J Korean Med Sci 2010; 25: 888-94

ISSN 1011-8934
DOI: 10.3346/jkms.2010.25.6.888

Clinical Presentations and Neurodevelopmental Outcomes of Perinatal
Stroke in Preterm and Term Neonates: A Case Series
Perinatal stroke in neonates can lead to disability in later life. However, its etiology
and prognosis are poorly understood. The aim of this study was to describe clinical
presentations and neurodevelopmental outcomes of our case series of perinatal
stroke in Korea. Thirteen term and preterm neonates who were diagnosed with perinatal stroke in two university hospitals from March 2003 to March 2007 were enrolled.
Seven term and 6 preterm neonates were diagnosed with perinatal stroke, based
on the brain MRI findings. Perinatal stroke presented with seizure (4/13), perinatal
distress (3/13) in term neonates, whereas stroke in preterm neonates did not present
with noticeable clinical symptoms. Only one neonate had positive thrombophilic test
(homozygous C677T polymorphism for MTHFR). Ten neonates had infarctions in
the territory of the middle cerebral artery (MCA), and 3 neonates had borderzone
infarctions between the anterior cerebral artery and MCA. Neurodevelopmental outcome was abnormal in 4 neonates. Infarction in MCA main branch or posterior limb
of internal capsule showed an abnormal neurodevelopmental outcome. Our study
is the first systematic study of perinatal stroke in Korea, and shows its clinical presentations and neurodevelopmental outcomes. The population-based study on incidence and prognosis of perinatal stroke in Korea is required in the future.
Key Words : Perinatal Stroke; Newborn; Magnetic Resonance Imaging
ⓒ 2010 The Korean Academy of Medical Sciences.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.

INTRODUCTION

Hyun Ju Lee1, 2, Byung Chan Lim 2,
Hee Hwang 2, Joon-Seok Hong 3,
Ee-Kyung Kim1, Han-Suk Kim1,
Beyong Il Kim1, 2, Jung-Hwan Choi 1,
and Chang Won Choi 1, 2
Department of Pediatrics1, Seoul National University
College of Medicine, Seoul; Department of Pediatrics 2,
Department of Obstetrics and Gynecology 3, Seoul
National University Bundang Hospital, Seongnam,
Korea

Received : 24 August 2009
Accepted : 17 November 2009

Address for Correspondence
Chang Won Choi, M.D.
Department of Pediatrics, Seoul National University
Bundang Hospital, 166 Gumiro, Bundang-gu,
Seongnam 463-707, Korea
Tel : +82.31-787-7286, Fax : +82.31-787-4054
E-mail : choicw@snu.ac.kr
The content of this paper was presented during a poster
session at the Recent Advances in Neonatal Medicine
in Wurzburg, Germany, October 2-4, 2008.

ental outcomes of perinatal stroke in term and preterm neonates in Korea.

Perinatal stroke is an increasingly recognized clinical entity that leads to hemiplegic cerebral palsy in later life (1). Although modern neonatal neuroimaging has improved the detection of infarctions, the etiology and prognosis of perinatal stroke have not been well described. The incidence of perinatal
stroke varies according to the availability of neuroimaging
and the diagnostic criteria used, but is believed to be about
one per 4,000 live births (2). Furthermore, its lack of specific
clinical features makes the diagnosis of perinatal stroke difficult resulting in its under-diagnosis (3, 4). Few studies (5-7)
have investigated clinical presentations and neurodevelopmental outcomes of perinatal stroke based on combined findings of
neuroimaging, electroencephalography (EEG) in neonates. To
the best of our knowledge, reports on perinatal stroke in Korea
have been relatively few, compared to those of western countries. Furthermore, there has been no report about perinatal
stroke of preterm infant in Korea. The major aim of this study
was to describe the clinical presentations and neurodevelopm-

MATERIALS AND METHODS
Case series

To search for the neonates diagnosed with perinatal stroke
during admission to newborn nursery or neonatal intensive
care unit in Seoul National University Children’s Hospital or
Seoul National University Bundang Hospital (level III teaching hospital), an electronic search of all head magnetic resonance imaging (MRI) reports generated from March 1, 2003
to March 1, 2008 was conducted. All neuroimaging reports
containing any of the following text strings were retrieved:
stroke, infarct, middle cerebral artery (MCA), posterior cerebral artery and anterior cerebral artery. Neuroimaging studies that revealed any of the followings were excluded; 1) an
acute infarction occurring after 28 days of life; 2) intraventric888

BSID-2, Bayley Scales of Infant Development-2

ular hemorrhage with unilateral parenchymal hemorrhage
(venous infarction); 3) cystic periventricular leukomalacia;
and 4) bacterial meningitis. The institutional review board
of Seoul National University Bundang Hospital approved the
study (B-0911/087-104), and informed consent was waivered.
Maternal and perinatal characteristics

Maternal and perinatal information was obtained from electronic medical records. Complications during pregnancy or
delivery were searched and included placental abruption, preeclampsia, intrauterine growth restriction, chorioamnionitis,
oligohydramnios, prolonged second stage of labor, maternal
prothrombotic disorder, and fetomaternal transfusion. Chorioamnionitis was diagnosed by placental histopathology, but
this information was available only in 6 neonates. Perinatal
factors included meconium-stained amniotic fluid, abnormal
fetal heart rate pattern, umbilical arterial blood pH, type of
delivery, and Apgar scores. Abnormal fetal heart rate patterns
included late deceleration and decreased variability. Perinatal distress was defined as umbilical arterial blood pH lower
than 7.0 or significant respiratory depression requiring tracheal intubation at the delivery room.
Thrombophilic factors

Thrombophilic screening test included prothrombin time,
activated partial thromboplastin time, platelet count, fibrinogen, protein C, protein S, antithrombin III, anticardiolipin
antibodies, and lupus anticoagulant. In addition, the presence
of heterozygous factor V Leiden, G20210A mutation of the
prothrombin gene, and homozygous C677T polymorphism
for MTHFR was screened by PCR-based mutation analysis.
Brain MRI

Brain MRI was performed as a part of routine evaluation
process for seizure, unexplained perinatal distress or prematurity. The infants were imaged on a 1.5 Tesla unit system
(Intra Philips Medical Systems, Best, Netherlands) using T1
weighted spin echo (SE 600/20 msec), inversion recovery
(3800/30/950), and T2 weighted spin echo (SE 3500/208
msec) sequences, at a slice thickness of 3-4 mm. The field of
view was 150-200 mm, and matrices were 256×256 or 512
×512. Single-shot, multi-slice spin echo and echo planar
imaging sequence were obtained with the following parameters comprise TR=800 msec, TE=123 msec, and diffusion
sensitivity (b=1,100 sec/mm2). The diffusion gradient was
applied to the cephalocaudal axis direction. The magnetic
resonance angiography images were performed in 8 neonates
using a 3-dimensional time-of-flight technique, and data was
processed with a maximum intensity projection method. Arterial distribution, involvement of the basal ganglia, thalamus,
and internal capsule, and the presence of coexisting hemor-

889

rhage were determined from radiologic reports. In term neonates, brain MRI scans were completed between days 2 and
4 of life except for one neonate in whom MRI scan was performed on day 16 after weaning from ventilator. Infarction
in preterm infants was first detected by sequential brain ultrasonography and later confirmed by brain MRI. Based on the
location, extent, and shape of the lesions, infarctions were
categorized as either being in the territory of main cerebral
arterial branch or having a borderzone distribution. Infarctions in the territory of the MCA were subdivided further
according to a modified version of the criteria suggested by
de Vries et al. into main cerebral branches, cortical branches,
and lenticulostriate branches (8).
Electroencephalography

Twelve neonates underwent full standard EEG (16 channels) at a recording speed of 15 mm/sec. States of the neonates
and all movements during examinations were recorded by a
single technician. Background rhythm and the presence of
epileptic discharges were evaluated.
Neurodevelopmental outcomes

Assessment of neurologic outcome was based on the neurologic examination findings performed at the last follow-up
visits (14 months to 6 yr of age). A diagnosis of developmental
delay was based on the results of Bayley Scales of Infant Development-2 (BSID-2) performed at 12 months corrected of age.
In patients born prematurely, the correction for prematurity
was made. BSID-2 was performed by a single pediatric rehabilitationist.

RESULTS
Clinical presentations of our case series

A total of 13 neonates, diagnosed with perinatal stroke during admission, were discovered. Of these neonates, 7 were
term and 6 were preterm neonates, and 6 (46%) were male.
Gestational age of preterm neonates ranged from 29 to 36
weeks, and birth weights ranged from 1,080 to 3,380 g
(Table 1). Presenting symptoms or signs of perinatal stroke
were seizure (4/13), significant perinatal distress (3/13), or
apnea (1/13). Seizures occurred between 2 and 6 days after
birth. Three neonates who presented with seizure were easily
recognized clinically and promptly diagnosed, whereas those
without seizure were unnoticed until stroke had been confirmed by brain MRI. In these neonates without seizure, brain
MRI was performed as a part of routine evaluation process for
unexplained perinatal distress in term neonates. In preterm
neonates, serial cerebral ultrasonography, which was available
in the neonatal intensive care unit at bedside, was performed

890

H.J. Lee, B.C. Lim, H. Hwang, et al.

as a routine evaluation of prematurity through the anterior
fontanel. In 5 of the 6 preterm neonates, infarction was first
detected by sequential brain ultrasonography and later confirmed by brain MRI. In one preterm neonate born at the 36th
week of gestation, infarction presented with a sudden onset
of apnea. The other preterm neonates with infarction were all
asymptomatic. In all term and preterm neonates with perinatal stroke, routine laboratory tests including serum electrolytes, glucose, creatinine, liver function tests, lactate, white
blood cell counts, C-reactive protein, and TORCH screening
were normal. There was no laboratory evidence of polycythemia, thrombocytopenia or coagulation defects. No infants
had structural cardiac abnormalities.
Maternal and perinatal characteristics

Maternal risk factors for perinatal stroke were present in 9
Table 1. Clinical presentations of perinatal stroke
Patients
1
2
3
4
5
6
7
8
9
10
11
12
13

Gestational
Sex
age (week)
29
31
32
33
36
36
38
39
40
40
40
41
41

F
M
M
F
F
F
M
F
M
M
F
M
F

Birth
Perinatal
Seizure
Apnea
weight (g)
distress
1,260
1,080
1,490
1,880
3,380
1,950
2,410
2,540
3,400
2,840
3,360
3,500
3,240

+
+
+
+

+
+
+
-

+
-

M, male; F, female.

(69%) of the 13 neonates: 1 placental abruption; 2 preeclampsia; 1 chorioamnionitis; 1 oligohydramnios; 2 prolonged second stage of labor; 2 maternal prothrombotic disorder (antiphospholipid syndrome). There was no evidence of placental
infarction in 6 neonates whose placenta were examined. Five
neonates were born by spontaneous vaginal delivery and eight
by cesarean section. Abnormal fetal heart rate patterns were
seen in 4 term and 1 preterm neonates. These 4 term neonates
were delivered by emergency cesarean section. Three of them
required tracheal intubation at the delivery room. One neonate intubated at the delivery room developed meconium
aspiration syndrome complicated by persistent pulmonary
hypertension. All six preterm neonates with perinatal stroke
did not require intubation at the delivery room. Perinatal distress was present in 3 neonates, and they had significant respiratory depression requiring tracheal intubation at the delivery room. One neonate had an umbilical arterial blood pH
lower than 7.0. Four neonates had low Apgar scores below 5
at 1 min, but none at 5 min. Details of individual maternal
and perinatal findings are shown in Table 2.
Thrombophilic factors

Thrombophilic screening test was performed in 10 of the 13
neonates and 1 of these had abnormality. Antithrombin III,
protein C, and protein S levels were within normal range.
Heterozygous factor V Leiden and G20210A mutation of the
prothrombin gene was not present. Homozygous C677T
polymorphism for MTHFR was present in one neonate.
Brain MRI findings

Eleven neonates (85%) had unilateral infarctions, which
were more common on the left side than the right side (7:4).
Ten neonates had infarctions in the territory of MCA, and 3

Table 2. Maternal and perinatal characteristics of patients with perinatal stroke
Patients
1
2
3
4
5
6
7
8
9
10
11
12
13

Maternal & perinatal event

FHRP

Delivery

UAB pH

AS (1-5 min)

Resuscitation

Chorioamnionitis
Preeclampsia, IUGR
Maternal APL syndrome, MCA infarction
Maternal APL syndrome
Placental abruption
Prolonged second stage of labor
Prolonged second stage of labor
Oligohydramnios, MAS
Preeclampsia
-

Absence of variability
Normal
Normal
Normal
Normal
Normal
Bradycardia
Deceleration
Deceleration
Deceleration
Normal
Normal
Normal

CS
VD
VD
CS
CS
CS
EmCS
EmCS
EmCS
EmCS
VD
VD
VD

7.18
7.26
7.27
NA
NA
7.27
6.62
NA
7.18
7.12
NA
NA
NA

0-5
3-8
8-9
3-5
4-6
2-6
8-9
7-8
8-9
8-9
9-10
8-9
6-8

Bag & mask
Bag & mask
Bag & mask
O2 only
Bag & mask
Intubation
Intubation
Intubation
O2 only
-

FHRP, fetal heart rate pattern; CS, cesarean section; UAB, umbilical arterial blood; AS, Apgar score; IUGR, intrauterine growth restriction; VD, spontaneous vaginal delivery; APL, antiphospholipid; MCA, middle cerebral artery; NA, not available; EmCS, emergency cesarean section; MAS, meconium
aspiration syndrome.

BSID-2, Bayley Scales of Infant Development-2

891

neonates had borderzone infarctions between the anterior and
middle cerebral artery. In 10 neonates who had infarctions in
the territory of MCA, 2 neonates had the involvement of main
branches, 5 of lenticulostriate branches, and 3 of cortical branches. Of 5 neonates with lenticulostriate branch infarctions,
3 were preterm neonates. Two neonates with the involvement
of lenticulostriate branches showed infarctions in posterior
limb of internal capsule. Involvement of cortical branches was
present in 3 full term neonates and borderzone infarction in 3
preterm neonates (Table 3).
Electroencephalography

EEGs were recorded in 11 neonates. In 6 of the 7 term neonates, EEG was completed between days 2 and 4 of life. The
other underwent EEG on day 16 after being weaned off from
a high-frequency oscillatory ventilator. In the 6 preterm neonates, EEG was performed between 37 and 39 postmenstrual

weeks after the infarction had been confirmed by brain MRI.
Of these 11 neonates, 2 had a completely normal EEG, 7 had
an abnormal background with epileptic discharges (3 on the
right side, 2 on the left side and 2 bilateral). Two neonates had
an abnormal background on the right or left side without
epileptic discharges. Details of individual EEG findings are
shown in Table 4.
Neurodevelopmental outcomes

Neurodevelopmental outcomes were assessed at 14 months
to 6 yr old. No infants experienced seizures after the neonatal period. Nine infants achieved a normal neurodevelopmental outcome. Four infants had an abnormal neurologic outcome. One infant had spasticity of left leg at the age of 18
months. Two infants had definite hemiplegia in the right side,
and 1 infant in the left side. These 4 infants with abnormal
neurologic outcome showed a developmental delay in BSID-2.

Table 3. Magnetic resonance imaging findings of patients with perinatal stroke
Patients

Age at brain MRI

1
2
3
4
5
6
7
8
9 Fig. 1
10
11
12
13Fig. 2

PMA 35 week
PMA 48 week
PMA 35 week
PMA 40 week
Day 4
Day 9
Day 4
Day 2
Day 4
Day 16
Day 3
Day 3
Day 2

Infarction locus
Lenticulostriate branch
Lenticulostriate branch
Borderzone
Lenticulostriate branch
Borderzone
Borderzone
Cortical branch
Lenticulostriate branch
Main branch (Left MCA)
Cortical branch
Main branch (Right MCA)
Cortical branch
Lenticulostriate branch

Cortex involvement

Basal ganglia/Thalamus/PLIC involvement

Left F, T
Left T
Left F, P
Bilateral P, T, Left F
Left F, P, T, O
Right P
Right F, P, T, O
Left F, T
-

Both basal ganglia
Left basal ganglia, PLIC
Right basal ganglia
Left basal ganglia
Left basal ganglia, thalamus, internal capsule
Right basal ganglia, thalamus, internal capsule
Right thalamus, PLIC

PLIC, posterior limb of internal capsule; PMA, postmenstrual age; F, frontal; T, temporal P, parietal; O, occipital; MCA, middle cerebral artery.

Table 4. Electroencephalography findings and neurodevelopmental outcomes of patients with perinatal stroke
Patients

Age at EEG

Background activity

Epileptic discharges

1
2

PMA 37 week
PMA 39 week

Normal
Bilateral
suppressed BA

None
Bilateral spike/
sharp wave

3
4
5
6
7
8
9
10
11
12
13

NA
NA
Day 6
Day 10
Day 4
Day 3
Day 3
Day 17
Day 4
Day 3
Day 2

Right suppressed BA
Left suppressed BA
Bilateral suppressed BA
Normal
Left suppressed BA
Right suppressed BA
Right suppressed BA
Left suppressed BA
Right suppressed BA

Right spike/sharp wave
None
Bilateral spike/sharp wave
None
Left spike/sharp wave
None
Right spike/sharp wave
Left spike/sharp wave
Right spike/sharp wave

BSID-2 at 12 month Neurodevelopmental outcome
Normal
MDI<70
PDI<70
Normal
Normal
Normal
Normal
Normal
Normal
PDI<70
Normal
PDI<70
Normal
PDI<70

Normal at CA 16 month
Right hemiplegia
at CA 22 month
Normal at CA 26 month
Normal at CA 14 month
Normal at 4 yr
Normal at 35 month
Normal at 18 month
Normal at 4 yr
Right hemiplegia at 3 yr
Normal at 14 month
Left hemiplegia at 18 month
Normal at 6 yr
Left leg spasticity at 18 month

BSID-2, Bayley Scales of Infant Development-2; PMA, postmenstrual age; CA, corrected age; BA, background activity; MDI, mental developmental
index; PDI, psychomotor developmental index; NA, not available.

892

H.J. Lee, B.C. Lim, H. Hwang, et al.

The present study is the first systematic study that shows
clinical presentations and neurodevelopmental outcomes of
perinatal stroke in Korea. Perinatal stroke occurs rarely and
are unnoticed clinically resulting in delay in its diagnosis (810). It is not easy to identify perinatal stroke unless neonates
present with clinical seizure. Perinatal stroke was presented
by seizure, apnea or respiratory distress requiring ventilatory
support in term neonates, whereas preterm neonates were
mostly asymptomatic in the present study. There is little literature available about perinatal stroke that is not associated
with an intraventricular hemorrhage in the preterm infant.
Benders et al. (11) found that lenticulostriate infarction appeared to be especially common in the preterm population,
whereas cortical infarction were uncommon in their cohort.
In the present study, no preterm neonate was involved with

main branch or cortical branch infarction. All preterm neonates had lenticulostriate branch or borderzone infarction,
and their neurodevelopmental outcomes were all favorable.
The 4 full-term neonates who had the involvement of main
branches or posterior limb of internal capsule resulted in abnormal neurodevelopmental outcome.
Brain MRI provides more details about distinct localization,
extension of lesion and noninvasive evaluation of vascular
integrity by magnetic resonance angiography. It is undoubtedly more sensitive method for predicting long term neurodevelopmental outcome than Apgar score or neonatal encephalopathy severity staging (2, 7, 11). Furthermore, MRI with
diffusion weight image and apparent diffusion coefficient
(ADC) measurements was very helpful for confirming tentative diagnosis in the first few days of life in our case series (Figs.
1, 2). Diffusion-weighted imaging can show early changes
in the reduction of diffusivity at the cellular level that are undetectable by any other imaging modality in the hyperacute
stage of infarction (13-16). Diffusion weight image has been
found to increase the sensitivity of detecting neonatal strokes
compared with conventional MRI.
The concomitant involvement of the cortex, basal ganglia,
thalamus and internal capsule by infarction in main cerebral
branch has been associated with poor neurodevelopmental
outcome (17). In the present study, 4 infants who had involvement of main branch or posterior limb of internal capsule,
had hemiplegia or spasticity and concurrent EEG abnormalities. Mercuri et al. (18) found that an infarction involving
the internal capsule predicts the development of hemiplegia,
whereas predictions based on involvements of other regions
are less reliable. They suggested that internal capsule plays an

A

B

Details of neurodevelopmental outcome are shown in Table 4.
Seizures were more common in infants with abnormal outcome. All 3 infants presenting with perinatal distress resulted in normal outcome. One infant with homozygous C677T
polymorphism for MTHFR had abnormal outcome. All 3
preterm infants with borderzone infarction had normal outcome. The 4 full term neonates who had the involvement of
main branches or posterior limb of internal capsule resulted
in abnormal neurodevelopmental outcome. Abnormal background activity (either unilateral or bilateral) in the EEG was
found in 9 neonates and 4 of these had a poor neurodevelopmental outcome.

DISCUSSION

Fig. 1. Brain MRI findings of patient 9. (A) Axial diffusion-weighted image showing hyperintensity in the territory of left middle cerebral
artery. (B) MR angiography demonstrates loss of flow distal to the left middle cerebral artery bifurcation.

BSID-2, Bayley Scales of Infant Development-2

Fig. 2. Brain MRI finding of patient 13. Axial diffusion-weighted
image showing hyperintensity in right thalamus and posterior
limb of internal capsule.

important role in the prognosis of motor outcome in patients
with perinatal lesions. De Vries et al. (19) suggested asymmetrical myelination of the posterior limb of the internal
capsule on brain MRI is an early predictor of hemiplegia. The
absence of myelination in the posterior limb of the internal
capsule, as a marker of Wallerian degeneration of corticospinal
tracts, appears to be correlated with abnormal EEG findings
and motor impairments in the extremities. Ten (77%) infants
had infarctions in the distribution of the MCA, and left side
was more common accounting for two thirds. These findings
are consistent with those of a previous study which found that
neonatal cerebral infarction occurs more commonly in the left
cerebral hemisphere and in the distribution of the MCA (20).
This predominance of left-sided lesions may be caused by vascular asymmetry due to patent ductus arteriosus (21).
Neonatal seizure is a common clinical finding that triggers
recognition of perinatal stroke in term infants. In the present
study, 2 of the 3 neonates who experienced seizure had an abnormal neurodevelopmental outcome. Other reports have also
suggested that concurrent seizure during the neonatal period
is associated with an unfavorable neurodevelopmental outcome in patients with perinatal stroke (22).
Inherited coagulation abnormalities may lead to adverse
maternal and fetal events through thrombosis at the placenta
(23-25). Thrombosis on the maternal side may lead to preeclampsia and intrauterine growth restriction, whereas on the
fetal side it is a possible source of emboli that can bypass the
hepatic and pulmonary circulations and reach the fetal brain.
Recent evidence suggests that thrombophilias, including heterozygous factor V Leiden, prothrombin gene mutation, and

893

homozygous C677T polymorphism for MTHFR may also
play a causative role in perinatal stroke (26, 27). Phospholipids are required for the activations of protein C and the
coagulation pathway. Anti-phospholipid antibodies, including lupus anticoagulant and anticardiolipin antibody, interfere with normal coagulation and may be a risk factor for perinatal stroke (28). There were no inherited coagulation abnormalities found in our patients except for a single case with
homozygous C677T polymorphism for MTHFR.
EEG is a useful and sensitive tool for evaluating the degree
of neurological damage in perinatal stroke (29). Mercuri et al.
(17) suggested that early neonatal EEG was a prognostic indicator of motor outcome. In their study, the abnormal background was associated with abnormal motor outcome whereas other EEG abnormalities such as epileptic discharges in the
presence of a normal background were not associated with abnormal outcome. In the present study, abnormal background
activity (either unilateral or bilateral) was found in 9 neonates
and 4 of these had a poor neurodevelopmental outcome. The
EEG data was not very informative in the preterm neonates
possibly as they were obtained rather late and electrical seizure
activity is not absolutely considered as abnormal in preterm
neonates.
Several limitations are noted in our current study, mainly
due to its limited subject size and retrospective nature. Regardless of these limitations, however, it is believed that this case
series may be able to add some valuable information to rare
perinatal stroke that have not been well described in Korea.
Finally this study may assist physicians predicting long-term
prognosis and planning rehabilitative care for the neonates
with perinatal stroke.

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