Brain & Development 27 (2005) 434–436
www.elsevier.com/locate/braindev

Case report

Increased cytokine levels in a cerebral mycotic aneurysm
in a child with Down’s syndrome
Hiroshi Ozawaa,*, Megumi Tobaa, Masaya Nakamotoa, Seiji Nomaa,
Takashi Ichiyamab, Hiroshi Takahashic
a

Department of Pediatrics, Tokyo Metropolitan Hachioji Children’s Hospital, Hachioji, Tokyo, Japan
b
Department of Pediatrics, Yamaguchi University, Ube, Yamaguchi, Japan
c
Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo, Japan
Received 8 October 2003; received in revised form 30 June 2004; accepted 15 September 2004

Abstract
Cerebral mycotic aneurysms are one of the most serious complications of bacterial endocarditis but the mechanism underlying cerebral
aneurysms is unclear. We reported the cytokine levels in a cerebral mycotic aneurysm in a child with Down’s syndrome. The patient was a
12-year-old female. She was diagnosed as having Down’s syndrome and congenital heart disease consisting of an endocardial cushion defect
at birth. She underwent a radical operation at 9 years but mitral valve regurgitation remained. She was hospitalized with high fever, vomiting,
loss of activity and gait disturbance. Neurological examination revealed facial palsy and hemiparesis on the left side. Cytokines such as IL-6,
TNF-a, sTNFR1 and sE-selectin were elevated in blood, and IL-6, TNF-a and sTNFR1 in cerebrospinal fluid. T2-weighted MRI disclosed a
low intensity area in the right Sylvian sulcus. MR angiography showed an aneurysm of the right middle cerebral artery. We think that
cytokines and the formation abnormality of collagen fibers are related to the production of aneurysms.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Cytokine; Mycotic aneurysm; Bacterial endocarditis; Down’s syndrome

1. Introduction

2. Case report

Cerebral mycotic aneurysms are one of the most serious
complications of bacterial endocarditis and there has been a
report of one in a child with Down’s syndrome [1]. The
mechanism underlying cerebral aneurysms is unclear.
Cytokines are important mediators of abdominal aortic
aneurysms [2] and coronary aneurysms of Kawasaki disease
[3]. We reported the cytokine levels in a cerebral mycotic
aneurysm in a child with Down’s syndrome.

The patient was a 12-year-old female. She was diagnosed
as having Down’s syndrome and congenital heart disease
consisting of an endocardial cushion defect at birth. She
underwent a radical operation at the age of 9 years but mitral
valve regurgitation remained. She had been admitted to our
hospital previously on 22 August 2001 because of infarction
of the middle cerebral artery on the left side with bacterial
endocarditis. She was hospitalized on 25 January 2002 with
high fever, vomiting, loss of activity and gait disturbance.
On admission, she was crying with displeasure. Neurological examination revealed facial palsy and hemiparesis on
the left side. She could not stand. Sense of pain in the upper
and lower limbs on the left side was present. Cerebellar and
extrapyramidal signs were not observed. Routine laboratory
tests revealed the following: white blood cells, 18,600/mm3
(referenceZ4000–8000); platelets, 177,000/mm3 (referenceZ150,000–300,000); C-reactive protein, 7.1 mg/dl

* Corresponding author. Address: Department of Pediatric Neurology,
Shimada Center for Rehabilitation and Neurodevelopmental Intervention,
1-31-1 Nakazawa, Tama-city, Tokyo 206-0036, Japan. Tel.: C81 42 374
2071; fax: C81 42 372 9363.
E-mail address: ozawa@shimaryo.or.jp (H. Ozawa).
0387-7604/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2004.09.012

H. Ozawa et al. / Brain & Development 27 (2005) 434–436

(reference!0.1) and ferritin, 197 mg/dl (referenceZ
2–128). The level of ferritin decreased at 167 mg/dl 2 days
later. Blood coagulation values including the partial
thromboplastin time, activated partial thromboplastin time,
protein S and protein C were all within normal range.
Antiphospholipid antibodies were negative. Cerebrospinal
fluid (CSF) analysis revealed pleocytosis (1867/mm3, 49%
polymorphs and 51% lymphocytes), 218 mg/dl protein and
49 mg/dl glucose. Herpes simplex antibodies were not
elevated. The beta 2 microglobulin levels in blood and urine
were 2.3 mg/l (referenceZ0.8–1.8) and 7390 mg/dl (reference!200). Two days later, beta 2 microglobulin levels of
urine was 931 mg/dl. The interleukin-6 (IL-6), tumor
necrosis factor-a (TNF-a), soluble TNF receptor 1
(sTNFR1), and soluble E selectin (sE-selectin) levels in
blood were 107 pg/ml (reference!3.1), 27.6 pg/ml (reference!4.4), 5.07 ng/ml (referenceZ0.55–1.33), and
284 ng/ml (referenceZ40–60), respectively. The IL-6,
TNF-a and sTNFR1 levels in CSF were 6059 pg/ml
(reference!3.1), 83.4 pg/ml (reference!4.4), and
3.13 ng/ml, respectively. Staphylococcus aureus was
detected in cultures of the pharynx swab. Blood, stool and
CSF cultures were negative. Mitral valve regurgitation and
vegetation were detected on echocardiography. Computed
tomography (CT) disclosed edema of the right cerebrum,
and high density of the Sylvian sulcus and suprasellar
cistern on the right side and in the longitudinal cerebral
fissure (Fig. 1). We considered it as cerebral bleeding.

Fig. 1. Computed tomography disclosed edema of the right cerebrum, and
high density of the Sylvian sulcus and suprasellar cistern on the right side
and in the longitudinal cerebral fissure. We considered it cerebral bleeding.

435

Fig. 2. T2-weighted MRI disclosed a low intensity area in the right Sylvian
sulcus (arrow).

T2-weighted MRI disclosed a low intensity area in the right
Sylvian sulcus (Fig. 2). MR angiography (MRA) showed an
aneurysm of the right middle cerebral artery (Fig. 3). The
aneurysm had not been seen 5 months ago. The patient was
treated with ampicillin, cefotaxm and glycerol. The
antibiotics was changed to cefotiam, which was administered for 4 weeks. Six weeks later, MRA disclosed
embolization of the aneurysm. So she did not undergo
surgical intervention. Repeated echocardiography disclosed
moderate residual mitral regurgitation. She was discharged
6 weeks later. She could walk but bilateral palsy remained.

Fig. 3. MR angiography showed an aneurysm of the right middle cerebral
artery (arrow).

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H. Ozawa et al. / Brain & Development 27 (2005) 434–436

3. Discussion
Cerebral mycotic aneurysms in bacterial endocarditis
with childhood have been reported in Down’s syndrome and
Ehlers–Danlos syndrome [1,4]. The mechanism underlying
cerebral aneurysms is unknown. The pathogenesis of
abdominal aortic aneurysms is a complex process in
which arterosclerosis and inflammation play leading roles.
Cytokines are important mediators of both processes. The
plasma concentrations of cytokines are higher in abdominal
aortic aneurysm patients [2]. In Kawasaki disease, cytokines
play important roles in the pathogenesis of both the immune
dysfunction and the endothelial cell damage characteristic
of coronary aneurysms. The highest serum levels of IL-6
and IL-8 are found in the first week after the onset of
disease, and the levels observed in the first week are highly
correlated with those of other acute phase reactants [3].
Regarding histological findings, endothelial swelling,
necrosis, macrophage and activated T cell infiltration, and
fibrin deposition are observed in endothelial lesions [5].
Leung et al. hypothesized that the endothelial cell damage
occurs through two immunological steps [6]. First, elevated
cytokines produced by the activated immune system induce
endothelial cells to express adhesion molecules. This results
in the infiltration of mononuclear cells into the endothelium.
Endothelial cells are also induced to express a new antigen.
Second, a cytotoxic antibody toward the new antigen is
produced. The already activated immune system may
support the production of this cytotoxic antibody. These
two steps comprise the initial stage of endothelial cell
injury.
Intracranial production of cytokines has been demonstrated
after acute disseminated encephalomyelitis [7] and encephalopathy [8]. The CSF IL-6, IL-10, TNF-a, and sTNFR1
concentration were elevated in 16, 13, 3, and 11 of the 18
patients with acute disseminated encephalomyelitis, respectively. Myelin basic protein levels in CSF of the patients with
elevated CSF sTNFR1 levels were significantly higher than
those in CSF of the patients with normal CSF sTNFR1 levels.
So they suggested that IL-6 and TNF-a were mediate
inflammation in the central nervous system in acute
disseminated encephalomyelitis [7]. And cytokines and
sTNFR1 in serum and CSF were elevated with influenza
virus-associated encephalopathy, and that the CSF TNF-a and
sTNFR1 levels may be important for predicting neurological
sequelae [8]. In our case, cytokines such as IL-6, TNF-a,
sTNFR1 and sE-selectin were elevated in blood, and IL-6,
TNF-a and sTNFR1 in CSF. IL-6 and TNF-a are well known
as cytokines that play important roles in inflammatory
responses. These cytokines are recognized as primary
mediators in the pathogenesis of inflammation. The concentrations of IL-6, TNF-a and sTNFR1 are often elevated in the
CSF of patients with infectious inflammatory disorders [7].
sE-selectin is an endothelial-specific surface protein.

Adhesion molecules such as sE-selectin are primarily found
in a soluble form after endothelial cell activation and
leukocyte–endothelial cell interaction [8]. In MRA, an
aneurysm of the right cerebral artery appears in the acute
phase. The aneurysms in our case was not seen 5 months ago.
The distribution of collagen type VI is different from normal in
the skin in trisomy 21, and there is overexpression of COL6A1
[9]. In Down’s syndrome with the moyamoya abnormality,
there were occlusions or stenosis in arteries due to fibrous
hypertrophy of the arterial intimal walls. The tunica media was
highly atrophic and the intermal elastic lamina was tortuous
and duplicate [10,11]. So we think that cytokines and the
formation abnormality of arteries are related to the production
of aneurysms.

Acknowledgements
The authors wish to thank Dr Naotaka Atsumi for the
advice regarding the manuscript.

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