Professional Documents
Culture Documents
SAH
SAH
ScienceDirect
ORIGINAL ARTICLE
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
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- in Table 2. The patients were predominantly male. Com-
ship between risk factors and perinatal stroke were mon characteristics of these stroke patients include the
reviewed according to the types of perinatal stroke. Using a following: they were mostly born at term or late preterm
systematic diagnostic approach proposed by Govaert gestation, mostly by cesarean section, and seizure was the
et al,8,9 the causes were classified as infection; cranial most common presenting feature, although 40% of the pa-
trauma; embolism; vasculopathy; prothrombotic condition; tients were asymptomatic. Forty percent of infants with
others, such as extracorporeal membrane oxygenation, PAIS and 50% with PHS had seizure at presentation.
TTTS, dehydration, polycythemia, and severe blood loss; Following seizure, cyanosis (30% vs. 35% in PAIS and PHS
and unclassifiable. This study was approved by the Institu- patients, respectively) and change in consciousness (10% vs.
tional Review Board of Chang Gung Memorial Hospital and 20%) were also the leading presenting features. Although
Chang Gung University. there were no significant differences in the clinical char-
acteristics between PAIS and PHS, in our case series no PAIS
2.3. Statistical analysis was diagnosed prenatally, and none of the PHS patients was
diagnosed beyond the neonatal period.
Statistical analysis was performed using SPSS statistical
software, version 22.0 (SPSS Inc., Chicago, IL, USA). The
3.3. Outcomes and etiologies
continuous variables are nonnormal distribution and
expressed as median and interquartile range (IQR;
Neurological outcomes in the surviving infants are summa-
25the75th percentiles). The categorical variables are
rized in Table 3. One (10%) infant with PAIS and four (20%)
expressed as number and percentage. The ManneWhitney
infants with PHS died during hospital stay. Among these five
U test was used for continuous variables, and the Chi-
infants, the infant with PAIS had no risk factors, one infant
square or Fishers exact tests were used for categorical
with PHS had TTTS, and the other three infants with PHS
variables for assessing outcome predictors. The binary lo-
had perinatal asphyxia. One (10%) infant with PAIS and
gistic regression was used to evaluate correlations between
three (15%) infants with PHS were lost to follow-up within 1
clinical characteristics and neurological outcome in sur-
year after discharge. The remaining eight surviving infants
viving infants. A p value < 0.05 was considered statistically
with PAIS were followed for a median of 51 months (IQR,
significant.
2119 months), and 13 surviving infants with PHS were
followed for a median of 60 months (IQR, 3875 months).
3. Results 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
3.1. Characteristics of stroke
(75%) and PHS (46%), more infants with PAIS were diagnosed
as having cerebral palsy (63%) as compared to infants with
Of the 867 infants who had neuroimaging study prior to 1
PHS (15%, p Z 0.06).
year of age, 284 met the inclusion criteria. However, 254 of
Among 13 surviving infants with PHS, six out of the seven
them were excluded according to the exclusion criteria of
infants who had acute seizure presentation developed
this study. Ultimately, 30 infants were enrolled (Figure 1);
poststroke epilepsy, and none of those infants (6) who had
10 (33%) of them had PAIS and 20 (67%) had PHS. No patient
no acute seizure at initial presentation developed post-
was diagnosed as CSVT. The clinical manifestations and
stroke epilepsy (86% vs. 0%, p Z 0.005). By contrast, among
stroke characteristics of the infants are listed in Table 1.
the eight infants with PAIS, none with acute seizure at
PAIS occurred mostly on the left MCA territory (70%), and
presentation developed poststroke epilepsy. Three of the
PHS also occurred predominantly on the left side (60%).
six infants with PAIS who had no seizure at initial presen-
Nearly all infants with perinatal stroke were diagnosed in
tation developed poststroke epilepsy (0% vs. 50%,
the neonatal period, except for two infants (Cases 11 and
p Z 0.464). In order to detect predictors of poor outcome,
25) with PHS who were diagnosed in the fetal period from
we used binary logistic regression to evaluate the correla-
prenatal screening ultrasound. There were three infants
tions between clinical characteristics and neurological
(Cases 1, 6, and 7) whose PAIS was diagnosed at an age older
disorders in both groups (PAIS and PHS). However, no sig-
than 28 days after birth. One (Case 1) presented with hy-
nificant correlation was found.
pertonicity, and the other two asymptomatic infants (Cases
Etiological factors were identified in 17 of the 30 infants
6 and 7) were diagnosed incidentally by neonatal head ul-
with perinatal stroke, as shown in Table 1. Of the 10 infants
trasound study. All three infants had encephalomalacia on
with PAIS, two had congenital heart diseases (total anom-
head ultrasound examination, and old infarctions were
alous pulmonary venous return, and coarctation of aorta,
confirmed on magnetic resonance imaging. These three in-
one of each); both infants were diagnosed with stroke after
fants had no acute symptoms of stroke prior to the brain
cardiac surgery. Moreover, two infants had low levels of
imaging study; therefore, they met the diagnostic criteria of
protein C (26.4% and 55%, respectively), low levels of
presumed PIS4,5 and were enrolled in our study.
antithrombin III (23.7% and 40.1%, respectively), and
normal levels of protein S (67% and 98%, respectively). No
3.2. Clinical manifestations risk factors were found in the remaining six infants. Among
the 20 infants with PHS, two had vascular anomalies, one
For the comparison of patients with PAIS and PHS, the de- had TTTS, one had neonatal lupus and thrombocytopenia,
mographic data and clinical manifestations are summarized 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
culture-proven sepsis and meningitis caused by Escherichia cohort of patients, there is a male predominance, and most
coli (n Z 1) and group B streptococcus (n Z 1), respec- patients were term or late preterm. Male predominance
tively, and six had perinatal asphyxia. Among the six infants had been described by some researchers at a ratio of
with perinatal asphyxia, one was delivered using instru- 1.3e1.6:1 (male/female).10e14 However, this is not gener-
mental traction, one had hydrops fetalis, and the mothers ally agreed upon.15e17 In this study, 40% of infants with
of the remaining two had preeclampsia and placental perinatal stroke were asymptomatic. This could be ascribed
abruption. No risk factors were found in the other seven to the obscure clinical manifestations in newborn infants.
infants. For those symptomatic infants, abnormal neurological signs
and hematological derangement are the common present-
ing features. However, there was no difference in the
4. Discussion clinical manifestations between PAIS and PHS. Therefore,
clinicians are unlikely to be able to differentiate these two
This is the first cohort study of perinatal stroke in Taiwan. types of perinatal stroke by clinical features.
In this 10-year observational study, 30 infants with peri- Seizure was the most common manifestation and pre-
natal stroke were identified after a rigorous search. There sented in nearly half of the infants in both groups. Our
were 10 infants with PAIS and 20 infants with PHS. In this 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
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
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 7
testing. In our literature search, there was one case report risk factors and a systematic diagnostic approach are
of an infant who had mild protein C deficiency and devel- helpful in identifying possible etiologies.
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 Conflicts of interest
(21%) and protein S (42%). Protein C deficiency caused by
heterozygous PROC mutation was confirmed as the cause of The authors declare there are no conflicts of interest.
stroke.34 Because the two infants with PAIS had dissociated
levels between protein C and protein S activity, and they
Acknowledgments
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 We are grateful to our colleagues in the Division of
factors in our study. Neonatology and the Division of Neurology, Department of
In our study, a prothrombotic condition, including pro- Pediatrics, for their help with this study.
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 References
common cause of perinatal stroke. Other etiologies
included culture-proven sepsis and meningitis (n Z 2), 1. Chabrier S, Husson B, Dinomais M, Landrieu P, Nguyen The
embolism after cardiac surgery (n Z 2), vascular malfor- Tich S. New insights (and new interrogations) in perinatal
mation (n Z 2), and TTTS (n Z 1). In a large cohort of 134 arterial ischemic stroke. Thromb Res 2011;127:13e22.
infants with perinatal ischemic or hemorrhagic stroke in 2. Lynch JK. Epidemiology and classification of perinatal stroke.
The Netherlands, Govaert et al5,8 reported embolism as the Semin Fetal Neonatal Med 2009;14:245e9.
most common cause of perinatal stroke. Our study, which 3. Mallick AA, OCallaghan FJ. The epidemiology of childhood
used the same diagnostic approach, showed that in Taiwan stroke. Eur J Paediatr Neurol 2010;14:197e205.
PAIS was mostly caused by dysfunctional hemostasis (20%) 4. Raju TN, Nelson KB, Ferriero D, Lynch JK, NICHD-NINDS
and embolism (20%), whereas PHS was mostly caused by Perinatal Stroke Workshop Participants. Ischemic perinatal
stroke: summary of a workshop sponsored by the National
birth asphyxia (30%). This variation suggested that the eti-
Institute of Child Health and Human Development and the
ology of perinatal stroke could differ geographically or in National Institute of Neurological Disorders and Stroke.
populations of different ethnic origin, as documented in Pediatrics 2007;120:609e16.
childhood stroke.35 5. Govaert P, Ramenghi L, Taal R, de Vries L, Deveber G. Diagnosis
of perinatal stroke: I. Definitions, differential diagnosis and
4.1. Limitations registration. Acta Paediatr 2009;98:1556e67.
6. Bogousslavsky J, Regli F, Uske A, Maeder P. Early spontaneous
hematoma in cerebral infarct: is primary cerebral hemorrhage
We investigated perinatal stroke including both PAIS and overdiagnosed? Neurology 1991;41:837e40.
PHS and used a systematic approach and causal relation- 7. Choi PM, Ly JV, Srikanth V, Ma H, Chong W, Holt M, et al.
ship evidence to explore possible etiologies. However, this Differentiating between hemorrhagic infarct and parenchymal
study has several limitations. First, this is a retrospective intracerebral hemorrhage. Radiol Res Pract 2012;2012:
observational study, and not all infants underwent an 475497.
extensive prothrombotic screening, nor was cerebral 8. Govaert P, Ramenghi L, Taal R, Dudink J, Lequin M. Diagnosis of
angiography performed in all infants. Second, our search perinatal stroke: II. Mechanisms and clinical phenotypes. Acta
strategy might have missed cases of perinatal stroke Paediatr 2009;98:1720e6.
9. Govaert P, Smith L, Dudink J. Diagnostic management of
caused by partial or complete occlusion of small vessels in
neonatal stroke. Semin Fetal Neonatal Med 2009;14:323e8.
infants with no or subtle symptoms.5,36 Third, some infants
10. Curry CJ, Bhullar S, Holmes J, Delozier CD, Roeder ER,
with perinatal stroke had subtle symptoms and were not Hutchison HT. Risk factors for perinatal arterial stroke: a
diagnosed until they developed neurological sequelae. study of 60 motherechild pairs. Pediatr Neurol 2007;37:
These infants may not have neuroimaging study within the 99e107.
1st year of life, and therefore would be missed by our 11. Kirton A, Deveber G, Pontigon AM, Macgregor D, Shroff M.
search strategy. Fourth, no infant was diagnosed with Presumed perinatal ischemic stroke: vascular classification
CSVT stroke. predicts outcomes. Ann Neurol 2008;63:436e43.
12. Golomb MR, Fullerton HJ, Nowak-Gottl U, Deveber G, Inter-
national Pediatric Stroke Study Group. Male predominance in
5. Conclusion childhood ischemic stroke: findings from the international
pediatric stroke study. Stroke 2009;40:52e7.
Perinatal stroke is a serious condition with high mortality 13. Golomb MR, Dick PT, MacGregor DL, Curtis R, Sofronas M,
and morbidity, yet a subtle or obscure clinical manifesta- deVeber GA. Neonatal arterial ischemic stroke and cerebral
tion makes the diagnosis difficult. Clinicians caring for in- sinovenous thrombosis are more commonly diagnosed in boys.
J Child Neurol 2004;19:493e7.
fants should always keep a high level of suspicion for this
14. Vasudevan C, Levene M. Epidemiology and aetiology of
condition, especially when infants have unexplained neonatal seizures. Semin Fetal Neonatal Med 2013;18:185e91.
seizure, cyanosis, conscious change, anemia, and/or 15. Lee J, Croen LA, Backstrand KH, Yoshida CK, Henning LH,
thrombocytopenia. It is difficult to distinguish PAIS and PHS Lindan C, et al. Maternal and infant characteristics associated
based on clinical manifestations. On patients with perinatal with perinatal arterial stroke in the infant. JAMA 2005;293:
stroke confirmed by neuroimaging, extensive screening for 723e9.
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
8 C.-C. Lee et al
16. Benders MJ, Groenendaal F, Uiterwaal CS, Nikkels PG, 26. Kersbergen KJ, Groenendaal F, Benders MJ, de Vries LS.
Bruinse HW, Nievelstein RA, et al. Maternal and infant char- Neonatal cerebral sinovenous thrombosis: neuroimaging and
acteristics associated with perinatal arterial stroke in the long-term follow-up. J Child Neurol 2011;26:1111e20.
preterm infant. Stroke 2007;38:1759e65. 27. Boardman JP, Ganesan V, Rutherford MA, Saunders DE,
17. Laugesaar R, Kolk A, Tomberg T, Metsvaht T, Lintrop M, Mercuri E, Cowan F. Magnetic resonance image correlates of
Varendi H, et al. Acutely and retrospectively diagnosed peri- hemiparesis after neonatal and childhood middle cerebral ar-
natal stroke: a population-based study. Stroke 2007;38: tery stroke. Pediatrics 2005;115:321e6.
2234e40. 28. Kirton A, Shroff M, Visvanathan T, deVeber G. Quantified cor-
18. Lehman LL, Rivkin MJ. Perinatal arterial ischemic stroke: ticospinal tract diffusion restriction predicts neonatal stroke
presentation, risk factors, evaluation, and outcome. Pediatr outcome. Stroke 2007;38:974e80.
Neurol 2014;51:760e8. 29. Mercuri E, Barnett A, Rutherford M, Guzzetta A, Haataja L,
19. Kirton A, Armstrong-Wells J, Chang T, deVeber G, Rivkin MJ, Cioni G, et al. Neonatal cerebral infarction and neuromotor
Hernandez M, et al. Symptomatic neonatal arterial ischemic outcome at school age. Pediatrics 2004;113:95e100.
stroke: the International Pediatric Stroke Study. Pediatrics 30. Fitzgerald KC, Williams LS, Garg BP, Golomb MR. Epilepsy in
2011;128:e1402e10. children with delayed presentation of perinatal stroke. J Child
20. Bruno CJ, Beslow LA, Witmer CM, Vossough A, Jordan LC, Neurol 2007;22:1274e80.
Zelonis S, et al. Haemorrhagic stroke in term and late preterm 31. Hsu CJ, Weng WC, Peng SS, Lee WT. Early-onset seizures are
neonates. Arch Dis Child Fetal Neonatal Ed 2014;99:F48e53. correlated with late-onset seizures in children with arterial
21. Farhadi R, Alaee A, Alipour Z, Abbaskhanian A, Nakhshab M, ischemic stroke. Stroke 2014;45:1161e3.
Derakhshanfar H. Prevalence of stroke in neonates who 32. Suppiej A, Mastrangelo M, Mastella L, Accorsi P, Grazian L,
admitted with seizures in neonatal intensive care unit. Iran J Casara G, et al. Pediatric epilepsy following neonatal seizures
Child Neurol 2015;9:41e7. symptomatic of stroke. Brain Dev 2016;38:27e31.
22. Delbos F, Bertrand G, Croisille L, Ansart-Pirenne H, Bierling P, 33. Ohga S, Ishiguro A, Takahashi Y, Shima M, Taki M, Kaneko M,
Kaplan C. Fetal and neonatal alloimmune thrombocytopenia: et al. Protein C deficiency as the major cause of thrombo-
predictive factors of intracranial hemorrhage. Transfusion philias in childhood. Pediatr Int 2013;55:267e71.
2016;56:59e66. 34. Ichiyama M, Ohga S, Ochiai M, Fukushima K, Ishimura M,
23. Lee J, Croen LA, Lindan C, Nash KB, Yoshida CK, Ferriero DM, Torio M, et al. Fetal hydrocephalus and neonatal stroke as the
et al. Predictors of outcome in perinatal arterial stroke: a first presentation of protein C deficiency. Brain Dev 2016;38:
population-based study. Ann Neurol 2005;58:303e8. 253e6.
24. Golomb MR. Outcomes of perinatal arterial ischemic stroke and 35. Lee YY, Lin KL, Wang HS, Chou ML, Hung PC, Hsieh MY, et al.
cerebral sinovenous thrombosis. Semin Fetal Neonatal Med Risk factors and outcomes of childhood ischemic stroke in
2009;14:318e22. Taiwan. Brain Dev 2008;30:14e9.
25. Kirton A, Deveber G. Life after perinatal stroke. Stroke 2013; 36. Govaert P. Sonographic stroke templates. Semin Fetal
44:3265e71. Neonatal Med 2009;14:284e98.
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