+ MODEL

Pediatrics and Neonatology (2016) xx, 1e8

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ORIGINAL ARTICLE

Clinical Manifestations, Outcomes, and

Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and
Hemorrhagic Stroke Based on 10-year
Experience in A Single Institute
Chien-Chung Lee a, Jainn-Jim Lin b, Kuang-Lin Lin b,
Wai-Ho Lim a, Kai-Hsiang Hsu a, Jen-Fu Hsu a,
Ren-Huei Fu a, Ming-Chou Chiang a, Shih-Ming Chu a,
Reyin Lien a,*

a
Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, School of
Medicine, Chang Gung University, No. 5, Fu-Shing Street, Kwei-Shan, Taoyuan, Taiwan, ROC
b
Division of Pediatric Neurology, Department of Pediatrics, Chang Gung Memorial Hospital, School of
Medicine, Chang Gung University, No. 5, Fu-Shing Street, Kwei-Shan, Taoyuan, Taiwan, ROC

Received Mar 29, 2016; received in revised form Jun 2, 2016; accepted Jul 8, 2016
Available online - - -

Key Words Background: Perinatal stroke is a common cause of established neurological sequelae.
hemorrhagic stroke; Although several risk factors have been identified, many questions regarding causes and clin-
ischemic stroke; ical outcomes remain unanswered. This study investigated the clinical manifestations and out-
neonatal stroke; comes of perinatal stroke and identified its etiologies in Taiwan.
perinatal stroke Methods: We searched the reports of head magnetic resonance imaging and computed tomog-
raphy performed between January 2003 and December 2012. The medical records of enrolled
infants with perinatal stroke were also reviewed.
Results: Thirty infants with perinatal stroke were identified; 10 infants had perinatal arterial
ischemic stroke (PAIS) and 20 had perinatal hemorrhagic stroke (PHS). Neonatal seizure was
the most common manifestation and presented in 40% of infants with PAIS and 50% of infants
with PHS. All survivors with PAIS and 77% of the surviving infants with PHS developed neurolog-
ical sequelae. Acute seizure manifestation was associated with poststroke epilepsy in infants
with PHS but not in infants with PAIS (86% vs. 0%, p Z 0.005). PAIS was mostly caused by

* Corresponding author. Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, School of Medicine, Chang
Gung University, No. 5, Fu-Shing Street, Kwei-Shan, Taoyuan 33305, Taiwan, ROC.
E-mail address: reyinl@adm.cgmh.org.tw (R. Lien).

http://dx.doi.org/10.1016/j.pedneo.2016.07.005
1875-9572/Copyright 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
 + MODEL
2 C.-C. Lee et al

dysfunctional hemostasis (20%) and embolism (20%), whereas PHS was mostly attributable to
birth asphyxia (30%).
Conclusion: Perinatal stroke is associated with high mortality and morbidity rates in infants.
Clinically, it can be difficult to distinguish PAIS and PHS. One should keep a high level of sus-
picion, especially for PHS, if infants develop unexplained seizure, cyanosis, conscious change,
anemia, and/or thrombocytopenia. A systematic diagnostic approach is helpful in identifying
the etiologies of perinatal stroke.
Copyright 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction 2. Methods

Perinatal stroke is identified as a major cause of long- 2.1. Participant selection

standing neurological sequelae including motor, cognitive,
and behavioral problems as well as epilepsy.1 Perinatal
stroke is estimated to affect one in 1600e5000 births.2 This
number is much higher than that of pediatric stroke, which
affects 1.3e13.0 per 100,000 children.3 Similar to pediatric
and adult stroke, perinatal stroke is classified into two
major types: perinatal ischemic stroke (PIS) and perinatal
hemorrhagic stroke (PHS).
PIS has been recently defined as a group of heteroge-
neous conditions in which there is focal disruption of cere-
bral blood flow secondary to arterial or cerebral venous
thrombosis or embolization, between 20 weeks of fetal life
through the 28th postnatal day, confirmed by neuroimaging
or neuropathologic studies.4 The two subtypes of PIS are
perinatal arterial ischemic stroke (PAIS) and cerebral sino-
venous thrombosis (CSVT). Three subcategories classified by
the time of diagnosis are also suggested: (1) fetal ischemic
stroke that is diagnosed prior to birth; (2) neonatal ischemic
stroke that is diagnosed within 28 days of age; and (3) pre-
sumed PIS that is diagnosed after the 28th postnatal day in
those infants in whom an ischemic event is presumed to
have occurred (but is not confirmed) between the 20th week
of fetal life and the 28th postnatal day.4 PHS is defined as an
intracranial hemorrhagic lesion in the intraventricular,
intraparenchymal, or subarachnoid compartment.5 Hemor-
rhagic stroke has two forms: primary hemorrhage resulting
from vascular anomalies or bleeding diatheses, and sec-
ondary conversion resulting from arterial or venous ischemic
infarction. Distinguishing between these two forms of
hemorrhagic stroke can be difficult, particularly if brain
imaging is delayed after the onset of stroke symptoms.6,7
Perinatal stroke remains poorly understood, and many
questions regarding its causes and clinical consequences are
unanswered. Although several risk factors including
maternal, neonatal, and placental conditions have been
proposed, most of them are identified with a focus on spe-
cific conditions and do not necessarily reflect a causal
relation. So far, there have been a limited number of studies
using a systematic approach to explore the etiologies of
perinatal stroke. Furthermore, almost all available knowl-
edge of perinatal stroke is based on foreign literature, and
local reports on this topic remain scant. Therefore, we
conducted this study to describe the etiologies, clinical
presentations, and outcomes of perinatal stroke in Taiwan,
with a focus on the comparison between PIS and PHS.
We searched the electronic medical database of Chang Gung
Memorial Hospital in Linkou, Taiwan, and retrieved all re-
ports of head magnetic resonance imaging and computer
tomography gathered between January 2003 and December
2012. We retrieved all the neuroimaging reports of patients
younger than 1 year that contained any of the following
keywords: stroke, infarct, thrombo, ischemia,
middle cerebral artery (MCA), posterior cerebral artery,
anterior cerebral artery (ACA), vascular insult,
vascular injury, vascular event, encephalomalacia,
hemorrhage, and hematoma. For this study, infants
with any of the following conditions were excluded: (1)
hemorrhage caused by head injury, such as epidural hem-
orrhage, subdural hemorrhage, skull fracture, or subgaleal
hemorrhage; (2) isolated intraventricular hemorrhage; (3)
bilateral periventricular white matter injury; (4) global
hypoxiceischemic injury; (5) a new (acute symptomatic)
event after the 28th postnatal day; and (6) unclear imaging.
Neuroimages of all infants were reviewed by an experienced
pediatric neurologist specifically to determine the stroke
characteristics, affected vessels, and location of the lesions.
2.2. Data abstraction
Medical records were reviewed. Clinical and demographic
data included age of diagnosis, presenting signs and symp-
toms, gestational age at birth, sex, mode of delivery, birth
weight, and Apgar scores. Risk factors were determined for
the identification of possible etiologies, which included
maternal factors (pregnancy-induced or pre-existing dia-
betes mellitus, hypertension, chorioamnionitis, placental
abruption, and autoimmune diseases); perinatal factors
[fetomaternal hemorrhage, twinetwin transfusion syn-
drome (TTTS), instrument-assisted delivery, and perinatal
asphyxia]; and neonatal factors (polycythemia, hematocrit
> 65%, prothrombotic risk factors, culture-proven sepsis or
meningitis, and complex congenital heart disease). Neuro-
developmental outcomes on surviving infants were fol-
lowed for at least 12 months and were determined on
the basis of medical records from clinic visits. Neuro-
developmental disorders included motor deficits, speech
delay, poststroke epilepsy, cognitive dysfunction, vision
impairment, and hearing impairment. To identify the

Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
 + MODEL
Perinatal stroke 3

possible etiologies of perinatal stroke, the causal relation-
ship between risk factors and perinatal stroke were
reviewed according to the types of perinatal stroke. Using a
systematic diagnostic approach proposed by Govaert
et al,8,9 the causes were classified as infection; cranial
trauma; embolism; vasculopathy; prothrombotic condition;
others, such as extracorporeal membrane oxygenation,
TTTS, dehydration, polycythemia, and severe blood loss;
and unclassifiable. This study was approved by the Institu-
tional Review Board of Chang Gung Memorial Hospital and
Chang Gung University.
2.3. Statistical analysis
Statistical analysis was performed using SPSS statistical
software, version 22.0 (SPSS Inc., Chicago, IL, USA). The
continuous variables are nonnormal distribution and
expressed as median and interquartile range (IQR;
25the75th percentiles). The categorical variables are
expressed as number and percentage. The ManneWhitney
U test was used for continuous variables, and the Chi-
square or Fishers exact tests were used for categorical
variables for assessing outcome predictors. The binary lo-
gistic regression was used to evaluate correlations between
clinical characteristics and neurological outcome in sur-
viving infants. A p value < 0.05 was considered statistically
significant.
3. Results
3.1. Characteristics of stroke
Of the 867 infants who had neuroimaging study prior to 1
year of age, 284 met the inclusion criteria. However, 254 of
them were excluded according to the exclusion criteria of
this study. Ultimately, 30 infants were enrolled (Figure 1);
10 (33%) of them had PAIS and 20 (67%) had PHS. No patient
was diagnosed as CSVT. The clinical manifestations and
stroke characteristics of the infants are listed in Table 1.
PAIS occurred mostly on the left MCA territory (70%), and
PHS also occurred predominantly on the left side (60%).
Nearly all infants with perinatal stroke were diagnosed in
the neonatal period, except for two infants (Cases 11 and
25) with PHS who were diagnosed in the fetal period from
prenatal screening ultrasound. There were three infants
(Cases 1, 6, and 7) whose PAIS was diagnosed at an age older
than 28 days after birth. One (Case 1) presented with hy-
pertonicity, and the other two asymptomatic infants (Cases
6 and 7) were diagnosed incidentally by neonatal head ul-
trasound study. All three infants had encephalomalacia on
head ultrasound examination, and old infarctions were
confirmed on magnetic resonance imaging. These three in-
fants had no acute symptoms of stroke prior to the brain
imaging study; therefore, they met the diagnostic criteria of
presumed PIS4,5 and were enrolled in our study.
3.2. Clinical manifestations
For the comparison of patients with PAIS and PHS, the de-
mographic data and clinical manifestations are summarized
in Table 2. The patients were predominantly male. Com-
mon characteristics of these stroke patients include the
following: they were mostly born at term or late preterm
gestation, mostly by cesarean section, and seizure was the
most common presenting feature, although 40% of the pa-
tients were asymptomatic. Forty percent of infants with
PAIS and 50% with PHS had seizure at presentation.
Following seizure, cyanosis (30% vs. 35% in PAIS and PHS
patients, respectively) and change in consciousness (10% vs.
20%) were also the leading presenting features. Although
there were no significant differences in the clinical char-
acteristics between PAIS and PHS, in our case series no PAIS
was diagnosed prenatally, and none of the PHS patients was
diagnosed beyond the neonatal period.
3.3. Outcomes and etiologies
Neurological outcomes in the surviving infants are summa-
rized in Table 3. One (10%) infant with PAIS and four (20%)
infants with PHS died during hospital stay. Among these five
infants, the infant with PAIS had no risk factors, one infant
with PHS had TTTS, and the other three infants with PHS
had perinatal asphyxia. One (10%) infant with PAIS and
three (15%) infants with PHS were lost to follow-up within 1
year after discharge. The remaining eight surviving infants
with PAIS were followed for a median of 51 months (IQR,
21
19 months), and 13 surviving infants with PHS were
followed for a median of 60 months (IQR, 38
75 months).
All surviving infants with PAIS and 77% with PHS devel-
oped neurological sequelae. Although motor dysfunction
was the most common neurological sequela both for PAIS
(75%) and PHS (46%), more infants with PAIS were diagnosed
as having cerebral palsy (63%) as compared to infants with
PHS (15%, p Z 0.06).
Among 13 surviving infants with PHS, six out of the seven
infants who had acute seizure presentation developed
poststroke epilepsy, and none of those infants (6) who had
no acute seizure at initial presentation developed post-
stroke epilepsy (86% vs. 0%, p Z 0.005). By contrast, among
the eight infants with PAIS, none with acute seizure at
presentation developed poststroke epilepsy. Three of the
six infants with PAIS who had no seizure at initial presen-
tation developed poststroke epilepsy (0% vs. 50%,
p Z 0.464). In order to detect predictors of poor outcome,
we used binary logistic regression to evaluate the correla-
tions between clinical characteristics and neurological
disorders in both groups (PAIS and PHS). However, no sig-
nificant correlation was found.
Etiological factors were identified in 17 of the 30 infants
with perinatal stroke, as shown in Table 1. Of the 10 infants
with PAIS, two had congenital heart diseases (total anom-
alous pulmonary venous return, and coarctation of aorta,
one of each); both infants were diagnosed with stroke after
cardiac surgery. Moreover, two infants had low levels of
protein C (26.4% and 55%, respectively), low levels of
antithrombin III (23.7% and 40.1%, respectively), and
normal levels of protein S (67% and 98%, respectively). No
risk factors were found in the remaining six infants. Among
the 20 infants with PHS, two had vascular anomalies, one
had TTTS, one had neonatal lupus and thrombocytopenia,
one had neonatal leukemia and thrombocytosis, two had

Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
 + MODEL
4 C.-C. Lee et al

Figure 1 Flowchart of infant selection.

culture-proven sepsis and meningitis caused by Escherichia
coli (n Z 1) and group B streptococcus (n Z 1), respec-
tively, and six had perinatal asphyxia. Among the six infants
with perinatal asphyxia, one was delivered using instru-
mental traction, one had hydrops fetalis, and the mothers
of the remaining two had preeclampsia and placental
abruption. No risk factors were found in the other seven
infants.
4. Discussion
This is the first cohort study of perinatal stroke in Taiwan.
In this 10-year observational study, 30 infants with peri-
natal stroke were identified after a rigorous search. There
were 10 infants with PAIS and 20 infants with PHS. In this
cohort of patients, there is a male predominance, and most
patients were term or late preterm. Male predominance
had been described by some researchers at a ratio of
1.3e1.6:1 (male/female).10e14 However, this is not gener-
ally agreed upon.15e17 In this study, 40% of infants with
perinatal stroke were asymptomatic. This could be ascribed
to the obscure clinical manifestations in newborn infants.
For those symptomatic infants, abnormal neurological signs
and hematological derangement are the common present-
ing features. However, there was no difference in the
clinical manifestations between PAIS and PHS. Therefore,
clinicians are unlikely to be able to differentiate these two
types of perinatal stroke by clinical features.
Seizure was the most common manifestation and pre-
sented in nearly half of the infants in both groups. Our
observation is consistent with those of previous studies

Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
 + MODEL
Perinatal stroke 5

Table 1 Detailed description of the 30 infants with perinatal stroke.

Patient Stroke GA Days Seizure EEG Other symptoms Location Risk factors
(wk)
1 PAIS 37 119 No Not done None Lt MCA TAPVR
2 PAIS 26 24 No Not done Cyanosis Lt MCA Protein C (26.4%),
antithrombin III (23.7%),
protein S (67%)
3 PAIS 33 2 No Not done None Rt MCA Protein C (55%),
antithrombin III (40.1%),
protein S (98%)
4 PAIS 40 2 No Normal None Lt MCA
5 PAIS 29 7 Subtle Focal, Lt P None Lt MCA
6 PAIS 38 48 No Diffuse cortical None Lt ACA Coarctation of aorta,
dysfunction arrhythmia
7 PAIS 26 100 No Not done None Rt MCA
8 PAIS 38 11 Subtle Focal, Lt P-O Cyanosis Lt MCA
9 PAIS 38 3 General Multifocal, Bil. F Cyanosis; Conscious Lt MCA
change
10 PAIS 40 13 Focal Focal, Lt T-P None Lt MCA
11 PHS 40
6 Subtle Focal, Bil. T Altered limb tone Rt P-O, IV, SA Arteriovenous
malformation
12 PHS 37 8 No Diffuse cortical Conscious change; Lt BG, IV, SA Asphyxia, preeclampsia
dysfunction altered limb tone
13 PHS 39 16 Focal and Multifocal, Bulging fontanelle Lt F Escherichia coli
general Bil. T-P meningitis
14 PHS 38 2 General Focal, Rt T-P None IV, SA
15 PHS 37 3 No Not done Cyanosis Lt T
16 PHS 38 19 General Multifocal, Bil. H Cyanosis Bil. BG, IV
17 PHS 33 3 No Not done None Bil. O Neonatal lupus
18 PHS 29 4 No Not done None Lt T-O, IV Mother SAH and seizure,
Infant TTTS and IUFD
19 PHS 39 3 Focal Multifocal, Rt P None Lt T, IV Arteriovenous
malformation
20 PHS 35 1 No Not done None SA
21 PHS 33 3 No Not done None Lt O, IV Asphyxia, hydrops fetalis
22 PHS 40 2 No Not done None Lt O
23 PHS 37 2 Subtle Multifocal, Bil. P Cyanosis; conscious Lt P-T-O, IV Asphyxia
change
24 PHS 35 1 General Normal Cyanosis Rt T, O, IV Leukemia
25 PHS 37
4 No Not done None Rt BG, IV, SA
26 PHS 37 29 General Diffuse cortical None Rt Th GBS meningitis
dysfunction
27 PHS 41 1 General Diffuse cortical Cyanosis; bulging SA, IV Asphyxia, instrumental
dysfunction fontanelle traction
28 PHS 38 25 No Not done Cyanosis; conscious Lt P Asphyxia, placental
change; altered abruption
limb tone
29 PHS 37 24 General Focal, Lt P-T Cyanosis; conscious Lt P, SA, IV Asphyxia
change; altered
limb tone
30 PHS 33 1 No Not done None Rt P, IV
ACA Z anterior cerebral artery; Bil. Z bilateral; F Z frontal; EEG Z electroencephalogram; GA Z gestational age; GBS Z group B
streptococcus; H Z hemisphere; IUFD Z intrauterine fetal death; IV Z intraventricular; Lt Z left; MCA Z middle cerebral artery;
O Z occipital; P Z parietal; PAIS Z perinatal arterial ischemic stroke; PHS Z perinatal hemorrhagic stroke; Rt Z right; SA Z subar-
achnoid; T Z temporal; TAPVR Z total anomalous pulmonary venous return; Th Z thalamus; TTTS Z twinetwin transfusion syndrome.

citing an incidence of seizure in infants with perinatal seizure. In a prospective study of 174 newborn infants with
stroke of between 34% and 92%.14,16e20 Perinatal stroke, neonatal seizure, the prevalence of stroke was 8% (14 of
following hypoxiceischemic encephalopathy, has also been 174).21 Therefore, perinatal stroke should always be
identified as the second most common cause of neonatal considered in infants experiencing unexplained seizure.

Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
 + MODEL
6 C.-C. Lee et al

hemorrhagic stroke, one or more hemostatic abnormalities

Table 2 Clinical characteristics between infants with PAIS
were found in 16 of 42 (38%) of the cohort, and 13 of them
and PHS.
had thrombocytopenia. Although severe neonatal alloim-
PAIS, N Z 10 PHS, N Z 20 p mune thrombocytopenia may lead to intracranial hemor-
Male 7 (70) 11 (55) 0.69 rhage and death,22 none of our infants with
Preterm 4 (40) 6 (30) 0.44 thrombocytopenia had a platelet count of less than
Gestational age (wk) 38 (31e39) 37 (35e39) 50  103/mL. The cause of thrombocytopenia in our study
Body weight 2295 2953 was more likely to be attributable to consumption by
at birth (g) (1379e3502) (2614e3292) hemorrhage or diffuse intravascular coagulopathy.
Apgar score at 1 min 8 (6e9) 8 (4e9) Even if those patients lost to follow-up were un-
Apgar score at 5 min 9 (8e10) 9 (7e10) counted, one (10%) infant with PAIS and four (20%) infants
Cesarean section 6 (60) 10 (50) 0.71 with PHS died in our study. The overall mortality rate (17%)
Resuscitation* 3 (30) 8 (40) 0.70 was not as low as reported by Lee et al23 or Golomb24
Time of diagnosis 0.03 (< 5% and 10%, respectively) but was similar to that
Fetal 0 2 (10) observed in the large cohort study conducted by Govaert
Neonatal 7 (70) 18 (90) et al5 (13.4%). The morbidity rate is also high in our study.
Beyond 28 d of age 3 (30) 0 In this series of patients, all surviving infants with PAIS and
Asymptomatic infants 5 (50) 7 (35) 0.46 77% of surviving infants with PHS developed at least one
Symptomatic infants type of neurological sequelae. The rate of motor
Seizure 4 (40) 10 (50) 0.71 dysfunction, cerebral palsy, cognition dysfunction, and
Cyanosis 3 (30) 7 (35) 1.00 poststroke epilepsy were similar to that reported previ-
Conscious change 1 (10) 4 (20) 0.64 ously.18,25,26 However, infants in our study had a higher
Altered limb tone 0 4 (20) 0.27 rate of speech delay and lower rate of visual impairment
Fontanel bulging 0 2 (10) 0.54 than previously reported.18,23,24 A high overall rate of
EEG confirmed 4 (40) 7 (35) 1.00 mortality and sequelae might result from different
seizure enrollment criteria, search strategies, and duration of
Abnormal hemogram 1 (10) 8 (40)y 0.20 follow-up. A large stroke size, lesion involving the corti-
Anemia 0 5 (25) 0.14 cospinal tract, basal ganglia or internal capsule, and
Thrombocytopenia 1 (10) 6 (30) 0.372 delayed presentations have been identified as risk factors
of poor motor outcome.23,27e29 However, we were unable
Data are presented as n (%) or median (interquartile).
to isolate the risk factors of poor neurological outcomes in
EEG Z electroencephalogram; PAIS Z perinatal arterial
ischemic stroke; PHS Z perinatal hemorrhagic stroke. our patients. This could very well be ascribed to our small
* Resuscitation includes intubation  chest compression prior patient number.
to diagnosis of stroke. As for poststroke epilepsy, we found that infants with
y
Three infants with PHS had both anemia and PHS who presented with seizure were associated with
thrombocytopenia. poststroke epilepsy (p Z 0.005), and this association was
not observed in infants with PAIS (p Z 0.464). Both Fitz-
gerald et al30 and Hsu et al,31 who reported on perinatal
Table 3 Complications in survivors. stroke, found that seizures at presentation and infantile
spasms were associated with poststroke epilepsy. However,
Surviving infants PAIS, N Z 8 PHS, N Z 13 p
this correlation was not supported by other researchers.32
Sequelae (any of 8 (100) 10 (77) 0.26 No previous investigators explored the association of
the below) seizure at the presentation of perinatal stroke and later
Motor dysfunction* 6 (75) 6 (46) 0.06 development of poststroke epilepsy based on different
Cerebral palsy 5 (63) 2 (15) 0.37 types of stroke. We have a novel observation, and we
Speech delay 4 (50) 6 (46) 1.00 speculate that different mechanisms causing PHS and PAIS
Epilepsy 3 (38) 6(46) 1.00 also contribute differently to neuronal injuries, thereby
Cognitive dysfunction 3 (38) 6 (46) 1.00 leading to a different expression in seizure activities.
Visual impairment 1 (13) 2 (15) 1.00 However, it could also be a bias from such a small number
Hearing impairment 0 2 (15) 0.51 of patients in our study.
Data are presented as n (%). A small number of studies have tried to explore the
PAIS Z perinatal arterial ischemic stroke; PHS Z perinatal etiologies of perinatal stroke because of the difficulty in
hemorrhagic stroke. establishing the causality. Using a diagnostic flowchart with
* Includes cerebral palsy. systematic approach for perinatal stroke, modified from
studies by Govaert et al,8,9 we determined the etiologies of
perinatal stroke in 17 of 30 infants. However, because
Other common manifestations of perinatal stroke, regard- neonatal protein C, protein S, and antithrombin levels are
less of type, are apnea and cyanosis, conscious change, markedly lower than those of the adult reference level, and
altered limb tonicity, and bulging fontanelle. In our study, the mean plasma activities of protein C and protein S in
derangements in hemogram (anemia or thrombocytopenia) healthy term infants are approximately 35%,33 it would be
were observed in 40% of infants with PHS. In Bruno et als20 doubtful to attribute the etiology of two infants in our se-
report on 42 term and late preterm neonates with ries with PAIS to protein C deficiency without genetic

Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
 + MODEL
Perinatal stroke
testing. In our literature search, there was one case report
of an infant who had mild protein C deficiency and devel-
oped perinatal stroke. Ichiyama et al,34 reported on one
term infant who had fetal hydrocephalus secondary to ce-
rebral thromboembolism and dissociated levels of protein C
(21%) and protein S (42%). Protein C deficiency caused by
heterozygous PROC mutation was confirmed as the cause of
stroke.34 Because the two infants with PAIS had dissociated
levels between protein C and protein S activity, and they
had no other identifiable causes or risk factors of stroke, we
cautiously attributed their stroke to protein C deficiency.
Only two infants received screening for prothrombotic
factors in our study.
In our study, a prothrombotic condition, including pro-
tein C deficiency (n Z 2), maternal lupus (n Z 1), neonatal
leukemia (n Z 1), and birth asphyxia (n Z 6), was the most
common cause of perinatal stroke. Other etiologies
included culture-proven sepsis and meningitis (n Z 2),
embolism after cardiac surgery (n Z 2), vascular malfor-
mation (n Z 2), and TTTS (n Z 1). In a large cohort of 134
infants with perinatal ischemic or hemorrhagic stroke in
The Netherlands, Govaert et al5,8 reported embolism as the
most common cause of perinatal stroke. Our study, which
used the same diagnostic approach, showed that in Taiwan
PAIS was mostly caused by dysfunctional hemostasis (20%)
and embolism (20%), whereas PHS was mostly caused by
birth asphyxia (30%). This variation suggested that the eti-
ology of perinatal stroke could differ geographically or in
populations of different ethnic origin, as documented in
childhood stroke.35
4.1. Limitations
We investigated perinatal stroke including both PAIS and
PHS and used a systematic approach and causal relation-
ship evidence to explore possible etiologies. However, this
study has several limitations. First, this is a retrospective
observational study, and not all infants underwent an
extensive prothrombotic screening, nor was cerebral
angiography performed in all infants. Second, our search
strategy might have missed cases of perinatal stroke
caused by partial or complete occlusion of small vessels in
infants with no or subtle symptoms.5,36 Third, some infants
with perinatal stroke had subtle symptoms and were not
diagnosed until they developed neurological sequelae.
These infants may not have neuroimaging study within the
1st year of life, and therefore would be missed by our
search strategy. Fourth, no infant was diagnosed with
CSVT stroke.
5. Conclusion
Perinatal stroke is a serious condition with high mortality
and morbidity, yet a subtle or obscure clinical manifesta-
tion makes the diagnosis difficult. Clinicians caring for in-
fants should always keep a high level of suspicion for this
condition, especially when infants have unexplained
seizure, cyanosis, conscious change, anemia, and/or
thrombocytopenia. It is difficult to distinguish PAIS and PHS
based on clinical manifestations. On patients with perinatal
stroke confirmed by neuroimaging, extensive screening for
Please cite this article in press as: Lee C-C, et al., Clinical Manifestations, Outcomes, and Etiologies of Perinatal Stroke in Taiwan:
Comparisons between Ischemic, and Hemorrhagic Stroke Based on 10-year Experience in A Single Institute, Pediatrics and Neonatology
(2016), http://dx.doi.org/10.1016/j.pedneo.2016.07.005
7
risk factors and a systematic diagnostic approach are
helpful in identifying possible etiologies.
Conflicts of interest
The authors declare there are no conflicts of interest.
Acknowledgments
We are grateful to our colleagues in the Division of
Neonatology and the Division of Neurology, Department of
Pediatrics, for their help with this study.
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