra SRL, Italy. The assay
according to inclusion and exclusion criteria. All subjects utilizes the double “sandwich” technique with two selected
with the clinical diagnosis of focal seizure presenting within monoclonal antibodies binding to different epitopes of the
48 h of an episode of seizure were included in the study [20]. γ-subunit of the enzyme. The method can detect S100B from
EEG was done in all patients as a supportive diagnostic aid 10 to 5000 pg/ml.
to localize the epileptogenic foci and confirm the diagno-
sis as a focal seizure. The recruited patients were treatment • Chalfont-National Hospital seizure severity scale (NHS3)
naïve or did not receive any treatment for at least 3 weeks [21, 22]
before recruitment. Patients with neuroendocrinal tumours,
or with a history of any brain injury, transient ischemic Seizure severity was assessed by the National Hospital Sei-
attack/stroke, neurosurgical/neuropsychiatric procedure zure Severity Scale (NHS3) which is a revised version of the

13
Journal of Neurology

Chalfont Seizure Severity Scale. It rates seven seizure-related
factors on a scale of 1–27.
• Quality of Life in Epilepsy Inventory (QOLIE-31) [23]
The Quality of Life in Epilepsy Inventory (QILIE-31) was
used to evaluate seven health concepts/domains: emotional
well-being, social functioning, energy/fatigue, cognitive func-
tioning, seizure worry, medication effects and overall quality
of life. A higher score reflects a more favourable health status.
Safety measures
The occurrence of adverse effects was investigated by the
nondirective questioning of the patient at the follow-up visit.
Patients had free access to the investigators for reporting any
adverse effects experienced by them.
Statistical analysis
Continuous variables have been represented as a
mean ± standard deviation (SD)/standard error of the mean
(SEM) and categorical variables as a percentage. Com-
parison of means between the groups was performed using
unpaired t test/Wilcoxon rank-sum test and within the group
by two-sided paired t test/Wilcoxon matched-pair test. Fish-
er’s exact test was used for comparing categorical variables
patients screened, 27 patients did not meet the inclusion cri-
teria and another four patients declined to participate. Five
patients in carbamazepine group and four patients in oxcar-
bazepine group were lost to follow-up at the end of treatment
period (Fig. 1). The reason for the loss of follow-up was
not known for these nine patients. There was no significant
difference between the groups at baseline (Table 1). Overall
mean age of the participants was 27.9 years and 26.7% were
female.
Change in serum S100B
At baseline
Mean serum S100B level among healthy controls was
0.049 ± 0.01; whereas, in carbamazepine and oxcarbaz-
epine group it was found to be 0.093 ± 0.02 and 0.083 ± 0.02,
respectively (Table 1). The difference in serum S100B lev-
els at baseline among the groups was found to be statisti-
cally significant (p < 0.001). Post hoc Dunnett test shows
that there was a significant increase in serum S100B in
carbamazepine group (− 0.044; 95% CI − 0.054 to − 0.034;
p < 0.01) and oxcarbazepine group (− 0.035; 95% CI − 0.045
Assessed for eligibility
(n = 91)

between the groups. For comparison between more than

Enrollment

Excluded (n = 31)
two groups, one-way ANOVA followed by post hoc Dun-
nett test was done. Intention to treat (ITT) was conducted by Not meeting inclusion criteria (n = 27)
Refused to participate (n = 4)
replacing missing values using multiple imputations and the
pooled data were used for analysis. Logistic regression was
performed to determine the significance and magnitude of
the correlation between S100B and the occurrence of a focal Randomized (n = 60)

seizure. Receiver operator characteristic (ROC) curve was

constructed to determine the cut-off value for the reliability Allocated to Allocated to
Carbamazepine group Oxcarbazepine group
of S100B as a biomarker in a focal seizure. SPSS 23.0 (IBM, (n = 30) (n = 30)
NY USA) was used for performing statistical analyses. R 3.4
Allocation

Received allocated Received allocated

along with the package pROC was used for ROC analysis intervention (n = 30) intervention (n = 30)

[24]. p < 0.05 was considered as significant. A sample size of

30 in each group was powered at 80% to detect a difference
of 0.1 µg/L in the change in serum S100B between the two
groups. The alpha error allowed was 0.05 and the standard Lost to follow up Lost to follow up
deviation was assumed to be 0.14 in each group based on (n = 5) (Dropouts) (n = 4) (Dropouts)
Follow up

previous studies. Discontinued intervention Discontinued intervention

(n = 0) (n = 0)

Results
Analysis

Analyzed (n=30) in ITT Analyzed (n=30) in ITT

Patient demographics and baseline characteristics

The recruitment process was started in April 2016 and the Fig. 1  CONSORT diagram showing the flow of participants through
study was completed by March 2017. Out of 91 focal seizure each stage of the randomized trial

13
 Journal of Neurology

Table 1  Baseline demographic Characteristics Carbamazepine group Oxcarbazepine group p ­valuea

data and clinical characteristics
Number of patients recruited 30 30
Number of patients at follow-up 25 26
Male:female ratio 23:7 21:9 0.77
Mean age in years 29.3 ± 8.77 26.4 ± 8.91 0.21
Age of epilepsy onset (year) 21.0 ± 3.84 19.7 ± 4.25 0.23
Mean duration of epilepsy (years) 8.3 ± 6.2 6.7 ± 6.1 0.31
Frequency of seizure (times/month) 4 (2.75-5) 5(3–5) 0.35
Seizure type
 Focal motor aware 25 27 0.71
 Focal motor impaired awareness 05 03
Serum S100B (µg/L) 0.093 ± 0.018 0.083 ± 0.021 0.07
NHS3 score 13.03 ± 2.41 13.30 ± 2.78 0.69
QOLIE-31: domain seizure worry 42.25 ± 13.94 49.13 ± 21.24 0.14
QOLIE-31: domain overall QoL 45.58 ± 12.84 49.92 ± 15.76 0.25
QOLIE-31: domain emotional 43.87 ± 10.26 49.60 ± 13.35 0.07
QOLIE-31: domain energy/fatigue 42.00 ± 12.91 45.33 ± 16.02 0.38
QOLIE-31: domain cognitive 45.24 ± 15.27 47.93 ± 20.83 0.57
QOLIE-31: domain medication effect 55.18 ± 13.97 57.49 ± 20.89 0.62
QOLIE-31: domain social function 57.67 ± 12.94 63.50 ± 13.76 0.10
QOLIE-31: final score 47.36 ± 9.14 51.80 ± 12.23 0.12

All data in mean ± SD except frequency of seizure (in median and IQR)
a
 Unpaired t test/Wilcoxon rank-sum test/Fisher’s exact test

to − 0.025; p < 0.01) in comparison to healthy controls. was 5.04 (95% CI 3.3–6.77). The odds ratio was found to be
There was no difference in S100B levels between the two 154 (Fig. 2).
treatment groups.

Change in serum S100B in study groups
In carbamazepine group, the change of serum S100B
was statistically significant (0.008; 95% CI 0.001–0.014;
p = 0.028) but in oxcarbazepine group, the change was not
significant (p = 0.17). A comparative analysis showed that
decrease in serum S100B was significantly higher with car-
bamazepine group (0.004; 95% CI 0.001–0.006; p = 0.01)
against oxcarbazepine group (Table 2).
Reliability of serum S100B as a biomarker
In logistic regression analysis, there was an increase in the
log odds of 0.17 (95% CI 0.08–0.25, p < 0.001) for focal
seizure positivity against healthy controls if S100B level
increases by 1 pg. The area under curve obtained by ROC
analysis was 0.96 (p < 0.001). The cut-off threshold for the
reliability of S100B as a biomarker was found to be 62 pg/
ml. The sensitivity and specificity for the threshold value
were found to be 0.93 and 0.92, respectively. The negative
and positive predictive values were 0.85 and 0.96, respec-
tively. The precision was 0.96. The diagnostic log odds ratio
Change in NHS3
In both study groups, NHS3 score decreased significantly
suggesting effective control of severity of seizure by both the
drugs. The mean change of NHS3 score in carbamazepine
group was compared with that of oxcarbazepine group and
was found to be non-significant (− 0.04; 95% CI − 0.97 to
0.64; p = 0.69) (Table 2).
Change in quality of life in epilepsy inventory
All seven domains of QOLIE-31 were assessed separately
at both visits and the overall final score was also calculated
and compared between the two groups. In both the groups,
there was a statistically significant improvement in the qual-
ity of life in all seven domains and in the final score. The
comparison of mean change between the groups revealed a
significant difference in change in the domain of emotion,
energy/fatigue, and the final score in carbamazepine group in
comparison to oxcarbazepine group. In other domains both
the drugs showed equal efficacy in improving the quality of
life (Table 2).

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 Journal of Neurology

Table 2  Change in efficacy parameters in study groups over a period of 4 weeks (intention to treat analysis)
Variables Carbamazepine group (n = 30) Oxcarbazepine group (n = 30) Difference between groups
Δ carbamazepine vs Δ oxcar-
bazepine
1st visit 2nd visit Mean diffΔ (95% CI) p ­valuea 1st visit 2nd visit Mean diffΔ (95% CI) p ­valuea Mean diffΔ (95% CI) p ­valueb

Serum S100B (µg/L) 0.093 ± 0.003 0.085 ± 0.004 0.008 ± (0.001 to 0.028 0.083 ± 0.004 0.079 ± 0.004 0.004 (− 0.002 to 0.172 0.004 (0.001 to 0.006) 0.01
0.014) 0.014)
NHS3 score 13.03 ± 0.44 6.53 ± 0.90 6.50 (4.83 to 8.17) < 0.0001 13.30 ± 0.51 6.76 ± 0.89 6.54 (4.83 to 8.25) < 0.0001 − 0.04 (− 0.97 to 0.64) 0.69
QOLIE-31: domain 42.25 ± 2.54 50.74 ± 3.16 − 8.49 (− 14.87 to 0.016 49.13 ± 3.88 58.66 ± 3.54 − 9.53 (− 16.63 to 0.011 − 1.04 (− 2.94 to 3.14) 0.95
seizure worry − 2.13) − 2.43)
QOLIE-31: domain 45.58 ± 2.34 57.06 ± 2.21 − 11.48 (− 15.49 to < 0.0001 49.92 ± 2.88 62.30 ± 2.34 − 12.38 (− 117.10 to < 0.0001 0.9 (− 2.86 to 1.30) 0.46
overall QoL − 7.46) − 7.67)
QOLIE-31: domain 43.87 ± 1.87 52.04 ± 1.82 − 8.17 (− 11.64 to < 0.0001 49.60 ± 2.44 54.90 ± 2.57 − 5.3 (− 9.11 to − 1.49) 0.013 − 2.87 (− 1.36 to < 0.001
emotional − 4.72) − 4.43)
QOLIE-31: domain 42.00 ± 2.36 51.32 ± 2.84 − 9.32 (− 13.29 to < 0.0001 45.33 ± 2.93 52.72 ± 2.45 − 7.39 (− 11.01 to < 0.0001 − 1.93 (− 0.386 to 0.017
energy/fatigue − 5.36) − 3.77) − 3.88)
QOLIE-31: domain 45.24 ± 2.79 51.77 ± 2.91 − 6.53 (− 10.35 to 0.001 47.93 ± 3.80 53.57 ± 3.58 − 5.22 (− 10.17 to 0.017 − 1.31 (− 0.984 to 0.32
cognitive − 2.71) − 1.11) 2.99)
QOLIE-31: domain 55.18 ± 2.55 64.68 ± 2.78 − 9.5 (− 16.83 to 0.014 57.49 ± 3.81 65.97 ± 3.68 − 8.48 (− 13.55 to 0.004 − 1.02 (− 1.71 to 3.88) 0.45
medication effect − 2.17) − 3.39)
QOLIE-31: domain 57.67 ± 2.36 66.55 ± 2.51 − 8.88 (− 12.20 to < 0.0001 63.50 ± 2.51 71.01 ± 2.69 − 7.51 (− 11.05 to < 0.0001 − 1.37 (− 0.02 to 3.10) 0.05
social function − 5.57) − 3.98)
QOLIE-31: final score 47.36 ± 1.67 55.91 ± 1.73 − 8.55 (− 10.84 to < 0.0001 51.80 ± 2.23 59.33 ± 2.12 − 7.53 (− 10.35 to < 0.0001 − 1.02 (− 1.63 to 5.69) 0.043
− 6.25) − 4.72)

All data in mean ± SEM

CI confidence interval
a
 Paired t test/Wilcoxon matched-pair test
b
 Unpaired t test/Wilcoxon rank-sum test

13

Fig. 2  ROC curve depicting the best threshold cut-off point (62  pg/
ml) for S100B for focal seizure positivity (sensitivity 91.7%; specific-
ity 93.3%)
Safety evaluation
There was no complaint of any adverse drug reaction from
patients who were on oxcarbazepine. In carbamazepine
group, four patients complained of sedation and dizziness
and another three patients complained of vertigo which was
significantly more (p = 0.004) than in the oxcarbazepine
group. All adverse drug reactions were mild and the drug
was not discontinued. This indicates that oxcarbazepine was
more safe and tolerable than carbamazepine.
Discussion
Serum S100B was the primary outcome measure in the
present study. There was a significant increase in the base-
line serum S100B in patients with focal seizure compared
with healthy controls suggesting neuronal and glial dam-
age. Previous studies by different scientists have suggested
that the epileptic seizure can increase serum S100B level
and support the findings of the present study [14–17]. As
there was no previous study on the effect of anti-epileptics
on serum S100B, we evaluated the change in serum S100B
after 1 month of monotherapy with either carbamazepine
or oxcarbazepine. After 1 month of therapy, serum S100B
level decreased significantly in carbamazepine group but the
reduction with oxcarbazepine was not significant. In car-
bamazepine group, though there was a definite decrease in
serum S100B level, the level was not normalized or brought
down to the mean level of healthy volunteers. This find-
ing suggests that a longer follow-up is required to ascertain
further changes in the biomarker levels over time. Neuronal
regeneration after an injury is a slow process and probably
it is indirectly facilitated by therapy with carbamazepine.
Reactive gliosis which is an astrocytic response to brain
injury is a conspicuous neuropathological feature of epilepsy
and may play a causal role in the development and mainte-
nance of seizures [25]. This astrocytosis consists of changed
13
Journal of Neurology
morphology, gene expression, proliferation and release of
cytokines [26]. S100B is produced and released primarily
by astrocytes in both physiological and pathological condi-
tions, which at low concentrations have neurotrophic and
gliotrophic actions contributing to the development and
maintenance of central nervous system [27, 28]. However,
elevated levels of S100B in cerebrospinal fluid (CSF) and
serum could signify reactive gliosis, astrocytic death and/
or dysfunction of the blood–brain barrier and thus, can be
noted as a marker of neuronal/glial damage in epilepsy [29].
So our finding of the significantly higher level of S100B in
patients with focal epilepsy may be due to reactive gliosis
especially astrocytosis.
The diagnostic odds ratio of 154 for S100B with a rela-
tively narrow confidence interval along with the sensitivity
and specificity of 0.93 and 0.92 shows that S100B could be
a potential prognostic biomarker (as neuronal damage can
be found in various other conditions too). Further studies
could be conducted to evaluate its application as a prognos-
tic marker in the pharmacotherapy of focal seizures.
In both the study groups there was a significant reduction
in severity of seizure episodes in terms of NHS3. The mean
change of NHS3 score was comparable between the two
treatment groups. Similarly, both the drugs improved the
scoring in all seven domains of QOLIE-31 and the overall
score. The results of NHS3 and QOLIE-31 suggest that both
the drugs are equally efficacious in controlling seizure sever-
ity and improving the quality of life.
Our study results revealed a significant reduction in
serum S100B after 1 month of carbamazepine therapy, but
the change after oxcarbazepine therapy was not significant.
Explaining the exact mechanism of reduction of serum
S100B by carbamazepine may not be feasible at this stage,
but we can get an idea about the effect of carbamazepine
on astrocytic signalling pathway from the previous in vitro
and animal studies. It has been found that carbamazepine
causes gradual intracellular alkalinization which leads
to inhibition of myo-inositol uptake, resulting in reduced
inositol phosphate/phospholipid signalling in astrocytes.
Subsequently, monoaminergic or glutamatergic stimula-
tion-induced increase in free intracellular ­Ca2+ ­([Ca2+]i) is
inhibited, reducing or aborting the release of astrocytic gli-
otransmitters [30–33]. The effect of carbamazepine may also
be explained by its ability to down-regulate GluK2 kainate
receptor expression on astrocytes [34]. Our literature search
could not find any study on the effect of oxcarbazepine on
signalling in astrocytes.
Limitations
The study setting being a tertiary care centre, the enrolled
patients may not be representative of those seen in general
practice, where there may be significant comorbidity with
Journal of Neurology
other neurological and psychiatric disorders. The main limi-
tation of the study was open-label design and a short follow-
up period of 4 weeks. A broader spectrum of geographical
locations and clinical settings and a multi-centric study set-
ting may increase the generalizability of the findings.
Conclusions
Increased serum S100B levels are detected in patients with
focal seizure as compared to the healthy volunteers and it
can be used as a prognostic biomarker in a focal seizure. A
significant decrease in serum levels of S100B is observed
with carbamazepine therapy in comparison to oxcarbaz-
epine. Though the efficacy of both the drugs in reducing
the severity of seizure and improving the quality of life was
found to be comparable, oxcarbazepine was found to be bet-
ter tolerated than carbamazepine. With potential limitations,
the findings of this study can further be corroborated by a
multi-centric, double-blind, large population-based study.
Funding None.
Compliance with ethical standards  E (1999) Cisternal S100 protein and neuron-specific enolase are
Conflicts of interest  None to declare.
Ethical standards  The present study have been approved by the appro-
priate ethics committee and have therefore been performed in accord-
ance with the ethical standards laid down in the 1964 Declaration of
Helsinki and its later amendments.
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