Stroke Study Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric
Stroke Study Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric
Stroke Study Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric
Stroke Study
Adam Kirton, Jennifer Armstrong-Wells, Taeun Chang, Gabrielle deVeber, Michael J.
Rivkin, Marta Hernandez, Jessica Carpenter, Jerome Y. Yager, John K. Lynch, Donna
M. Ferriero and for the International Pediatric Stroke Study Investigators
Pediatrics 2011;128;e1402; originally published online November 28, 2011;
DOI: 10.1542/peds.2011-1148
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/128/6/e1402.full.html
disability. The pathogenesis is poorly understood, which limits the de- National Institutes of Health, Bethesda, Maryland; and jNewborn
Brain Research Institute, University of California San Francisco,
velopment of treatment and prevention strategies. Multicenter studies
UCSF Benioff Children’s Hospital, San Francisco, California
must define epidemiology, risk factors, treatment practices, and out-
comes to advance clinical trials and improve the adverse outcomes KEY WORDS
stroke, newborn, perinatal stroke
suffered by most survivors.
ABBREVIATIONS
METHODS: The International Pediatric Stroke Study is a global re- AIS—arterial ischemic stroke
search initiative of 149 coinvestigators (30 centers in 10 countries). IPSS—International Pediatric Stroke Study
Patients with clinical and neuroimaging confirmation of symptomatic OR—odds ratio
neonatal AIS were enrolled (2003–2007). Standardized, Web-based CI—confidence interval
data entry collected clinical presentations, risk factors, investigations, CT—computed tomography
treatments, and early outcomes. We examined predictors of infarct All listed authors made substantive intellectual contributions to
characteristics and discharge outcome by using multivariate logistic this study, including conception and design, acquisition of data,
and/or analysis and interpretation of data; drafting and/or
regression. revising of the article for important intellectual content; and
RESULTS: Two hundred forty-eight neonates were studied (57% male, final approval of the version to be published. All listed authors
10% premature). Most of them presented with seizure (72%) and non- qualify for authorship and have participated sufficiently in the
focal neurologic signs (63%). MRI was completed for 92% of the infants, work to take public responsibility for appropriate portions of
the content.
although ⬍50% had vascular imaging. Infarcts preferentially involved
the anterior circulation and left hemisphere and were multifocal in www.pediatrics.org/cgi/doi/10.1542/peds.2011-1148
30%. Maternal health and pregnancies were usually normal. Neonates doi:10.1542/peds.2011-1148
often required resuscitation (30%) and had systemic illnesses (23%). Accepted for publication Aug 15, 2011
Cardiac and prothrombotic abnormalities were identified in ⬍20% of Address correspondence to Adam Kirton, MD, Alberta Children’s
the infants. Antithrombotic treatment was uncommon (21%) and var- Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta, Canada T3B
ied internationally. Half (49%) of the infants had deficits at discharge, 6A8. E-mail: adam.kirton@albertahealthservices.ca
and data on their long-term outcomes are pending. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
CONCLUSIONS: Newborns with AIS are often systemically sick, Copyright © 2011 by the American Academy of Pediatrics
whereas their mothers are usually healthy. Definitive causes for most FINANCIAL DISCLOSURE: The authors have indicated they have
neonatal AISs have not been established, and large-scale case-control no financial relationships relevant to this article to disclose.
studies are required to understand pathogenesis if outcomes are to be
improved. Pediatrics 2011;128:e1402–e1410
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ARTICLES
Perinatal stroke has emerged as a demiologists. The long-term goal of the expressed by postnatal week (ethical
common cause of lifelong neurologic prospective registry was to develop restrictions on birth dates). Neonates
disability. Neonatal arterial ischemic and execute international clinical born at ⱕ36 or ⱖ41 weeks’ gestation
stroke (AIS) is a common variety and is trials (https://app3.ccb.sickkids.ca/ were considered to be premature or
defined as acute symptomatic, focal cstrokestudy/). Prospective enroll- postmature, respectively. Investiga-
cerebral infarction in an arterial terri- ment extended from January 1, 2003, tional sites were grouped according to
tory between birth and 28 days of life to July 1, 2007 (149 coinvestigators, 30 region (Europe, Canada, United States,
that is confirmed by neuroimaging.1,2 centers, 10 countries) and included South America, Asia, or Australia).
Most survivors suffer neurologic mor- symptomatic neonatal AIS but not pre- Birth weight was trichotomized
bidity, and perinatal stroke is the lead- sumed perinatal ischemic strokes. The (⬍2500, 2500 – 4000, or ⬎4000 g). Sea-
ing cause of hemiplegic cerebral IPSS office (Hospital for Sick Children) son of event was adjusted according to
palsy.2 Many infants with AIS incur ad- managed Web-based data entry and hemisphere.
ditional sequelae including impair- the master database. Consensus- Potential risk factors were classified
ments in language, cognition, and be- based definitions for diagnosis, inves- into consensus IPSS categories based
havior and epilepsy.3–5 Case-control tigations, outcomes, and treatment on case-control studies and theoreti-
data are limited, and little is under- were applied. Study identification cal considerations only including
stood regarding pathophysiology.2,6 numbers were assigned at enrollment. cardiac, prothrombotic, acute and
That adverse outcomes last for de- Data were deidentified and entered chronic illnesses, arteriopathy, and
cades amplifies the impact of neonatal into a password-protected, Web-based neonatal (maternal, pregnancy, neo-
AIS on patients, their families, and system. Clinical care was not pre- natal, and obstetric). Neonates with
society. scribed by the IPSS. Methods were ap- systemic illness or significant resusci-
Studies of neonatal AIS have been lim- proved by site research ethics boards tation were classified as having “acute
ited by sample size and inconsistent with informed consent. The complete neonatal illness.” Prothrombotic testing
terminology, data collection, and risk- IPSS methodology is described and investigator interpretation varied
factor evaluations. The International elsewhere.11 across institutions, hence the term “pos-
Pediatric Stroke Study (IPSS) was es- sible” prothrombotic abnormality. Treat-
Population
tablished to standardize approaches ment categories included antithrom-
to childhood stroke research on a Cases were enrolled by site investiga- botic, anticonvulsant, and other.
global scale. Treatment options re- tors using established clinical and Outcomes, discharge destination, and
main to be established, and practice radiographic criteria5 including (1) causes of death were recorded.
patterns seem widely discrepant.7 acute neurologic deficit or seizure and
Consensus-based guidelines for pedi- (2) radiographic confirmation of acute Analysis
atric stroke8–10 offer little direction in focal cerebral infarction(s) within ar-
Numerators were expressed over the
neonatal AIS, and global practices re- terial territories corresponding to
available population unless otherwise
garding identification, investigation, clinical manifestations. Infants with
stated. For each outcome of interest,
and management must be established the following conditions were exclud-
variables predefined on evidence were
ed: neonatal cerebral sinovenous
to facilitate systematic studies and compared (2 analysis, dichotomous; t
clinical trials. thrombosis,12 presumed perinatal
tests, continuous) and expressed as
ischemic stroke, intracranial hemor-
We examine here the presentations, odds ratios (ORs) with 95% confidence
rhage, global hypoxic-ischemic injury,
clinical associations, investigations, intervals (CIs). To determine indepen-
periventricular leukomalacia, and
treatments, and early outcomes of a dent predictors, multivariate logistic re-
metabolic injury.
large, global population of neonates gression models incorporated univari-
with AIS. Data Abstraction ate P values of ⱕ .1 with testing for
colinearity. Stata 10.0 (College Station,
METHODS Investigators collected data—
TX) was used for statistical calculations.
demographics (age, gender, race/eth-
International Pediatric Stroke nicity, location), clinical presentations, RESULTS
Study imaging, potential risk factors and
The IPSS was established in 2003 by 11 evaluations, treatments, and dis- Patient Population
coinvestigators including pediatric charge outcomes— by using stan- A total of 1194 patients were enrolled
neurologists, hematologists, and epi- dardized forms. Age at diagnosis was in the IPSS, 347 (29%) of which were
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e1406 KIRTON et al
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ARTICLES
dently associated with discharge radiation to the neonatal brain.17 Our ing of the head and neck is required in
deficit. results have helped better character- neonatal stroke protocols to help re-
ize hemorrhagic changes associated solve this issue.
DISCUSSION with neonatal AIS. Associations with Disordered coagulation has long been
To our knowledge, this is the first re- markers of acute disease suggest that suspected of contributing to perinatal
port of a large multinational cohort of systemic processes such as altered stroke. Previous case-control data for
newborns with symptomatic AIS. Our hemostatic mechanisms might in- neonatal AIS are sparse, and estimates
data include several clinically relevant crease the likelihood of intracranial have varied widely (20%– 68%).18–22 Ev-
findings. Our population was generally bleeding. Although not evaluated in de- idence does support a role for throm-
“sicker” than those in previous stud- tail, severe hemorrhages that required a bophilia in neonatal AIS, particularly
ies. Neonates with AIS are typically de- change in management were not re- protein C deficiency, elevated lipopro-
scribed as nonencephalopathic, other- ported. Therefore, repeat imaging for tein(a) level, and factor V Leiden.23 A
wise well children who present at 1 to hemorrhagic changes might not be re- 2010 meta-analysis of thrombophilia in
2 days of life with seizures.3,13–15 How- quired, particularly with CT scanning. Ad- pediatric stroke found only 22 of 185
ever, at least 25% of our neonates dition of blood-sensitive magnetic reso- studies eligible, and only 6 focused on
showed signs of acute illness, includ- nance sequences (gradient echo, “perinatal stroke.”23 The authors con-
ing emergent cesarean delivery, re- susceptibility-weighted images) is a via- cluded that studies have been “contra-
suscitation, low Apgar scores, and/or ble alternative, and incorporation of dictory or inconclusive due to lack of
systemic illness. Despite this, the term such sequences to neonatal neuroim- statistical power.”23 Additional limiting
“birth asphyxia” or suggestion of aging protocols might enhance our un- factors of these studies and ours in-
global hypoxic-ischemic encephalopa- derstanding of disease mechanisms. clude inconsistent laboratory methods
thy was rare. Although they likely Noninvasive vascular imaging is now with a lack of controls matched for
share risk factors and AIS can co- routinely available and recommended perinatal factors including age, in
occur with hypoxic-ischemic encepha- by current pediatric stroke consensus which developmental changes in he-
lopathy,16 most cases seemed to guidelines.8 Despite this, fewer than mostasis are paramount and norma-
clearly distinguish the two. Such in- half of the neonates with AIS had cere- tive values are not well established.24
creased accuracy in diagnosis might bral angiographic studies performed. Our results do little to resolve the
reflect a combination of better neuro- Furthermore, dedicated angiography poorly understood role of thrombo-
imaging (diffusion MRI), enhanced ex- of the cervical vasculature was rarely philia in neonatal AIS, and fully pow-
perience of the IPSS investigators, and reported. Arterial dissection in neo- ered, carefully controlled studies are
better awareness of disease patterns. nates has been described and might required.
Such distinctions are essential for represent an underrecognized entity Consistent with the controversial role
choosing investigations, treatment op- with cervical imaging so underper- of antithrombotic treatment for neo-
tions, outcome prediction, family coun- formed. The documentation of arterial natal AIS, treatment was uncommon
seling, and research progress. occlusion in ⬍10% of the cases with and varied according to region. Recent
Neonates were unlikely to present with angiographic studies suggests multi- neonatal cerebral sinovenous throm-
focal deficits, which emphasizes the ple possibilities. This finding is per- bosis studies within the IPSS12 and
need for a high index of clinical suspi- haps most consistent with systemic elsewhere25 found similar interna-
cion and prompt neuroimaging to di- embolic events, although obvious risks tional discrepancies in treatment. Cur-
agnose stroke. Modern neuroimaging for embolism are present in a small rent consensus-based guidelines8–10
has greatly improved the detection minority of patients (eg, congenital vary in their recommendations re-
and understanding of neonatal AIS. heart disease). In addition, recanaliza- garding neonatal AIS treatment, al-
Our findings support the use of MRI tion of cerebral arteries might occur though they consistently support anti-
with diffusion-weighted sequences as quickly, and with most imaging per- coagulation therapy in congenital
the first-line imaging modality in most formed days after birth, occlusions heart disease, and such an association
cases of neonatal encephalopathy, might often not be evident. It is inter- was observed here. Our study could
which facilitates the accurate diagno- esting to note that despite a very low not examine the safety or efficacy of
sis of neonatal AIS. The role of CT scan- number of cases, “arteriopathy” was such interventions, although serious
ning is limited and has little advantage associated with deficits at discharge complications were not reported, and
over MRI but poses additional risk of (8 of 9 cases). Routine vascular imag- no association with intracranial hem-
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ARTICLES
many (122) (Ulrike Nowak- Göttl, MD, University School of Medicine (54) ter, Bangkok, Thailand (Montri Saeng-
Christine Düring, MD, and Anne Krüm- (Steve Ashwal, MD, and Chalmer Mc- pattrachai, MD), British Columbia Chil-
pel, MD), University of Texas South- Clure, MD, PhD), Schneider Children’s dren’s Hospital, Vancouver, British
western Medical Center, Dallas, Texas Hospital, New Hyde Park, New York (46) Columbia, Canada (Bruce Bjornson,
(94) (Michael M. Dowling, MD, PhD, Pa- (Li Kan, MD, MS, Robin Smith, MD, Jo- MD), Children’s Central Hospital,
tricia Plumb, RN, MSN, Janna Journey- seph Maytal, MD, and Rosemarie Sy- Tbilisi, Georgia (Nana Tatishvili, MD),
cake, MD, and Katrina van de Bruin- Kho, MD), Children’s National Medical Children’s Hospital of Buffalo, Buffalo,
horst, MA), Ohio Stroke Registry (94) Center, Washington, DC (39) (Jessica New York (E. Ann Yeh, MD), Children’s
Akron Children’s Hospital, Akron, Ohio Carpenter, MD, Taeun Chang, MD, and Hospital of Eastern Ontario, Ottawa,
(Abdalla Abdalla, MD), Cincinnati Chil- Steven Weinstein, MD), University of Ontario, Canada (Peter Humpherys,
dren’s Hospital Medical Center, Cincin- California, San Francisco (37) (Donna MD), Children’s Hospital of Wisconsin,
nati, Ohio (Tonya Phillips, MD), Cleve- Ferriero, MD, and Heather Fullerton, Milwaukee, Wisconsin (Catherine
land Clinic, Cleveland, Ohio (Neil MD, MAS), Maimonides Medical Center Amlie-Lefond, MD, and Harry T. Whelan,
Friedman, MD), MetroHealth Medical (26) (Steve Pavlakis, MD, Sharon Good-
MD), Denver Children’s Hospital, Den-
Center, Cleveland (Elie Rizkallah, MD), man, PNP, and Kim Levinson, PNP), Ri-
ver, Colorado (Timothy Bernard, MD,
Nationwide Children’s Hospital, Colum- ley Hospital, Indianapolis, Indiana (26)
and Neil A. Goldenberg, MD, PhD), Hos-
bus, Ohio (Warren Lo, MD, and Khaled (Meredith Golomb, MD, MSc), Winnipeg
pital Dr Sotero del Rio, Puente Alto,
Zamel, MD), Rainbow Babies and Chil- Children’s Hospital, Winnipeg, Mani-
Chile (Manuel Arriaza Ortiz, MD), Mc-
dren’s Hospital, Cleveland (Max Wiz- toba, Canada (24) (Mubeen Rafay,
Master University Medical Centre,
nitzer, MD, and Karen Lidsky, MD), Pon- MBBS, MSc, Frances Booth, MD, Mi-
tificia Universidad Catolica de Chile, chael Salman, MD, Charuta Joshi, MD, Hamilton, Ontario, Canada (Anthony
Santiago, Chile (78) (Marta Isabel Her- Namrata Shah, MD, and Monica Nash, Chan, MBBS), Miami Children’s Hospi-
nandez Chavez, MD), Royal Children’s RN), Children’s Hospital of New York, tal, Miami, Florida (Marcel Deray, MD,
Hospital, Melbourne, Victoria, Austra- New York, New York (22) (Geoffrey and Zaid Khatib, MD), Queen Mary Hos-
lia (75) (Professor Paul Monagle, Mark Heyer, MD), Great Ormond Street Hos- pital, Hong Kong, China (Virginia Wong,
MacKay, MD, Chris Barnes, MD, Janine pital, London, United Kingdom (21) (Vi- MD), Université de Sherbrooke Fleuri-
Furmedge, RN, BSc, and Anne Gordon, jeya Ganesan, MBChB, MD), Stollery mont (Guillaume Sebire, MD, PhD), Uni-
MSc, BAppSc), University of Utah and Children’s Hospital, Edmonton, Al- versity of Rochester Medical Center,
Primary Children’s Medical Center, berta, Canada (21) (Jerome Y. Yager, Rochester, New York (Jill M. Cholette,
Salt Lake City, Utah (70) (Susan L. Bene- MD), and Pediatric Institute Hospital, MD, Shalu Narang, MD, and Norma B.
dict, MD, and James F. Bale Jr, MD), Kuala Lumpur, Malaysia (20) (Hussain Lerner, MD, MPH), and University of
Children’s Hospital of Philadelphia (63) Imam, MBBS, FRCP, DCH); and the IPSS Texas, San Antonio, Texas (Shannon
(Rebecca Ichord, MD, Daniel Licht, MD, institutions that enrolled ⬍20 patients Carpenter, MD, and Kurt Bischoff,
and Sabrina Smith, MD), Loma Linda were Bangkok Hospital Medical Cen- MSc).
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e1410 KIRTON et al
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Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric
Stroke Study
Adam Kirton, Jennifer Armstrong-Wells, Taeun Chang, Gabrielle deVeber, Michael J.
Rivkin, Marta Hernandez, Jessica Carpenter, Jerome Y. Yager, John K. Lynch, Donna
M. Ferriero and for the International Pediatric Stroke Study Investigators
Pediatrics 2011;128;e1402; originally published online November 28, 2011;
DOI: 10.1542/peds.2011-1148
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/128/6/e1402.full.
html
References This article cites 38 articles, 2 of which can be accessed free
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