J BCMD 2017 03 003

Accepted Manuscript
Pediatric arterial ischemic stroke: Epidemiology, risk factors, and

management
Ryan J. Felling, Lisa R. Sun, Emily C. Maxwell, Neil Goldenberg,

Timothy Bernard
PII: S1079-9796(16)30230-3
DOI: doi: 10.1016/j.bcmd.2017.03.003
Reference: YBCMD 2166
To appear in: Blood Cells, Molecules and Diseases
Received date: 11 October 2016
Revised date: 6 March 2017
Accepted date: 6 March 2017
Please cite this article as: Ryan J. Felling, Lisa R. Sun, Emily C. Maxwell, Neil
Goldenberg, Timothy Bernard , Pediatric arterial ischemic stroke: Epidemiology, risk
factors, and management. The address for the corresponding author was captured as
affiliation for all authors. Please check if appropriate. Ybcmd(2017), doi: 10.1016/
j.bcmd.2017.03.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As
a service to our customers we are providing this early version of the manuscript. The
manuscript will undergo copyediting, typesetting, and review of the resulting proof before
it is published in its final form. Please note that during the production process errors may
be discovered which could affect the content, and all legal disclaimers that apply to the
journal pertain.
ACCEPTED MANUSCRIPT
Pediatric Arterial Ischemic Stroke: Epidemiology, Risk Factors, and Management
Ryan J. Felling1, Lisa R. Sun1, Emily C. Maxwell2,, Neil Goldenberg3,4,, Timothy Bernard2,5
1
Johns Hopkins University School of Medicine
Department of Neurology
Baltimore, MD 21287
T
2
Department of Pediatrics, Section of Child Neurology
IP
University of Colorado School of Medicine
CR
Aurora, CO 80045
US
3
All Children’s Hospital Johns Hopkins Medicine and All Children’s Research Institute
St. Petersburg, FL
AN
4
M
Division of Hematology, Department of Pediatrics

ED
Baltimore, MD
PT
5
Hemophilia and Thrombosis Center
University of Colorado School of Medicine
CE
Aurora, CO 80045
AC
Correspondence:
Ryan J. Felling
Department of Neurology
200 N. Wolfe Street, Suite 2158
Baltimore, MD 21287
Email: rfelling@jhmi.edu
ACCEPTED MANUSCRIPT
Abstract
Pediatric arterial ischemic stroke (AIS) is an uncommon but important cause of neurologic morbidity in
neonates and children, with consequences including hemiparesis, intellectual disabilities, and epilepsy.
The causes of pediatric AIS are unique to those typically associated with stroke in adults. Familiarity
with the risk factors for AIS in children will help with efficient diagnosis, which is unfortunately
T
frequently delayed. Here we review the epidemiology and risk factors for AIS in neonates and children.
IP
We also outline consensus-based practices in the evaluation and management of pediatric AIS. Finally
CR
we discuss the outcomes observed in this population. While much has been learned in recent decades,
many uncertainties sill persist in regard to pediatric AIS. The ongoing development of specialized
US
centers and investigators dedicated to pediatric stroke will continue to answer such questions and
AN
improve our ability to effectively care for these patients.
M
Key Words
ED
infarct, children, neonates, brain injury

PT
CE
AC
ACCEPTED MANUSCRIPT
Introduction
Pediatric arterial ischemic stroke (AIS) is an important cause of neurologic morbidity in children.
Consequences can include sensorimotor deficits, language impairment, intellectual disability, behavioral
problems, and epilepsy. While guidelines have been published regarding the evaluation and
T
management of stroke in children, these are largely consensus-based and not usually supported by strong
IP
evidence. Based on experience in adults in whom AIS is much more common, it is likely that early
CR
recognition and institution of neuroprotective measures is crucial to improving outcomes in children
with stroke. Unfortunately, the diagnosis of stroke in children is often delayed (1, 2). Understanding
US
the populations at risk is essential to improving the efficiency with which we can diagnose and manage
AN
AIS. Here we review the most updated data regarding the epidemiology of pediatric AIS, and discuss
the most prevalent risk factors associated with this potentially devastating neurologic emergency. We
M
also summarize important aspects in the evaluation and management of these patients.
ED
Epidemiology
PT
Various nomenclatures have been utilized to classify pediatric AIS based on age. A National Institutes
of Health workshop defined perinatal stroke as “a group of heterogeneous conditions in which there is a
CE
focal disruption of cerebral blood flow secondary to arterial or cerebral venous thrombosis or
AC
embolization, between 20 weeks of fetal life through the twenty-eighth postnatal day confirmed by
neuroimaging or neuropathologic studies (3).” Within this group, patients with AIS often fall into two
distinct categories based on timing of presentation. Perinatal AIS is typically used to define patients
who present acutely in the neonatal period, often with symptomatic seizures rather than the focal
neurologic deficits typically associated with stroke. Presumed perinatal AIS, on the other hand, refers to
patients who do not present until later in the first year of life, often with an emerging hemiparesis. In
these cases AIS is retrospectively diagnosed by the presence of a chronic infarct on neuroimaging (4).
ACCEPTED MANUSCRIPT
When pediatric AIS occurs outside of the perinatal period, which in the literature is typically defined as
anything beyond the first month of life, we use the term childhood AIS. The use of standardized
terminology is essential, because the pathophysiology underlying each subtype is distinct and has
implications on recurrence risk, outcomes, and treatment strategies.
Estimates of the incidence of childhood AIS are variable and highly dependent on the search strategy
T
employed as well as the study population. In a retrospective cohort study of a California managed care
IP
plan consisting of 2.3 million children under 20 years of age, key word searches of both radiology
CR
reports and diagnostic codes were performed, yielding an incidence of childhood AIS of 2.4 per 100,000
person-years (5). This estimate is double that of prior reported studies that used only diagnostic code
US
searches. The largest of such studies searched a California-wide discharge database and found an
AN
incidence of pediatric AIS of 1.2 per 100,000 person-years (6). The highest published rate of childhood
AIS is 7.9 per 100,000 person-years (7). Notably, this study was the only prospective analysis, raising
M
the possibility that retrospective studies may be underestimating the incidence of childhood AIS. The
ED
incidence of childhood AIS appears to be relatively stable over time, with only one study finding a non-
significant increase in incidence between 1988 and 1999 (8).

PT
The incidence of perinatal AIS is considerably higher than that of childhood AIS; in fact, the perinatal
CE
period is recognized as one of the highest risk epochs of life with regard to stroke (9). In the National
Hospital Discharge Survey, conducted 1980 through 1998, the rate of AIS was 17.8 per 100,000 live
AC
births per year (10). A more recent study performed in Switzerland between 2000 and 2010 found a rate
of symptomatic perinatal AIS of 13 per 100,000 live births per year (11). Notably, the rates in these
studies were derived from diagnoses made within the first month of life. The incidence of presumed
perinatal AIS is more challenging to determine, because only those children who develop symptomatic
neurologic deficits are detected. The diagnosis of presumed perinatal AIS shows that there is a
ACCEPTED MANUSCRIPT
significant population of infants with subclinical AIS in the neonatal period, and underscores the idea
that the frequency of perinatal AIS is likely underestimated.
The risk of AIS in children and neonates is highly age dependent, with children less than one year of age
at the highest risk even after accounting for perinatal AIS. After one year of age, the incidence declines
considerably and stays low until mid-adolescence, when it begins to increase (6). Stroke incidence also
T
varies significantly by race. In one study, when compared with white children, black children were at an
IP
increased risk of AIS (relative risk 2.59), and Hispanic children were at a decreased risk (relative risk
CR
0.7) (6). In that study, the risk was similar in white and Asian children. Interestingly, the difference in
risk between white and black children persisted even when children with sickle cell disease were
US
excluded from the study. Perinatal AIS is also more common in African Americans when compared with
AN
white infants (11), though data on other races is lacking. In childhood AIS, case fatality rates have been
reported to be similar among all ethnic groups (6). Sex is also a risk determinant, with boys having a
M
higher risk of both childhood (relative risk 1.25) and perinatal (relative risk 2.0) AIS (6, 11). The
ED
difference between boys and girls persists in childhood AIS even after adjusting for trauma.
Ellis and colleagues recently reviewed six studies examining the cost of pediatric stroke. The costs were
PT
highly variable but ranged from $15,000-$140,000. However, these studies typically only included costs
CE
accrued in the first year after stroke. Therefore, these studies greatly underestimate the true cost of
childhood stroke because of the challenges inherent in predicting many of the less tangible costs such as
AC
lost productivity for families as well as the children themselves due to persistent neurologic disability
later in life. As Ellis et al. point out, pediatric stroke survivors often have normal lifespans, and so costs
accumulate over much longer periods when compared with adult strokes (12).
Risk Factors and Etiology
Pediatric AIS has been associated with diverse risk factors that vary substantially between the perinatal
period and later in childhood. Perinatal AIS is typically thought of as truly multifactorial with risk
ACCEPTED MANUSCRIPT
factors often specific to pregnancy as detailed below. Childhood AIS on the other hand has numerous
risk factors, many of which are quite different from those typically found in adult AIS (Table 1). As a
result, the systems often used to classify adult AIS, such as the TOAST criteria, are inadequate to
describe pediatric AIS. Recently, experts in the field of pediatric AIS have established a classification
scheme to provide a standardized language for describing the types of strokes that are often encountered.
The Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE) criteria
T
IP
describe strokes in terms of their distribution as well as their behavior in both the acute and chronic
phases (13). This system has excellent interrater reliability and will provide more consistency across
CR
future multicenter studies, although the classification of arteriopathies in the CASCASDE criteria still
US
needs further refinement (14). Together with an understanding of the underlying risk factors for
childhood AIS, an improved classification system will provide a better clinical understanding of
AN
pediatric AIS subtypes, especially arteriopathic AIS. It is important to note that risk factors for AIS are
M
different from the cause of AIS which is often a combination of one or more risk factors and inciting
events in childhood AIS. Studies have shown that multiple risk factors are frequently present in the
ED
same patient (15, 16). For this reason, we advocate a comprehensive evaluation for risk factors in all
PT
children with a first AIS (Figure 1).

CE
Perinatal and Presumed Perinatal AIS
Perinatal AIS is frequently separated from childhood AIS because of distinct pathophysiological
AC
mechanisms that are more extensively reviewed elsewhere (17, 18). The cause of perinatal AIS is most
often multifactorial due to the relatively hypercoagulable nature of pregnancy itself and the complex
interaction of the maternal and fetal circulations. As an evolutionary defense against hemorrhage,
changes in hemostasis occur throughout pregnancy, peaking near term gestation. These include
increases in many procoagulant factors, decreases in natural anticoagulants, and decreased activity of
fibrinolytic systems (19). Several case series and case-control studies have identified additional
ACCEPTED MANUSCRIPT
characteristics that are frequently associated with perinatal AIS (20-25). These include a history of
infertility, primiparity, intrauterine growth restriction, oligohydramnios, gestational hypertension or pre-
eclampsia, prolonged rupture of membranes, chorioamnionitis or maternal fever, prolonged second stage
of labor, complicated delivery (including forceps, vacuum, or emergency C-section), abnormal
cardiotocography, umbilical cord abnormalities, birth asphyxia, 5 minute Apgar score < 7,
hypoglycemia, and early onset sepsis/meningitis. Unfortunately, there is little consistency of risk factors
T
IP
identified across studies as is often the case with smaller retrospective studies. Many of these risk
factors are also nonspecific and not necessarily causal etiologies for perinatal AIS. The consistent
CR
association of infections such as chorioamnionitis or neonatal sepsis with perinatal AIS highlights the
US
important but incompletely understood role of inflammation in the genesis and evolution of perinatal
brain injury. Often, the source of perinatal AIS is presumed to be thrombosis at the level of the placenta
AN
with subsequent embolization across the fetal patent foramen ovale. While reported in small numbers of
M
patients after perinatal AIS, this has yet to be studied in a systematic fashion because often placental
pathology is not available on a retrospective basis (26, 27). This is an area that deserves attention in
ED
future studies of perinatal AIS.

PT
The low recurrence rate of perinatal AIS either later in childhood or in a subsequent pregnancy supports
CE
the concept that risk factors are usually confined to the perinatal period. Nevertheless, there are
undoubtedly rare cases where maternal and/or infant risk factors confer additional risk beyond the
AC
perinatal period. For example, cardiac disease is an important cause of AIS in the perinatal period that
confers an ongoing risk in many cases. In the International Pediatric Stroke Study, 18% of the 248
patients with symptomatic perinatal AIS had associated cardiac risk factors, most commonly congenital
heart disease (CHD) (28). Studies have utilized imaging to define the timing of brain injury in CHD
patients, and stroke appears to occur preoperatively at least half of the time (29, 30). The need for
cardiac procedures also increases the risk for AIS, and possibly more so in neonates than in older
ACCEPTED MANUSCRIPT
children. In a study of the data from Extracorporeal Life Support Organization, neonates who required
extracorporeal membrane oxygenation (ECMO) after cardiac surgery were significantly more likely to
have had a stroke compared to older children (odds ratio 1.73) (31). Only a few case reports raise the
possibility that arteriopathies (congenital, infectious, or traumatic) might predispose neonates to
perinatal AIS (21, 32-34), but advances in fetal imaging and our knowledge of genetic disorders that
predispose to congenital vascular anomalies may further our understanding of the role these play in
T
IP
perinatal AIS (35).
CR
Hypercoagulable disorders are perhaps the most extensively investigated causes of perinatal AIS. In
two studies of mother-child pairs, at least 50% of both the mothers and the infants had prothrombotic
US
risk factors including Factor V Leiden, prothrombin g20210a mutation, methylene tetrahydrofolate
AN
reductase (MTHFR) mutations, low protein C or protein S, elevated lipoprotein(a), elevated
homocysteine, or antiphospholipid antibodies (36, 37). A prospective study of pregnant women with
M
known C677T mutations in the MTHFR gene found AIS in 2/91 neonates, but no concurrent control
ED
population was examined (38). In the largest case-control study of neonatal prothrombotic risk factors
to date, 68.1% of neonates with AIS had at least one prothrombotic risk factor compared to 24.2% of
PT
matched controls (39). In a recent study using rotation thromboelastometry to investigate the
CE
coagulation system in infants with a history of perinatal AIS, the patients exhibited significantly
elevated clot firmness compared to an unmatched control population, although none of the other
AC
measured parameters were different, and there were no differences in the patients who had known
prothrombotic risk factors compared to those who did not (40). Recurrence of AIS later in childhood is
very rare, with the exception to this rule being children with cardiac disease in whom a recurrence rate
of 14% has been reported (41). Otherwise, recurrence has been reported to be about 3.3% for any type
of thromboembolic event in one cohort study of 215 patients (42). Most of the patients who did have a
recurrence (5/7) had an identified prothrombotic abnormality present with their incident AIS.
ACCEPTED MANUSCRIPT
Recurrence of perinatal AIS within families is even rarer, substantiated only by single case reports (43).
Further prospective cohort studies may help to clarify the role of risk factors in recurrence, but the
overall low rate of recurrence further emphasizes the multifactorial nature of perinatal AIS. Given the
very small recurrence risk, assessment of thrombotic risk factors in perinatal AIS remains uncertain and
controversial; however multiple thromboembolic events and/or a history of thrombosis in first degree
relatives should always prompt a thorough thrombosis evaluation.
T
IP
Arteriopathies
CR
Arteriopathies are arguably the most important risk factor for childhood AIS. In one survey of risk
factors, arterial abnormalities were seen in 40-80% of those children with AIS in whom vascular
US
imaging is performed. (44, 45). Efforts spearheaded by the International Pediatric Stroke Study to
AN
classify subtypes of AIS have helped to standardize the nomenclature used to identify arteriopathies
commonly seen in children. (13, 46). In perhaps the first discussion of arteriopathies in childhood AIS,
M
Daniels et al. noted a high frequency of angiographic findings in children with lipid profile
ED
abnormalities and family histories of early cardiovascular disease. (47). Sebire and colleagues
subsequently described the entity of transient cerebral arteriopathy (TCA) as a focal stenosis or
PT
segmental narrowing in the vessel wall, typically in the large vessels of the intracranial anterior
CE
circulation, which exhibited fluctuation on serial angiographic studies (48). In this description, TCA
usually involves a vasculopathy of the distal ICA, proximal MCA, and sometimes the circle of Willis.
AC
Typically, this entity involves a basal ganglia stroke of the lenticulostriates, and the arteriopathy
demonstrates a transient worsening over the first 3-6 months, followed by improvement and/or
sometimes resolution of vascular irregularity/stenosis. The term “transient” underscores the importance
of longitudinal evaluation of childhood intracranial arteriopathies. Recent imaging studies have
suggested that other types of arteriopathy, such as intracranial dissection, may mimic the presentation of
TCA, and a small percentage (6%) will go on to develop frank moyamoya with progressive narrowing
ACCEPTED MANUSCRIPT
and collateral formation (49). Recently, the term focal cerebral arteriopathy (FCA) has been adopted as
a broader category to include TCA and other forms of arteriopathy that may have overlapping
presentations, as described in the CASCADE criteria (13).
Understanding the pathophysiology of FCAs is an ongoing challenge to investigators in the field of
childhood AIS. One known cause of FCA is post-varicella angiopathy, but this is rare in our experience.
T
While there is a clear association between TCA and varicella infection within 1 year of diagnosis, most
IP
cases lack pathologic evidence (50). More recently, the Vascular Effects of Infection in Pediatric Stroke
CR
(VIPS) study identified serological evidence of acute herpes virus infection in 45% of a prospectively
enrolled population of childhood AIS patients (51). To complicate the relationship between infection
US
and arteriopathy, however, the VIPS study discovered a similar prevalence of recent infection across all
AN
AIS subtypes, regardless of arteriopathy diagnosis. Another entity diagnosed in children is primary
CNS angiitis, which can affect either small vessels or medium to large vessels. While diagnostic criteria
M
have been delineated in adults, the clinical and angiographic appearance can resemble many of the other
ED
diagnoses that fall under the FCA rubric. Understandably, pathology is typically not available to study
in patients with childhood AIS, and this leaves persisting questions about whether such arteriopathies
PT
result from direct infection of the vessels themselves, a parainfectious process, or an autoimmune
CE
disease. While Fullerton and colleagues have found a high likelihood of prodromal infection in the days
leading up to AIS occurrence, the role of recent infection in these arteriopathies remains unknown. (52,
AC
53). Many of these infections were common childhood upper respiratory infections typically caused by
viruses without known vascular tropism, and the rates of infection were similar across childhood AIS
subtypes, supporting a general inflammatory or parainfectious role (54). While certain infections such
as VZV and HSV are known to directly affect the blood vessels and are associated with childhood AIS,
the role of infection and inflammation in these arteriopathies is clearly yet to be fully understood.
ACCEPTED MANUSCRIPT
Noninflammatory arteriopathies are also important considerations in childhood AIS. Arterial dissection
of the craniocervical or intracranial vessels is likely an under-recognized cause of arteriopathy in
children, particularly when relying solely on MR angiography for diagnosis (49, 55, 56). There is some
evidence that intracranial dissection may be more common in children compared to adults, and it often
occurs without the preceding history of trauma that is typically expected with extracranial dissection
(57, 58). While common lore suggests that craniocervical dissections occur commonly in connective
T
IP
tissue disorders such as Marfan, Ehlers Danlos, and Loeys-Dietz syndromes, the true prevalence in these
patients is unknown due to a lack of good case-control or prospective studies (59). Nonetheless, these
CR
disorders are important considerations, particularly in patients with evidence of multiple dissections.
US
The fibromuscular dysplasias (FMD) are a group of noninflammatory arteriopathies typically affecting
the carotid and renal arteries, though they can involve any vessel. These have classically been described
AN
to have a “stacked coin” or “string of beads” appearance on angiography. While dissections have been
M
reported in this group, a study of 27 children with AIS and pathologically confirmed FMD found no
corroborating evidence of dissection and a relative infrequency of the classic angiographic appearance
ED
compared to adult studies (60). These findings suggest that the pathogenesis of AIS in children with
PT
FMD may be different than in adult patients with FMD. Moyamoya disease is a progressive
noninflammatory arteriopathy involving the distal carotid artery, first described by Suzuki in Japan
CE
where it remains most prevalent (61). The term moyamoya was originally coined to describe the hazy
AC
appearance of the network of basal collateral vessels that form as the result of progressive stenosis of the
carotid terminus. Pathologically, moyamoya disease is characterized by fibrocellular intimal thickening,
possibly due to a constrictive remodeling process (62). Idiopathic moyamoya disease can exhibit
sporadic or hereditary occurrence, and susceptibility loci are beginning to be identified, such as the
RFN213 gene (63). In contrast to idiopathic moyamoya disease, a moyamoya syndrome refers to similar
angiographic findings that occur in the context of other underlying diseases including Trisomy 21,
Neurofibromatosis Type 1, and sickle cell anemia. Understanding of this disease entity is important
ACCEPTED MANUSCRIPT
because its treatment is unique in the context of other arteriopathies, relying on surgical
revascularization (64).
Evaluation for arteriopathy is one of the essential points of management in childhood AIS. Multiple
studies have demonstrated a markedly increased risk of recurrent AIS when an arteriopathy is present
(65-67). As evident from the discussion above, however, the angiographic diagnosis of arteriopathy
T
may not definitively indicate the underlying etiology. This has produced a field rife with opportunity for
IP
biomarker discovery (68, 69). Inflammatory biomarkers such as high-sensitivity CRP and serum
CR
amyloid A are associated with increased risk of recurrence in arteriopathic AIS and may have value in
predicting progression of the arteriopathy (70). Others have identified circulating endothelial cells and
US
BDNF as markers of an endothelial repair response that is predictive of AIS recurrence in the setting of
AN
an arteriopathy (71). The presence of an arteriopathy in the context of an elevated D-dimer may portend
a poor clinical outcome, even in the absence of AIS recurrence (72). Advanced imaging techniques are
M
providing additional strategies for studying arteriopathies as well. High resolution vessel wall imaging
ED
is increasingly utilized on a clinical basis and promises to provide a noninvasive means of further
understanding the pathophysiology of arteriopathy (Bernard et al., communication).

PT
Cardiac Disease
CE
Children with cardiac disease represent one of the most significant subsets of pediatric AIS patients.
AC
Across most series, cardiac risk factors are present in 2-31% of children with AIS, with the incidence
notably higher in Western populations compared to Eastern populations (15, 44, 73-78). In a
retrospective study of the Intermountain Pediatric Stroke Database, children with either acquired or
congenital heart disease had a 16.1-fold increased risk of AIS compared to the general pediatric
population, and those with single ventricle physiology exhibited the highest incidence (79). A similar
increase in risk was observed in a case-control study from Northern California (80). CHD is the most
commonly cited risk factor, representing more than half of the children with AIS attributed to cardiac
ACCEPTED MANUSCRIPT
disease in the International Pediatric Stroke Study registry, but acquired conditions such as arrhythmias,
cardiomyopathy, or endocarditis are diagnostic concerns as well (81). Multiple studies have found
children with cardiac causes of AIS to have an earlier age at presentation (80, 81). Recurrent AIS is a
significant concern in patients with cardiac disease as well. In a study of the Canadian Pediatric
Ischemic Stroke Registry, 27% of patients with CHD and AIS had a recurrent stroke in the 10 years
following the sentinel event (41). Conditions associated with recurrence included a mechanical valve,
T
IP
prothrombotic condition, or acute infection, and about half had recurrence despite being treated with
anticoagulation at the time. A point of uncertainty persists regarding the role of an isolated patent
CR
foramen ovale (PFO), in part because there is significant variability in how this has been considered
US
across studies, with some lumping it in with other structural heart diseases while others have separated it
as a distinct diagnosis. While there is some evidence suggesting an important role of right-to-left
AN
shunting across an atrial defect, particularly among patients with prothrombotic conditions or
M
cryptogenic stroke (82), the role of device closure remains undefined due to lack of sufficient evidence
(83).
ED
An important consideration in the association of cardiac disease with pediatric AIS is the inevitable
PT
necessity of invasive cardiac procedures with many of these conditions. These include corrective
CE
surgeries, cardiac catheterization (either diagnostic or therapeutic), and augmentation of cardiac function
with ventricular assist devices or ECMO. In a study of the Northern California population, a history of
AC
CHD surgery increased the risk of AIS more than 30-fold compared to controls, and the risk remained
elevated even after adjusting for perioperative stroke (80). Patients undergoing Fontan procedure for
palliation of single ventricle physiology represent one of the most extensively studied groups of CHD
patients at risk for AIS. In one retrospective study of these patients, 9% suffered AIS within a median
follow-up period of 3.5 years. Of these strokes, 16% occurred pre-surgery, and the majority of the rest
could be directly attributed to either the perioperative period or a defined cardiac event such as arrest or
ACCEPTED MANUSCRIPT
catheterization (84). While this study found a statistically reduced incidence of AIS with antithrombotic
treatment, other studies have not found such an association, and the inconsistency in antithrombotic
practice in these patients is highlighted in a multicenter cross-sectional study from the Pediatric Heart
Network (85-87). Future multidisciplinary efforts are needed to optimize strategies for reducing
neurologic morbidity in these patients.
T
Sickle Cell Disease
IP
Arterial Ischemic stroke is a well-recognized complication of sickle cell disease (SCD), and prior to
CR
2000 SCD represented one of the most common causes of stroke in children (88, 89). Publication of the
pivotal STOP trial in 1998, which demonstrated that chronic transfusion therapy is effective in primary
US
prevention of AIS in high risk children with SCD, has dramatically reduced the stroke risk in this
AN
population in high income countries (90). Nonetheless, SCD remains an important cause of neurologic
morbidity worldwide, even more so in low to middle income nations where access to transfusion therapy
M
is not as readily available. Even in high income countries such as the United States, regional differences
ED
in access to transcranial Doppler (TCD) screening causes some children who would benefit to be missed
(91). Despite well characterized risk of AIS in SCD, the underlying pathophysiology remains poorly
PT
understood and is likely multifactorial (92). The development of a vasculopathy, typically involving the
CE
internal carotid or middle cerebral arteries, is common in SCD and a well described risk factor for AIS.
As demonstrated in the STOP trial, TCD is a reliable method to identify children with elevated cerebral
AC
blood flow velocity (CBFV), intracranial vasculopathy, and high stroke risk (93-95). In addition to the
presence of a vasculopathy, other concomitant risk factors may also contribute to AIS in children with
SCD including acute illnesses or infection, severe anemia, paradoxical shunting, and thrombophilia. All
of these conditions can impact cerebral metabolic demand or oxygen delivery and thus exacerbate an
already high-risk condition.

ACCEPTED MANUSCRIPT
Studies in children with SCD often differentiate between overt stroke and silent cerebral infarctions
(SCI), which are MRI lesions without any corresponding abnormality on neurologic exam. While useful
from study perspectives, it is more likely that these are two ends of the same pathophysiologic spectrum
rather than distinct entities. Supporting this idea is the fact that SCI is a strong risk factor for developing
overt stroke (96, 97). Additionally, transfusion therapy is also effective in preventing SCI (98). A study
of children undergoing screening MRI for clinical trials identified acute but asymptomatic infarcts in
T
IP
1.3% of the patients, and other studies have found even higher rates for patients admitted to the hospital
for severe anemia but without frank neurologic symptoms (99, 100). In addition to TCD screening and
CR
SCI detection, there is substantial interest in developing additional biomarkers for stroke risk in children
US
with SCD. One potential candidate is glial fibrillary acidic protein (GFAP) which may be evident in the
blood prior to the development of overt stroke in at-risk patients (101). Future efforts at developing
AN
such biomarkers will be very useful in risk stratifying patients and identifying which ones may need
M
escalation of therapy or additional preventive measures under certain circumstances.

ED
Thrombophilia
Prothrombotic conditions, either acquired or inherited, are frequently cited risk factors for pediatric AIS,
PT
but the extent of their contribution remains controversial, partly due to variability in the extent of testing
CE
across small case series. Studies suggest that prothrombotic factors can be identified in 20-50% of
children, much higher than similar observations in adults with AIS (102-108). While many of the
AC
putative thrombophilic risk factors for AIS have been described in small series or case control studies,
an extensive meta-analysis of 22 studies found statistically significant association between first AIS and
the following thrombophilia traits: deficiency of protein C or antithrombin, factor V G1691A (Leiden),
factor II G20210A, MTHFR C677T polymorphism, elevated level of lipoprotein(a), and the presence of
antiphospholipid antibodies (109). Some believe that thrombophilia is simply a permissive trait in
promoting thrombosis in the setting of other risk factors, but there is evidence that at least some
ACCEPTED MANUSCRIPT
prothrombotic factors independently increase the risk of AIS. In a case-control study of 148 pediatric
AIS patients and 296 age-matched controls without any other known risk factors, Nowak-Gӧttl and
colleagues identified elevated lipoprotein(a), factor V Leiden, factor II G20210A, protein C deficiency
and MTHFR polymorphisms as independent risk factors for AIS (107). Liporotein(a) is intriguing
because it is a well-recognized risk factor for atherogenesis in adult populations, but it’s role as an
independent prothrombotic factor due to inhibition of fibrinolysis through competition with plasminogen
T
IP
is debated (110). Such a role would seem to be supported, however, by its emergence in multiple
studies as a risk factor for both incident and recurrent AIS in pediatric patients where atherosclerosis is
CR
not felt to be a contributing factor (66, 107, 108, 111).
Cancer
US
AN
Stroke is one of many neurologic morbidities that can accompany pediatric cancers and their treatment.
M
Data regarding frequency and details about predisposing factors, however, are lacking. Studies of
ED
cohorts of children with cancer have revealed the incidence of AIS to be of 0.5-4% with substantial
variation based on the underlying malignancy (112-114). Stroke is rarely a primary manifestation of the
PT
underlying malignancy, but more often is a complication during therapy (115, 116). L-asparaginase and
CE
cytarabine are two of the more high-risk chemotherapeutic agents associated with stroke or stroke-like
syndromes (117, 118). The highest and most enduring risk, however, is associated with cranial
AC
irradiation therapy and subsequent development of vasculopathy (119-121).
Other Causes
We have reviewed the best-studied risk factors for AIS in neonates and children, but a host of other
systemic diseases can also predispose to AIS. Inherited vascular syndromes such as Sturge-Weber
(122), incontinentia pigmentii (123), and PHACE syndrome (124) have been associated with childhood
AIS. Other metabolic disorders such as MELAS or Fabry disease can result in AIS either through
ACCEPTED MANUSCRIPT
effects on the blood vessels or through energy depletion (125, 126). Inflammation has already been
noted as an important risk factor for AIS in the setting of infection, but autoimmune diseases such as
lupus and systemic vasculitides can be associated with childhood AIS (127, 128). The proliferation of
genetic testing has also identified novel gene mutations that confer risk for AIS such as Adenosine
deaminase 2 (ADA2) deficiency (129) and Notch3 mutations (Cerebral Autosomal Dominant
Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, or CADASIL) (130). The rapidly
T
IP
declining costs of genomic testing will likely expand the list of associated genes in the near future, as
has already been demonstrated by the recently discovered ADA2 deficiency syndrome (131). Given the
CR
urgency of the diagnosis, AIS should be considered early in the differential for any child presenting with
US
a focal neurologic deficit, particularly in the context of acute systemic illness or with a family history of
the above conditions.

AN
M
Management of Pediatric AIS

ED
Several guidelines have been published regarding the management of AIS in the pediatric population
PT
(132, 133). Recognizing that AIS is an evolving injury, treatment must be focused on distinct phases:
the acute phase, the recovery phase, and the chronic phase. Acute treatments have revolutionized the
CE
management of adult stroke and include interventions directed toward revascularization and protection
AC
of the ischemic penumbra. Intravenous recombinant tissue plasminogen activator (tPA) improves
outcomes in adult AIS when administered within an appropriate time window, currently defined as 4.5
hours from the time of stroke onset (or time the patient was last seen normal) (134). More recently,
interventional mechanical thrombectomy has further improved outcomes in multiple clinical trials with
appropriate patient selection (135). The Thrombolysis in Pediatric Stroke (TIPS) trial was designed as a
dose escalation safety study of IV tPA in children 2-17 years old. Although it was closed due to lack of
enrollment, it provided a valuable consensus regarding proposed (but unconfirmed) safety criteria for the
ACCEPTED MANUSCRIPT
use of IV tPA in children, and helped to identify some of the barriers to thrombolytic use pediatric AIS
patients (136). Current strategies for treating acute childhood AIS with IV tPA or endovascular
therapies are uncertain and controversial, without much consensus. As a result, most centers target
efforts during the acute phase of pediatric AIS at supportive neuroprotective measures including
maintenance of cerebral perfusion through permissive hypertension and reduction of metabolic demand
with aggressive treatment of fevers and seizures.
T
IP
Currently the mainstay of treatment both acutely and for secondary prevention in the chronic phase is
CR
antithrombotic therapies. These include anticoagulation with either heparin or warfarin, and antiplatelet
agents, most commonly aspirin. One nonrandomized, prospective study compared low molecular
US
weight heparin (LMWH) with aspirin for secondary prevention in childhood AIS and found that neither
AN
demonstrated superiority in regard to prevention of recurrence (137). While significant bleeding events
with anticoagulation in pediatric AIS are thought to be rare based on retrospective studies, the risk of
M
hemorrhagic conversion in the ischemic brain during the acute phase must still be considered (138). In
ED
addition, the use of anticoagulation in extracranial dissection and cardioembolic stroke is recommended
by the American Heart Association guidelines, while aspirin is recommended for idiopathic stroke
PT
(133). Without strong evidence, however, the optimal treatment strategy remains undefined, and
CE
standard practices vary both geographically and based upon AIS subtype (139). Given the very real risk
of recurrence in pediatric AIS, future randomized, controlled treatment trials are needed to better
AC
understand which therapies are most effective.
Other disease specific treatments may be warranted depending on the etiology of pediatric AIS. In SCD,
exchange transfusion is frequently used to improve cerebral blood flow in the setting of acute AIS (140).
Chronic transfusion has been the standard of care for primary prevention, with a reported 92% risk
reduction for the occurrence of AIS (90). More recently, results from the Twitch trial have shown that
hydroxyurea offers comparable efficacy and may be more easily accessible to patients (141).
ACCEPTED MANUSCRIPT
Moyamoya disease and syndrome are amenable to surgical revascularization, a procedure that is well
tolerated and effective in preventing recurrent AIS (64). Other approaches to treatment of AIS are
available and variably used such as steroids, but these have not been well studied in terms of safety and
efficacy. Novel modalities of treatment such as transcranial magnetic stimulation (TMS) are also
increasingly being investigated and incorporated into managing the recovery phase after pediatric AIS
(142).
T
IP
CR
Outcomes After Pediatric Stroke
US
Significant neurologic deficits (i.e. moderate to severe impairment) have been reported in 31-51% of
patients with childhood AIS (143-146), while no neurological deficits were observed in 25-41% of these
AN
children (3, 143, 145, 147, 148). Rates of hemiparesis in childhood AIS fall between 55-62% of patients
M
(149). With respect to cognition, overall intellectual functioning in patients with childhood AIS
generally falls within the average range; however, the mean score for this group falls significantly below
ED
the normative sample (148, 150). Some research has suggested that childhood AIS patients tend to
PT
exhibit higher verbal intellectual abilities than performance/nonverbal intellectual abilities (144).
Pavlovic and colleagues interestingly found better cognitive functioning following childhood AIS when
CE
the stroke occurred during the school-aged years compared to toddlerhood and adolescence (144).
AC
Studies have also indicated that childhood AIS patients have poorer performance compared to the
normative sample on tasks of working memory (144, 145, 150), processing speed (148, 150), visual-
spatial/visual-constructional skills (144, 145), inhibitory control (150), and problem solving (147).
Additionally, these children exhibit impairments in language, facial memory, and attention measures
compared to controls (151). Furthermore, 27-33% of patients with childhood AIS receive academic
instruction within a special education classroom (144, 147). In terms of psychological functioning, up to
60% of childhood AIS patients experience emotional or behavioral difficulties (143), although only 15%
ACCEPTED MANUSCRIPT
meet diagnostic criteria for a psychiatric disorder (143). In general, parents of childhood AIS patients
report a greater number of problems with respect to their child’s quality of life compared to parents of
healthy children (143). Of these parents, approximately 18% rated their child as having poor quality of
life overall (152). Predictors of outcome are desperately sought to help with early prognosis, but remain
very limited. Larger infarct volumes (3, 150, 153) and neuroimaging abnormalities, such as the presence
of arteriopathy (3, 139), have been associated with poorer outcomes for these children. Future studies
T
IP
will hopefully provide new strategies for improved prediction of recovery.
CR
Studies have demonstrated that poor neurological outcomes (i.e. moderate to severe impairment) are
present in 37-62% of children with perinatal AIS (144, 146, 151, 154); however, up to a third of these
US
children do not exhibit any neurological impairment (155). Hemiparesis has been reported in upwards of
AN
58% within this population (11, 156, 157). In terms of early development, children with perinatal AIS
display lower developmental quotients on standardized testing compared to the normative sample (144),
M
with 31-41% demonstrating delayed developmental performance (11, 155). Westmacott et al. found that
ED
preschoolers with a history of perinatal AIS do not display evidence of cognitive impairment when
measured by IQ; however, by school age, children with perinatal AIS demonstrate lower intellectual
PT
functioning than the normative sample, thus clinicians and parents must recognize the potential for late
CE
emergence of neurologic deficits in these children (158, 159). Moreover, research has indicated that
children with perinatal AIS experience difficulties with various measures of language, facial memory,
AC
and attention compared to controls (151) and exhibit lower visual-motor integration, visual-spatial, and
visual-constructional skills compared to the normative sample (151, 159). Quality of life overall is
reportedly poor in 8% of these children based on parental report (152). Outcomes following perinatal
AIS appear to be negatively impacted by a number of different factors, particularly the presence of
epilepsy (144, 151, 159). Following presumed perinatal AIS, 92-95% of children are hemiparetic (157,
160), and 91-96% of these children are diagnosed with cerebral palsy (161, 162). Studies have found
ACCEPTED MANUSCRIPT
that cognitive impairment occurs in 42-52% of children with presumed perinatal AIS (160, 161) and
approximately 50% of these children have a speech delay (160). Furthermore, approximately 17% of
children with presumed perinatal AIS exhibit behavioral difficulties (160). While on the surface it
appears that children with presumed perinatal AIS have worse outcomes, we must consider the selection
bias inherent in these studies because only patients with some sort of neurologic problem get the
imaging necessary for diagnosis.
T
IP
CR
The Future of Pediatric AIS
US
The burgeoning field of pediatric stroke has realized remarkable advances over the past decade, but
clearly many unanswered questions persist. Patients will continue to benefit from the ongoing work of
AN
collaborative multicenter groups studying this rare but costly disease. The importance of time and
M
recognition of AIS in children cannot be overemphasized. These factors are well recognized in adult
AIS, and benchmarks are constantly evolving to improve the efficiency with which these patients are
ED
identified and treated. Additionally, while the acute phase of AIS is often a primary focus of treatment,
PT
the recovery phase is just as critically important and deserves further attention and study. This is best
achieved through a multidisciplinary team approach with the capability of following patients
CE
longitudinally from the time they present throughout long-term follow up. These principles have begun
AC
to develop with the emerging concept of a primary pediatric stroke center (163). Improvements in
systems of care and standardized care pathways, larger scale studies of treatment strategies, and novel
technologies in neuroimaging and neurorehabilitation will lead to better understanding of the
pathophysiology of pediatric AIS and allow us to achieve better outcomes for these children.
ACCEPTED MANUSCRIPT
1. Rafay MF, Pontigon AM, Chiang J, Adams M, Jarvis DA, Silver F, Macgregor D, Deveber GA. Delay to
diagnosis in acute pediatric arterial ischemic stroke. Stroke; a journal of cerebral circulation. 2009;40(1):58-64.
doi: 10.1161/STROKEAHA.108.519066. PubMed PMID: 18802206.
2. Gabis LV, Yangala R, Lenn NJ. Time Lag to Diagnosis of Stroke in Children. Pediatrics.
2002;110(5):924-8. doi: 10.1542/peds.110.5.924.
3. Lynch JK, Hirtz DG, DeVeber G, Nelson KB. Report of the National Institute of Neurological Disorders
T
and Stroke Workshop on Perinatal and Childhood Stroke. Pediatrics. 2002;109(1):116-23. doi:
IP
10.1542/peds.109.1.116.
CR
4. Kirton A, deVeber G. Advances in perinatal ischemic stroke. Pediatric neurology. 2009;40(3):205-14.
doi: 10.1016/j.pediatrneurol.2008.09.018. PubMed PMID: 19218034.
US
5. Agrawal N, Johnston SC, Wu YW, Sidney S, Fullerton HJ. Imaging data reveal a higher pediatric stroke
incidence than prior US estimates. Stroke; a journal of cerebral circulation. 2009;40(11):3415-21. doi:
AN
10.1161/STROKEAHA.109.564633. PubMed PMID: 19762687; PMCID: PMC3387270.
M
6. Fullerton HJ, Wu YW, Zhao S, Johnston SC. Risk of stroke in children: ethnic and gender disparities.
Neurology. 2003;61(2):189-94. PubMed PMID: 12874397.

ED
7. Giroud M, Lemesle M, Gouyon JB, Nivelon JL, Milan C, Dumas R. Cerebrovascular disease in children
under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993. J
PT
Clin Epidemiol. 1995;48(11):1343-8. PubMed PMID: 7490597.

CE
8. Kleindorfer D, Khoury J, Kissela B, Alwell K, Woo D, Miller R, Schneider A, Moomaw C, Broderick JP.
Temporal trends in the incidence and case fatality of stroke in children and adolescents. Journal of child
AC
neurology. 2006;21(5):415-8. PubMed PMID: 16901448.
9. Raju TN, Nelson KB, Ferriero D, Lynch JK, Participants N-NPSW. Ischemic perinatal stroke: summary
of a workshop sponsored by the National Institute of Child Health and Human Development and the National
Institute of Neurological Disorders and Stroke. Pediatrics. 2007;120(3):609-16. doi: 10.1542/peds.2007-0336.
PubMed PMID: 17766535.
10. Lynch JK, Nelson KB. Epidemiology of perinatal stroke. Curr Opin Pediatr. 2001;13(6):499-505.

ACCEPTED MANUSCRIPT
11. Grunt S, Mazenauer L, Buerki SE, Boltshauser E, Mori AC, Datta AN, Fluss J, Mercati D, Keller E,
Maier O, Poloni C, Ramelli GP, Schmitt-Mechelke T, Steinlin M. Incidence and outcomes of symptomatic
neonatal arterial ischemic stroke. Pediatrics. 2015;135(5):e1220-8. doi: 10.1542/peds.2014-1520. PubMed PMID:
25896840.
12. Ellis C, McGrattan K, Mauldin P, Ovbiagele B. Costs of pediatric stroke care in the United States: a
systematic and contemporary review. Expert Rev Pharmacoecon Outcomes Res. 2014;14(5):643-50. doi:
T
10.1586/14737167.2014.933672. PubMed PMID: 24970735.
IP
13. Bernard TJ, Manco-Johnson MJ, Lo W, MacKay MT, Ganesan V, DeVeber G, Goldenberg NA,
CR
Armstrong-Wells J, Dowling MM, Roach ES, Tripputi M, Fullerton HJ, Furie KL, Benseler SM, Jordan LC,
Kirton A, Ichord R. Towards a consensus-based classification of childhood arterial ischemic stroke. Stroke; a
US
journal of cerebral circulation. 2012;43(2):371-7. doi: 10.1161/STROKEAHA.111.624585. PubMed PMID:
22156694; PMCID: 3312781.

AN
14. Bernard TJ, Beslow LA, Manco-Johnson MJ, Armstrong-Wells J, Boada R, Weitzenkamp D, Hollatz A,
M
Poisson S, Amlie-Lefond C, Lo W, deVeber G, Goldenberg NA, Dowling MM, Roach ES, Fullerton HJ, Benseler
SM, Jordan LC, Kirton A, Ichord RN. Inter-Rater Reliability of the CASCADE Criteria: Challenges in
ED
Classifying Arteriopathies. Stroke; a journal of cerebral circulation. 2016;47(10):2443-9. doi:
10.1161/STROKEAHA.116.013544. PubMed PMID: 27633024.

PT
15. Mackay MT, Wiznitzer M, Benedict SL, Lee KJ, Deveber GA, Ganesan V, International Pediatric Stroke
CE
Study G. Arterial ischemic stroke risk factors: the International Pediatric Stroke Study. Annals of neurology.
2011;69(1):130-40. doi: 10.1002/ana.22224. PubMed PMID: 21280083.

AC
16. Lanthier S, Carmant L, David M, Larbrisseau A, de Veber G. Stroke in children: the coexistence of
multiple risk factors predicts poor outcome. Neurology. 2000;54(2):371-8. PubMed PMID: 10668698.
17. Lehman LL, Rivkin MJ. Perinatal arterial ischemic stroke: presentation, risk factors, evaluation, and
outcome. Pediatric neurology. 2014;51(6):760-8. doi: 10.1016/j.pediatrneurol.2014.07.031. PubMed PMID:
25444092.
18. Nelson KB. Perinatal ischemic stroke. Stroke; a journal of cerebral circulation. 2007;38(2 Suppl):742-5.
doi: 10.1161/01.STR.0000247921.97794.5e. PubMed PMID: 17261729.

ACCEPTED MANUSCRIPT
19. Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114(5-6):409-14. doi:
10.1016/j.thromres.2004.08.004. PubMed PMID: 15507271.
20. Martinez-Biarge M, Cheong JL, Diez-Sebastian J, Mercuri E, Dubowitz LM, Cowan FM. Risk Factors
for Neonatal Arterial Ischemic Stroke: The Importance of the Intrapartum Period. The Journal of pediatrics.
2016;173:62-8 e1. doi: 10.1016/j.jpeds.2016.02.064. PubMed PMID: 27049002.
21. Chabrier S, Saliba E, Nguyen The Tich S, Charollais A, Varlet MN, Tardy B, Presles E, Renaud C, Allard
T
D, Husson B, Landrieu P. Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term
IP
newborns with symptomatic arterial ischemic stroke. European journal of paediatric neurology : EJPN : official
CR
journal of the European Paediatric Neurology Society. 2010;14(3):206-13. doi: 10.1016/j.ejpn.2009.05.004.
US
22. Ecury-Goossen GM, Raets MM, Lequin M, Feijen-Roon M, Govaert P, Dudink J. Risk factors, clinical
presentation, and neuroimaging findings of neonatal perforator stroke. Stroke; a journal of cerebral circulation.
AN
2013;44(8):2115-20. doi: 10.1161/STROKEAHA.113.001064. PubMed PMID: 23723310.
M
23. Lee J, Croen LA, Backstrand KH, Yoshida CK, Henning LH, Lindan C, Ferriero DM, Fullerton HJ,
Barkovich AJ, Wu YW. Maternal and infant characteristics associated with perinatal arterial stroke in the infant.
ED
JAMA. 2005;293(6):723-9. doi: 10.1001/jama.293.6.723. PubMed PMID: 15701914.
24. Harteman JC, Groenendaal F, Kwee A, Welsing PM, Benders MJ, de Vries LS. Risk factors for perinatal
PT
arterial ischaemic stroke in full-term infants: a case-control study. Archives of disease in childhood Fetal and
CE
neonatal edition. 2012;97(6):F411-6. doi: 10.1136/archdischild-2011-300973. PubMed PMID: 22445901.
25. Wu YW, March WM, Croen LA, Grether JK, Escobar GJ, Newman TB. Perinatal stroke in children with
AC
motor impairment: a population-based study. Pediatrics. 2004;114(3):612-9. doi: 10.1542/peds.2004-0385.
26. Elbers J, Viero S, MacGregor D, DeVeber G, Moore AM. Placental pathology in neonatal stroke.
Pediatrics. 2011;127(3):e722-9. doi: 10.1542/peds.2010-1490. PubMed PMID: 21339263.
27. Kraus FT. Fetal Thrombotic Vasculopathy: Perinatal Stroke, Growth Restriction, and Other Sequelae.
Surg Pathol Clin. 2013;6(1):87-100. doi: 10.1016/j.path.2012.10.001. PubMed PMID: 26838704.

ACCEPTED MANUSCRIPT
28. Kirton A, Armstrong-Wells J, Chang T, Deveber G, Rivkin MJ, Hernandez M, Carpenter J, Yager JY,
Lynch JK, Ferriero DM, International Pediatric Stroke Study I. Symptomatic neonatal arterial ischemic stroke: the
International Pediatric Stroke Study. Pediatrics. 2011;128(6):e1402-10. doi: 10.1542/peds.2011-1148. PubMed
PMID: 22123886.
29. McQuillen PS, Barkovich AJ, Hamrick SE, Perez M, Ward P, Glidden DV, Azakie A, Karl T, Miller SP.
Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke; a
T
journal of cerebral circulation. 2007;38(2 Suppl):736-41. doi: 10.1161/01.STR.0000247941.41234.90. PubMed
IP
PMID: 17261728.
CR
30. Chen J, Zimmerman RA, Jarvik GP, Nord AS, Clancy RR, Wernovsky G, Montenegro LM, Hartman
DM, Nicolson SC, Spray TL, Gaynor JW, Ichord R. Perioperative stroke in infants undergoing open heart
US
operations for congenital heart disease. The Annals of thoracic surgery. 2009;88(3):823-9. doi:
10.1016/j.athoracsur.2009.03.030. PubMed PMID: 19699905; PMCID: PMC2840405.

AN
31. Werho DK, Pasquali SK, Yu S, Donohue J, Annich GM, Thiagarajan RR, Hirsch-Romano JC, Gaies M,
M
Centers EM. Epidemiology of Stroke in Pediatric Cardiac Surgical Patients Supported With Extracorporeal
Membrane Oxygenation. The Annals of thoracic surgery. 2015;100(5):1751-7. doi:

ED
10.1016/j.athoracsur.2015.06.020. PubMed PMID: 26298170; PMCID: PMC4630110.
32. Pysden K, Fallon P, Moorthy B, Ganesan V. Presumed perinatal stroke in a child with Down syndrome
PT
and moyamoya disease. Developmental medicine and child neurology. 2010;52(2):212-4. doi: 10.1111/j.1469-
CE
8749.2009.03377.x. PubMed PMID: 19583743.
33. Lequin MH, Peeters EA, Holscher HC, de Krijger R, Govaert P. Arterial infarction caused by carotid
AC
artery dissection in the neonate. European journal of paediatric neurology : EJPN : official journal of the
European Paediatric Neurology Society. 2004;8(3):155-60. doi: 10.1016/j.ejpn.2004.02.001. PubMed PMID:
15120687.
34. Fluss J, Garcia-Tarodo S, Granier M, Villega F, Ferey S, Husson B, Kossorotoff M, Muehlethaler V,
Lebon S, Chabrier S. Perinatal arterial ischemic stroke related to carotid artery occlusion. European journal of
paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2016;20(4):639-48.
doi: 10.1016/j.ejpn.2016.03.003. PubMed PMID: 27025300.

ACCEPTED MANUSCRIPT
35. Govaert P. Neonatal brain arteriopathies. Developmental medicine and child neurology. 2010;52(2):117-
8. doi: 10.1111/j.1469-8749.2009.03472.x. PubMed PMID: 20412251.
36. Curry CJ, Bhullar S, Holmes J, Delozier CD, Roeder ER, Hutchison HT. Risk factors for perinatal arterial
stroke: a study of 60 mother-child pairs. Pediatric neurology. 2007;37(2):99-107. doi:
10.1016/j.pediatrneurol.2007.04.007. PubMed PMID: 17675024.
37. Simchen MJ, Goldstein G, Lubetsky A, Strauss T, Schiff E, Kenet G. Factor v Leiden and
T
antiphospholipid antibodies in either mothers or infants increase the risk for perinatal arterial ischemic stroke.
IP
Stroke; a journal of cerebral circulation. 2009;40(1):65-70. doi: 10.1161/STROKEAHA.108.527283. PubMed
CR
PMID: 18927445.
38. Pogliani L, Cerini C, Penagini F, Duca P, Mameli C, Zuccotti GV. Cerebral ultrasound abnormalities in
US
offsprings of women with C677T homozygous mutation in the MTHFR gene: a prospective study. World J
Pediatr. 2015;11(2):134-40. doi: 10.1007/s12519-014-0490-0. PubMed PMID: 24974211.

AN
39. Gunther G, Junker R, Strater R, Schobess R, Kurnik K, Heller C, Kosch A, Nowak-Gottl U, Childhood
M
Stroke Study G. Symptomatic ischemic stroke in full-term neonates : role of acquired and genetic prothrombotic
risk factors. Stroke; a journal of cerebral circulation. 2000;31(10):2437-41. PubMed PMID: 11022077.
ED
40. Kocak O, Yarar C, Turhan AB, Akay OM, Carman KB, Yakut A. Evaluation of hypercoagulability state
in perinatal arterial ischemic stroke with rotation thromboelastometry. Child's nervous system : ChNS : official
PT
journal of the International Society for Pediatric Neurosurgery. 2016. doi: 10.1007/s00381-016-3213-0. PubMed
CE
PMID: 27514779.
41. Rodan L, McCrindle BW, Manlhiot C, MacGregor DL, Askalan R, Moharir M, deVeber G. Stroke
AC
recurrence in children with congenital heart disease. Annals of neurology. 2012;72(1):103-11. doi:
10.1002/ana.23574. PubMed PMID: 22829272.
42. Kurnik K, Kosch A, Strater R, Schobess R, Heller C, Nowak-Gottl U, Childhood Stroke Study G.
Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a
prospective follow-up study. Stroke; a journal of cerebral circulation. 2003;34(12):2887-92. doi:
10.1161/01.STR.0000103745.03393.39. PubMed PMID: 14631084.

ACCEPTED MANUSCRIPT
43. Del Balzo F, Spalice A, Perla M, Properzi E, Iannetti P. MTHFR homozygous mutation and additional
risk factors for cerebral infarction in a large Italian family. Pediatric neurology. 2009;40(1):63-7. doi:
10.1016/j.pediatrneurol.2008.09.023. PubMed PMID: 19068258.
44. Ganesan V, Prengler M, McShane MA, Wade AM, Kirkham FJ. Investigation of risk factors in children
with arterial ischemic stroke. Annals of neurology. 2003;53(2):167-73. doi: 10.1002/ana.10423. PubMed PMID:
12557282.
T
45. Wintermark M, Hills NK, deVeber GA, Barkovich AJ, Elkind MS, Sear K, Zhu G, Leiva-Salinas C, Hou
IP
Q, Dowling MM, Bernard TJ, Friedman NR, Ichord RN, Fullerton HJ, Investigators V. Arteriopathy diagnosis in
CR
childhood arterial ischemic stroke: results of the vascular effects of infection in pediatric stroke study. Stroke; a
US
25388419; PMCID: 4260818.
46. Sebire G, Fullerton H, Riou E, deVeber G. Toward the definition of cerebral arteriopathies of childhood.
AN
Curr Opin Pediatr. 2004;16(6):617-22. PubMed PMID: 15548922.
M
47. Daniels SR, Bates S, Lukin RR, Benton C, Third J, Glueck CJ. Cerebrovascular arteriopathy
(arteriosclerosis) and ischemic childhood stroke. Stroke; a journal of cerebral circulation. 1982;13(3):360-5.
ED
48. Chabrier S, Rodesch G, Lasjaunias P, Tardieu M, Landrieu P, Sebire G. Transient cerebral arteriopathy: a
PT
disorder recognized by serial angiograms in children with stroke. Journal of child neurology. 1998;13(1):27-32.
CE
49. Dlamini N, Freeman JL, Mackay MT, Hawkins C, Shroff M, Fullerton HJ, Deveber GA. Intracranial
AC
dissection mimicking transient cerebral arteriopathy in childhood arterial ischemic stroke. Journal of child
neurology. 2011;26(9):1203-6. doi: 10.1177/0883073811408904. PubMed PMID: 21743063.
50. Lanthier S, Armstrong D, Domi T, deVeber G. Post-varicella arteriopathy of childhood: natural history of
vascular stenosis. Neurology. 2005;64(4):660-3. doi: 10.1212/01.WNL.0000151851.66154.27. PubMed PMID:
15728288.
51. Elkind MS, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, Kneen R, Hod EA, Wintermark
M, deVeber GA, Fullerton HJ, Investigators* V. Herpesvirus Infections and Childhood Arterial Ischemic Stroke:
ACCEPTED MANUSCRIPT
Results of the VIPS Study. Circulation. 2016;133(8):732-41. doi: 10.1161/CIRCULATIONAHA.115.018595.
PubMed PMID: 26813104; PMCID: PMC4766042.
52. Hills NK, Johnston SC, Sidney S, Zielinski BA, Fullerton HJ. Recent trauma and acute infection as risk
factors for childhood arterial ischemic stroke. Annals of neurology. 2012;72(6):850-8. doi: 10.1002/ana.23688.
53. Hills NK, Sidney S, Fullerton HJ. Timing and number of minor infections as risk factors for childhood
T
arterial ischemic stroke. Neurology. 2014;83(10):890-7. doi: 10.1212/WNL.0000000000000752. PubMed PMID:
IP
25142897; PMCID: PMC4153847.
CR
54. Fullerton HJ, Hills NK, Elkind MS, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ,
Titomanlio L, Barkovich AJ, deVeber GA, Investigators V. Infection, vaccination, and childhood arterial
US
ischemic stroke: Results of the VIPS study. Neurology. 2015;85(17):1459-66. doi:
10.1212/WNL.0000000000002065. PubMed PMID: 26423434; PMCID: PMC4631070.

AN
55. Tan MA, DeVeber G, Kirton A, Vidarsson L, MacGregor D, Shroff M. Low detection rate of
M
craniocervical arterial dissection in children using time-of-flight magnetic resonance angiography: causes and
strategies to improve diagnosis. Journal of child neurology. 2009;24(10):1250-7. doi:

ED
10.1177/0883073809333539. PubMed PMID: 19351813.
56. Stence NV, Fenton LZ, Goldenberg NA, Armstrong-Wells J, Bernard TJ. Craniocervical arterial
PT
dissection in children: diagnosis and treatment. Current treatment options in neurology. 2011;13(6):636-48. doi:
CE
10.1007/s11940-011-0149-2. PubMed PMID: 21979145; PMCID: PMC3297486.
57. Fullerton HJ, Johnston SC, Smith WS. Arterial dissection and stroke in children. Neurology.
AC
2001;57(7):1155-60. PubMed PMID: 11601431.
58. Rafay MF, Armstrong D, Deveber G, Domi T, Chan A, MacGregor DL. Craniocervical arterial dissection
in children: clinical and radiographic presentation and outcome. Journal of child neurology. 2006;21(1):8-16.
59. Kim ST, Brinjikji W, Lanzino G, Kallmes DF. Neurovascular manifestations of connective-tissue
diseases: A review. Interv Neuroradiol. 2016. doi: 10.1177/1591019916659262. PubMed PMID: 27511817.
ACCEPTED MANUSCRIPT
60. Kirton A, Crone M, Benseler S, Mineyko A, Armstrong D, Wade A, Sebire G, Crous-Tsanaclis AM,
deVeber G. Fibromuscular dysplasia and childhood stroke. Brain : a journal of neurology. 2013;136(Pt 6):1846-
56. doi: 10.1093/brain/awt111. PubMed PMID: 23715093.
61. Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal net-like vessels in
base of brain. Archives of neurology. 1969;20(3):288-99. PubMed PMID: 5775283.
62. Bang OY, Fujimura M, Kim SK. The Pathophysiology of Moyamoya Disease: An Update. J Stroke.
T
2016;18(1):12-20. doi: 10.5853/jos.2015.01760. PubMed PMID: 26846756; PMCID: PMC4747070.
IP
63. Fujimura M, Sonobe S, Nishijima Y, Niizuma K, Sakata H, Kure S, Tominaga T. Genetics and
CR
Biomarkers of Moyamoya Disease: Significance of RNF213 as a Susceptibility Gene. J Stroke. 2014;16(2):65-72.
doi: 10.5853/jos.2014.16.2.65. PubMed PMID: 24949311; PMCID: PMC4060268.
US
64. Smith ER, Scott RM. Spontaneous occlusion of the circle of Willis in children: pediatric moyamoya
summary with proposed evidence-based practice guidelines. A review. J Neurosurg Pediatr. 2012;9(4):353-60.
AN
doi: 10.3171/2011.12.PEDS1172. PubMed PMID: 22462697.
M
65. Fullerton HJ, Wintermark M, Hills NK, Dowling MM, Tan M, Rafay MF, Elkind MS, Barkovich AJ,
deVeber GA, Investigators V. Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective
ED
International Study. Stroke; a journal of cerebral circulation. 2016;47(1):53-9. doi:

PT
66. Strater R, Becker S, von Eckardstein A, Heinecke A, Gutsche S, Junker R, Kurnik K, Schobess R,
CE
Nowak-Gottl U. Prospective assessment of risk factors for recurrent stroke during childhood--a 5-year follow-up
study. Lancet. 2002;360(9345):1540-5. doi: 10.1016/S0140-6736(02)11520-0. PubMed PMID: 12443591.

AC
67. Fullerton HJ, Wu YW, Sidney S, Johnston SC. Risk of recurrent childhood arterial ischemic stroke in a
population-based cohort: the importance of cerebrovascular imaging. Pediatrics. 2007;119(3):495-501. doi:
10.1542/peds.2006-2791. PubMed PMID: 17332202.
68. Bernard TJ, Fenton LZ, Apkon SD, Boada R, Wilkening GN, Wilkinson CC, Soep JB, Miyamoto SD,
Tripputi M, Armstrong-Wells J, Benke TA, Manco-Johnson MJ, Goldenberg NA. Biomarkers of
hypercoagulability and inflammation in childhood-onset arterial ischemic stroke. The Journal of pediatrics.
2010;156(4):651-6. doi: 10.1016/j.jpeds.2009.10.034. PubMed PMID: 20022340.

ACCEPTED MANUSCRIPT
69. Goldenberg NA, Everett AD, Graham D, Bernard TJ, Nowak-Gottl U. Proteomic and other mass
spectrometry based "omics" biomarker discovery and validation in pediatric venous thromboembolism and
arterial ischemic stroke: current state, unmet needs, and future directions. Proteomics Clin Appl. 2014;8(11-
12):828-36. doi: 10.1002/prca.201400062. PubMed PMID: 25379629.
70. Fullerton HJ, deVeber GA, Hills NK, Dowling MM, Fox CK, Mackay MT, Kirton A, Yager JY, Bernard
TJ, Hod EA, Wintermark M, Elkind MS, Investigators V. Inflammatory Biomarkers in Childhood Arterial
T
Ischemic Stroke: Correlates of Stroke Cause and Recurrence. Stroke; a journal of cerebral circulation.
IP
CR
71. Eleftheriou D, Ganesan V, Hong Y, Klein NJ, Brogan PA. Endothelial Repair in Childhood Arterial
Ischaemic Stroke with Cerebral Arteriopathy. Cerebrovasc Dis Extra. 2015;5(2):68-74. doi: 10.1159/000381963.
US
72. Goldenberg NA, Jenkins S, Jack J, Armstrong-Wells J, Fenton LZ, Stence NV, Oleszek J, Boada R,
AN
Wilkening GN, Wilkinson C, Soep JB, Miyamoto SD, Bajaj L, Mourani PM, Manco-Johnson MJ, Bernard TJ.
M
Arteriopathy, D-dimer, and risk of poor neurologic outcome in childhood-onset arterial ischemic stroke. The
Journal of pediatrics. 2013;162(5):1041-6 e1. doi: 10.1016/j.jpeds.2012.11.035. PubMed PMID: 23260102;

ED
PMCID: PMC4115645.
73. Barnes C, Newall F, Furmedge J, Mackay M, Monagle P. Arterial ischaemic stroke in children. J Paediatr
PT
Child Health. 2004;40(7):384-7. doi: 10.1111/j.1440-1754.2004.00407.x. PubMed PMID: 15228568.

CE
74. Deng Y, Wang Y, Yang W, Yu Y, Xu J, Wang Y, Gao B. Risk factors and imaging characteristics of
childhood stroke in china. Journal of child neurology. 2015;30(3):339-43. doi: 10.1177/0883073814538667.

AC
75. Lee YY, Lin KL, Wang HS, Chou ML, Hung PC, Hsieh MY, Lin JJ, Wong AM. Risk factors and
outcomes of childhood ischemic stroke in Taiwan. Brain & development. 2008;30(1):14-9. doi:
10.1016/j.braindev.2007.05.002. PubMed PMID: 17573220.
76. Lo W, Stephens J, Fernandez S. Pediatric stroke in the United States and the impact of risk factors.
Journal of child neurology. 2009;24(2):194-203. doi: 10.1177/0883073808322665. PubMed PMID: 19182157;
PMCID: PMC3720133.
ACCEPTED MANUSCRIPT
77. Mallick AA, Ganesan V, Kirkham FJ, Fallon P, Hedderly T, McShane T, Parker AP, Wassmer E, Wraige
E, Amin S, Edwards HB, Tilling K, O'Callaghan FJ. Childhood arterial ischaemic stroke incidence, presenting
features, and risk factors: a prospective population-based study. Lancet Neurol. 2014;13(1):35-43. doi:
10.1016/S1474-4422(13)70290-4. PubMed PMID: 24304598.
78. Per H, Unal E, Poyrazoglu HG, Ozdemir MA, Donmez H, Gumus H, Uzum K, Canpolat M, Akyildiz BN,
Coskun A, Kurtsoy A, Kumandas S. Childhood stroke: results of 130 children from a reference center in Central
T
Anatolia, Turkey. Pediatric neurology. 2014;50(6):595-600. doi: 10.1016/j.pediatrneurol.2013.12.023. PubMed
IP
PMID: 24842257.
CR
79. Hoffman JL, Mack GK, Minich LL, Benedict SL, Heywood M, Stoddard GJ, Saarel EV. Failure to
impact prevalence of arterial ischemic stroke in pediatric cardiac patients over three decades. Congenit Heart Dis.
US
2011;6(3):211-8. doi: 10.1111/j.1747-0803.2011.00510.x. PubMed PMID: 21450034.
80. Fox CK, Sidney S, Fullerton HJ. Community-based case-control study of childhood stroke risk associated
AN
with congenital heart disease. Stroke; a journal of cerebral circulation. 2015;46(2):336-40. doi:
M
81. Dowling MM, Hynan LS, Lo W, Licht DJ, McClure C, Yager JY, Dlamini N, Kirkham FJ, Deveber G,
ED
Pavlakis S, International Paediatric Stroke Study G. International Paediatric Stroke Study: stroke associated with
cardiac disorders. International journal of stroke : official journal of the International Stroke Society. 2013;8
PT
Suppl A100:39-44. doi: 10.1111/j.1747-4949.2012.00925.x. PubMed PMID: 23231361; PMCID: PMC4940849.

CE
82. Benedik MP, Zaletel M, Meglic NP, Podnar T. A right-to-left shunt in children with arterial ischaemic
stroke. Archives of disease in childhood. 2011;96(5):461-7. doi: 10.1136/adc.2010.203992. PubMed PMID:

AC
21377993.
83. Khan R, Chan AK, Mondal TK, Paes BA, Thrombosis, Hemostasis in Newborns G. Patent foramen ovale
and stroke in childhood: A systematic review of the literature. European journal of paediatric neurology : EJPN :
official journal of the European Paediatric Neurology Society. 2016;20(4):500-11. doi:
10.1016/j.ejpn.2016.04.012. PubMed PMID: 27169856.

ACCEPTED MANUSCRIPT
84. Barker PC, Nowak C, King K, Mosca RS, Bove EL, Goldberg CS. Risk factors for cerebrovascular
events following fontan palliation in patients with a functional single ventricle. Am J Cardiol. 2005;96(4):587-91.
doi: 10.1016/j.amjcard.2005.04.025. PubMed PMID: 16098317.
85. Anderson PA, Breitbart RE, McCrindle BW, Sleeper LA, Atz AM, Hsu DT, Lu M, Margossian R,
Williams RV. The Fontan patient: inconsistencies in medication therapy across seven pediatric heart network
centers. Pediatric cardiology. 2010;31(8):1219-28. doi: 10.1007/s00246-010-9807-5. PubMed PMID: 20938655;
T
PMCID: PMC3050513.
IP
86. Mahnke CB, Boyle GJ, Janosky JE, Siewers RD, Pigula FA. Anticoagulation and incidence of late
CR
cerebrovascular accidents following the Fontan procedure. Pediatric cardiology. 2005;26(1):56-61. doi:
10.1007/s00246-003-0684-z. PubMed PMID: 14994183.
US
87. Chun DS, Schamberger MS, Flaspohler T, Turrentine MW, Brown JW, Farrell AG, Girod DA. Incidence,
outcome, and risk factors for stroke after the Fontan procedure. Am J Cardiol. 2004;93(1):117-9. PubMed PMID:
AN
14697484.
M
88. Earley CJ, Kittner SJ, Feeser BR, Gardner J, Epstein A, Wozniak MA, Wityk R, Stern BJ, Price TR,
Macko RF, Johnson C, Sloan MA, Buchholz D. Stroke in children and sickle-cell disease: Baltimore-Washington
ED
Cooperative Young Stroke Study. Neurology. 1998;51(1):169-76. PubMed PMID: 9674798.
89. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, Wethers DL, Pegelow
PT
CH, Gill FM. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288-94.
CE
90. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A,
AC
Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell
anemia and abnormal results on transcranial Doppler ultrasonography. The New England journal of medicine.
1998;339(1):5-11. doi: 10.1056/NEJM199807023390102. PubMed PMID: 9647873.
91. Armstrong-Wells J, Grimes B, Sidney S, Kronish D, Shiboski SC, Adams RJ, Fullerton HJ. Utilization of
TCD screening for primary stroke prevention in children with sickle cell disease. Neurology. 2009;72(15):1316-
21. doi: 10.1212/WNL.0b013e3181a110da. PubMed PMID: 19365052.

ACCEPTED MANUSCRIPT
92. DeBaun MR, Kirkham FJ. Central nervous system complications and management in sickle cell disease.
Blood. 2016;127(7):829-38. doi: 10.1182/blood-2015-09-618579. PubMed PMID: 26758917.
93. Abboud MR, Cure J, Granger S, Gallagher D, Hsu L, Wang W, Woods G, Berman B, Brambilla D,
Pegelow C, Lewin J, Zimmermann RA, Adams RJ, study S. Magnetic resonance angiography in children with
sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study.
Blood. 2004;103(7):2822-6. doi: 10.1182/blood-2003-06-1972. PubMed PMID: 14684415.
T
94. Adams RJ, Nichols FT, Figueroa R, McKie V, Lott T. Transcranial Doppler correlation with cerebral
IP
angiography in sickle cell disease. Stroke; a journal of cerebral circulation. 1992;23(8):1073-7. PubMed PMID:
CR
1636180.
95. Helton KJ, Adams RJ, Kesler KL, Lockhart A, Aygun B, Driscoll C, Heeney MM, Jackson SM,
US
Krishnamurti L, Miller ST, Sarnaik SA, Schultz WH, Ware RE, Investigators SW. Magnetic resonance
imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial.
AN
Blood. 2014;124(6):891-8. doi: 10.1182/blood-2013-12-545186. PubMed PMID: 24914136; PMCID:
M
PMC4126329.
96. Miller ST, Macklin EA, Pegelow CH, Kinney TR, Sleeper LA, Bello JA, DeWitt LD, Gallagher DM,
ED
Guarini L, Moser FG, Ohene-Frempong K, Sanchez N, Vichinsky EP, Wang WC, Wethers DL, Younkin DP,
Zimmerman RA, DeBaun MR, Cooperative Study of Sickle Cell D. Silent infarction as a risk factor for overt
PT
stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease. The Journal
CE
of pediatrics. 2001;139(3):385-90. doi: 10.1067/mpd.2001.117580. PubMed PMID: 11562618.
97. Cancio MI, Helton KJ, Schreiber JE, Smeltzer MP, Kang G, Wang WC. Silent cerebral infarcts in very
AC
young children with sickle cell anaemia are associated with a higher risk of stroke. Br J Haematol.
2015;171(1):120-9. doi: 10.1111/bjh.13525. PubMed PMID: 26058476.
98. DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, Meier ER, Howard TH,
Majumdar S, Inusa BP, Telfer PT, Kirby-Allen M, McCavit TL, Kamdem A, Airewele G, Woods GM, Berman B,
Panepinto JA, Fuh BR, Kwiatkowski JL, King AA, Fixler JM, Rhodes MM, Thompson AA, Heiny ME, Redding-
Lallinger RC, Kirkham FJ, Dixon N, Gonzalez CE, Kalinyak KA, Quinn CT, Strouse JJ, Miller JP, Lehmann H,
Kraut MA, Ball WS, Jr., Hirtz D, Casella JF. Controlled trial of transfusions for silent cerebral infarcts in sickle
ACCEPTED MANUSCRIPT
cell anemia. The New England journal of medicine. 2014;371(8):699-710. doi: 10.1056/NEJMoa1401731.
99. Dowling MM, Quinn CT, Plumb P, Rogers ZR, Rollins NK, Koral K, Buchanan GR. Acute silent
cerebral ischemia and infarction during acute anemia in children with and without sickle cell disease. Blood.
2012;120(19):3891-7. doi: 10.1182/blood-2012-01-406314. PubMed PMID: 22948048; PMCID: PMC3496951.
100. Quinn CT, McKinstry RC, Dowling MM, Ball WS, Kraut MA, Casella JF, Dlamini N, Ichord RN, Jordan
T
LC, Kirkham FJ, Noetzel MJ, Roach ES, Strouse JJ, Kwiatkowski JL, Hirtz D, DeBaun MR. Acute silent cerebral
IP
ischemic events in children with sickle cell anemia. JAMA neurology. 2013;70(1):58-65. doi:
CR
10.1001/jamaneurol.2013.576. PubMed PMID: 23108767; PMCID: PMC3677221.
101. Savage WJ, Everett AD, Casella JF. Plasma glial fibrillary acidic protein levels in a child with sickle cell
US
disease and stroke. Acta Haematol. 2011;125(3):103-6. doi: 10.1159/000321791. PubMed PMID: 21099215;
PMCID: PMC3202928.
AN
102. deVeber G, Monagle P, Chan A, MacGregor D, Curtis R, Lee S, Vegh P, Adams M, Marzinotto V,
M
Leaker M, Massicotte MP, Lillicrap D, Andrew M. Prothrombotic disorders in infants and children with cerebral
thromboembolism. Archives of neurology. 1998;55(12):1539-43. PubMed PMID: 9865798.

ED
103. Duran R, Biner B, Demir M, Celtik C, Karasalihoglu S. Factor V Leiden mutation and other
thrombophilia markers in childhood ischemic stroke. Clin Appl Thromb Hemost. 2005;11(1):83-8. PubMed
PT
PMID: 15678277.
CE
104. Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited
Thrombophilia in Ischemic Stroke and Its Pathogenic Subtypes. Stroke; a journal of cerebral circulation.
AC
2001;32(8):1793-9. doi: 10.1161/01.str.32.8.1793.
105. Haywood S, Liesner R, Pindora S, Ganesan V. Thrombophilia and first arterial ischaemic stroke: a
systematic review. Archives of disease in childhood. 2005;90(4):402-5. doi: 10.1136/adc.2004.049163. PubMed
PMID: 15781933; PMCID: PMC1720343.
106. Kenet G, Sadetzki S, Murad H, Martinowitz U, Rosenberg N, Gitel S, Rechavi G, Inbal A. Factor V
Leiden and antiphospholipid antibodies are significant risk factors for ischemic stroke in children. Stroke; a
journal of cerebral circulation. 2000;31(6):1283-8. PubMed PMID: 10835445.

ACCEPTED MANUSCRIPT
107. Nowak-Gottl U, Strater R, Heinecke A, Junker R, Koch HG, Schuierer G, von Eckardstein A. Lipoprotein
(a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are
risk factors of spontaneous ischemic stroke in childhood. Blood. 1999;94(11):3678-82. PubMed PMID:
10572079.
108. Strater R, Vielhaber H, Kassenbohmer R, von Kries R, Gobel U, Nowak-Gottl U. Genetic risk factors of
thrombophilia in ischaemic childhood stroke of cardiac origin. A prospective ESPED survey. Eur J Pediatr.
T
1999;158 Suppl 3:S122-5. PubMed PMID: 10650850.
IP
109. Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, Chabrier S, Chan A, deVeber G,
CR
Fiedler B, Fullerton HJ, Goldenberg NA, Grabowski E, Gunther G, Heller C, Holzhauer S, Iorio A, Journeycake
J, Junker R, Kirkham FJ, Kurnik K, Lynch JK, Male C, Manco-Johnson M, Mesters R, Monagle P, van Ommen
US
CH, Raffini L, Rostasy K, Simioni P, Strater RD, Young G, Nowak-Gottl U. Impact of thrombophilia on risk of
arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and
AN
meta-analysis of observational studies. Circulation. 2010;121(16):1838-47. doi:
M
10.1161/CIRCULATIONAHA.109.913673. PubMed PMID: 20385928.
110. Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?
ED
J Lipid Res. 2016;57(5):745-57. doi: 10.1194/jlr.R060582. PubMed PMID: 26647358; PMCID: PMC4847635.
111. Goldenberg NA, Bernard TJ, Hillhouse J, Armstrong-Wells J, Galinkin J, Knapp-Clevenger R, Jacobson
PT
L, Marcovina SM, Manco-Johnson MJ. Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial
CE
ischemic stroke in North American children. Haematologica. 2013;98(5):802-7. doi:
10.3324/haematol.2012.073833. PubMed PMID: 23349301; PMCID: 3640128.

AC
112. Mueller S, Fullerton HJ, Stratton K, Leisenring W, Weathers RE, Stovall M, Armstrong GT, Goldsby RE,
Packer RJ, Sklar CA, Bowers DC, Robison LL, Krull KR. Radiation, atherosclerotic risk factors, and stroke risk
in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol
Phys. 2013;86(4):649-55. doi: 10.1016/j.ijrobp.2013.03.034. PubMed PMID: 23680033; PMCID: PMC3696633.
113. Noje C, Cohen K, Jordan LC. Hemorrhagic and ischemic stroke in children with cancer. Pediatric
neurology. 2013;49(4):237-42. doi: 10.1016/j.pediatrneurol.2013.04.009. PubMed PMID: 23942224; PMCID:
PMC3783522.
ACCEPTED MANUSCRIPT
114. Packer RJ, Rorke LB, Lange BJ, Siegel KR, Evans AE. Cerebrovascular accidents in children with
cancer. Pediatrics. 1985;76(2):194-201. PubMed PMID: 3860796.
115. DiMario FJ, Jr., Packer RJ. Acute mental status changes in children with systemic cancer. Pediatrics.
1990;85(3):353-60. PubMed PMID: 2304789.
116. Kuskonmaz B, Unal S, Gumruk F, Cetin M, Tuncer AM, Gurgey A. The neurologic complications in
pediatric acute lymphoblastic leukemia patients excluding leukemic infiltration. Leuk Res. 2006;30(5):537-41.
T
doi: 10.1016/j.leukres.2005.09.009. PubMed PMID: 16249027.
IP
117. Tibussek D, Natesirinilkul R, Sun LR, Wasserman BA, Brandao LR, deVeber G. Severe Cerebral
CR
Vasospasm and Childhood Arterial Ischemic Stroke After Intrathecal Cytarabine. Pediatrics.
2016;137(2):e20152143. doi: 10.1542/peds.2015-2143. PubMed PMID: 26787046.
US
118. Vagace JM, de la Maya MD, Caceres-Marzal C, Gonzalez de Murillo S, Gervasini G. Central nervous
system chemotoxicity during treatment of pediatric acute lymphoblastic leukemia/lymphoma. Crit Rev Oncol
AN
Hematol. 2012;84(2):274-86. doi: 10.1016/j.critrevonc.2012.04.003. PubMed PMID: 22578745.
M
119. Bowers DC, Mulne AF, Reisch JS, Elterman RD, Munoz L, Booth T, Shapiro K, Doxey DL.
Nonperioperative strokes in children with central nervous system tumors. Cancer. 2002;94(4):1094-101. PubMed
ED
PMID: 11920480.
120. Campen CJ, Kranick SM, Kasner SE, Kessler SK, Zimmerman RA, Lustig R, Phillips PC, Storm PB,
PT
Smith SE, Ichord R, Fisher MJ. Cranial irradiation increases risk of stroke in pediatric brain tumor survivors.
CE
Stroke; a journal of cerebral circulation. 2012;43(11):3035-40. doi: 10.1161/STROKEAHA.112.661561. PubMed
PMID: 22968468; PMCID: PMC3492057.

AC
121. Fullerton HJ, Stratton K, Mueller S, Leisenring WW, Armstrong GT, Weathers RE, Stovall M, Sklar CA,
Goldsby RE, Robison LL, Krull KR. Recurrent stroke in childhood cancer survivors. Neurology.
2015;85(12):1056-64. doi: 10.1212/WNL.0000000000001951. PubMed PMID: 26311747; PMCID:
PMC4603599.
122. Bay MJ, Kossoff EH, Lehmann CU, Zabel TA, Comi AM. Survey of aspirin use in Sturge-Weber
syndrome. Journal of child neurology. 2011;26(6):692-702. doi: 10.1177/0883073810388646. PubMed PMID:
21427442.
ACCEPTED MANUSCRIPT
123. Meuwissen ME, Mancini GM. Neurological findings in incontinentia pigmenti; a review. Eur J Med
Genet. 2012;55(5):323-31. doi: 10.1016/j.ejmg.2012.04.007. PubMed PMID: 22564885.
124. Siegel DH, Tefft KA, Kelly T, Johnson C, Metry D, Burrows P, Pope E, Cordisco M, Holland KE,
Maheshwari M, Keith P, Garzon M, Hess C, Frieden IJ, Fullerton HJ, Drolet BA. Stroke in children with posterior
fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye
abnormalities (PHACE) syndrome: a systematic review of the literature. Stroke; a journal of cerebral circulation.
T
IP
125. Lorenzoni PJ, Werneck LC, Kay CS, Silvado CE, Scola RH. When should MELAS (Mitochondrial
CR
myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? Arq Neuropsiquiatr.
2015;73(11):959-67. doi: 10.1590/0004-282X20150154. PubMed PMID: 26517220.
US
126. Kolodny E, Fellgiebel A, Hilz MJ, Sims K, Caruso P, Phan TG, Politei J, Manara R, Burlina A.
Cerebrovascular involvement in Fabry disease: current status of knowledge. Stroke; a journal of cerebral
AN
circulation. 2015;46(1):302-13. doi: 10.1161/STROKEAHA.114.006283. PubMed PMID: 25492902.
M
127. Kohrman MH, Huttenlocher PR. Takayasu arteritis: a treatable cause of stroke in infancy. Pediatric
neurology. 1986;2(3):154-8. PubMed PMID: 2907858.

ED
128. Muscal E, Brey RL. Antiphospholipid syndrome and the brain in pediatric and adult patients. Lupus.
2010;19(4):406-11. doi: 10.1177/0961203309360808. PubMed PMID: 20353978; PMCID: PMC2980850.

PT
129. Van Montfrans JM, Hartman EA, Braun KP, Hennekam EA, Hak EA, Nederkoorn PJ, Westendorp WF,
CE
Bredius RG, Kollen WJ, Scholvinck EH, Legger GE, Meyts I, Liston A, Lichtenbelt KD, Giltay JC, Van Haaften
G, De Vries Simons GM, Leavis H, Sanders CJ, Bierings MB, Nierkens S, Van Gijn ME. Phenotypic variability
AC
in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford).
2016;55(5):902-10. doi: 10.1093/rheumatology/kev439. PubMed PMID: 26867732.
130. Cleves C, Friedman NR, Rothner AD, Hussain MS. Genetically confirmed CADASIL in a pediatric
patient. Pediatrics. 2010;126(6):e1603-7. doi: 10.1542/peds.2010-0714. PubMed PMID: 21078731.
131. Tan RY, Markus HS. Monogenic causes of stroke: now and the future. Journal of neurology.
2015;262(12):2601-16. doi: 10.1007/s00415-015-7794-4. PubMed PMID: 26037017.

ACCEPTED MANUSCRIPT
132. Monagle P, Chan AK, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Gottl U, Vesely SK,
American College of Chest P. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e737S-801S. doi: 10.1378/chest.11-2308. PubMed PMID: 22315277;
PMCID: 3278066.
133. Roach ES, Golomb MR, Adams R, Biller J, Daniels S, Deveber G, Ferriero D, Jones BV, Kirkham FJ,
T
Scott RM, Smith ER, American Heart Association Stroke C, Council on Cardiovascular Disease in the Y.
IP
Management of stroke in infants and children: a scientific statement from a Special Writing Group of the
CR
American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke; a
US
18635845.
134. Saver JL, Gornbein J, Starkman S. Graphic reanalysis of the two NINDS-tPA trials confirms substantial
AN
treatment benefit. Stroke; a journal of cerebral circulation. 2010;41(10):2381-90. doi:
M
10.1161/STROKEAHA.110.583807. PubMed PMID: 20829518; PMCID: 2949055.
135. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, Majoie CB,
ED
van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy
EI, Berkhemer OA, Pereira VM, Rempel J, Millan M, Davis SM, Roy D, Thornton J, Roman LS, Ribo M,
PT
Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG, collaborators
CE
H. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data
from five randomised trials. Lancet. 2016;387(10029):1723-31. doi: 10.1016/S0140-6736(16)00163-X. PubMed

AC
PMID: 26898852.
136. Rivkin MJ, deVeber G, Ichord RN, Kirton A, Chan AK, Hovinga CA, Gill JC, Szabo A, Hill MD, Scholz
K, Amlie-Lefond C. Thrombolysis in pediatric stroke study. Stroke; a journal of cerebral circulation.
2015;46(3):880-5. doi: 10.1161/STROKEAHA.114.008210. PubMed PMID: 25613306; PMCID: PMC4342311.
137. Strater R, Kurnik K, Heller C, Schobess R, Luigs P, Nowak-Gottl U. Aspirin versus low-dose low-
molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up
study. Stroke; a journal of cerebral circulation. 2001;32(11):2554-8. PubMed PMID: 11692016.

ACCEPTED MANUSCRIPT
138. Bernard TJ, Goldenberg NA, Tripputi M, Manco-Johnson MJ, Niederstadt T, Nowak-Gottl U.
Anticoagulation in childhood-onset arterial ischemic stroke with non-moyamoya arteriopathy: findings from the
Colorado and German (COAG) collaboration. Stroke; a journal of cerebral circulation. 2009;40(8):2869-71. doi:
10.1161/STROKEAHA.109.550699. PubMed PMID: 19478216; PMCID: 4115644.
139. Goldenberg NA, Bernard TJ, Fullerton HJ, Gordon A, deVeber G, International Pediatric Stroke Study G.
Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a
T
multicentre, observational, cohort study. Lancet Neurol. 2009;8(12):1120-7. doi: 10.1016/S1474-4422(09)70241-
IP
8. PubMed PMID: 19801204.
CR
140. Hulbert ML, Scothorn DJ, Panepinto JA, Scott JP, Buchanan GR, Sarnaik S, Fallon R, Chu JY, Wang W,
Casella JF, Resar L, Berman B, Adamkiewicz T, Hsu LL, Smith-Whitley K, Mahoney D, Woods G, Watanabe M,
US
DeBaun MR. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated
with a lower risk of subsequent stroke: a retrospective cohort study of 137 children with sickle cell anemia. The
AN
Journal of pediatrics. 2006;149(5):710-2. doi: 10.1016/j.jpeds.2006.06.037. PubMed PMID: 17095350.
M
141. Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen W,
Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller ST,
ED
Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA,
Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, Luden J,
PT
Mortier NA, Stuber SE, Luban NL, Cohen AR, Pressel S, Adams RJ. Hydroxycarbamide versus chronic
CE
transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With
Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

AC
Lancet. 2016;387(10019):661-70. doi: 10.1016/S0140-6736(15)01041-7. PubMed PMID: 26670617.
142. Kirton A, Andersen J, Herrero M, Nettel-Aguirre A, Carsolio L, Damji O, Keess J, Mineyko A, Hodge J,
Hill MD. Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS Trial.
Neurology. 2016;86(18):1659-67. doi: 10.1212/WNL.0000000000002646. PubMed PMID: 27029628; PMCID:
PMC4854585.
ACCEPTED MANUSCRIPT
143. Cnossen MH, Aarsen FK, Akker S, Danen R, Appel IM, Steyerberg EW, Catsman-Berrevoets CE.
Paediatric arterial ischaemic stroke: functional outcome and risk factors. Developmental medicine and child
neurology. 2010;52(4):394-9. doi: 10.1111/j.1469-8749.2009.03580.x. PubMed PMID: 20089051.
144. Pavlovic J, Kaufmann F, Boltshauser E, Capone Mori A, Gubser Mercati D, Haenggeli CA, Keller E,
Lutschg J, Marcoz JP, Ramelli GP, Roulet Perez E, Schmitt-Mechelke T, Weissert M, Steinlin M.
Neuropsychological problems after paediatric stroke: two year follow-up of Swiss children. Neuropediatrics.
T
2006;37(1):13-9. doi: 10.1055/s-2006-923932. PubMed PMID: 16541363.
IP
145. Studer M, Boltshauser E, Capone Mori A, Datta A, Fluss J, Mercati D, Hackenberg A, Keller E, Maier O,
CR
Marcoz JP, Ramelli GP, Poloni C, Schmid R, Schmitt-Mechelke T, Wehrli E, Heinks T, Steinlin M. Factors
affecting cognitive outcome in early pediatric stroke. Neurology. 2014;82(9):784-92. doi:
US
10.1212/WNL.0000000000000162. PubMed PMID: 24489131.
146. deVeber GA, MacGregor D, Curtis R, Mayank S. Neurologic outcome in survivors of childhood arterial
AN
ischemic stroke and sinovenous thrombosis. Journal of child neurology. 2000;15(5):316-24. PubMed PMID:
M
10830198.
147. De Schryver EL, Kappelle LJ, Jennekens-Schinkel A, Boudewyn Peters AC. Prognosis of ischemic stroke
ED
in childhood: a long-term follow-up study. Developmental medicine and child neurology. 2000;42(5):313-8.

PT
148. Westmacott R, Askalan R, MacGregor D, Anderson P, Deveber G. Cognitive outcome following

CE
unilateral arterial ischaemic stroke in childhood: effects of age at stroke and lesion location. Developmental
medicine and child neurology. 2010;52(4):386-93. doi: 10.1111/j.1469-8749.2009.03403.x. PubMed PMID:

AC
19694778.
149. Steinlin M, Roellin K, Schroth G. Long-term follow-up after stroke in childhood. Eur J Pediatr.
2004;163(4-5):245-50. doi: 10.1007/s00431-003-1357-x. PubMed PMID: 14986120.
150. Hajek CA, Yeates KO, Anderson V, Mackay M, Greenham M, Gomes A, Lo W. Cognitive outcomes
following arterial ischemic stroke in infants and children. Journal of child neurology. 2014;29(7):887-94. doi:
10.1177/0883073813491828. PubMed PMID: 23760990.

ACCEPTED MANUSCRIPT
151. Kolk A, Ennok M, Laugesaar R, Kaldoja ML, Talvik T. Long-term cognitive outcomes after pediatric
stroke. Pediatric neurology. 2011;44(2):101-9. doi: 10.1016/j.pediatrneurol.2010.08.012. PubMed PMID:
21215909.
152. Friefeld SJ, Westmacott R, Macgregor D, Deveber GA. Predictors of quality of life in pediatric survivors
of arterial ischemic stroke and cerebral sinovenous thrombosis. Journal of child neurology. 2011;26(9):1186-92.
doi: 10.1177/0883073811408609. PubMed PMID: 21836124.
T
153. Ganesan V, Ng V, Chong WK, Kirkham FJ, Connelly A. Lesion volume, lesion location, and outcome
IP
after middle cerebral artery territory stroke. Archives of disease in childhood. 1999;81(4):295-300. PubMed
CR
PMID: 10490431; PMCID: PMC1718101.
154. Tuckuviene R, Christensen AL, Helgestad J, Johnsen SP, Kristensen SR. Paediatric arterial ischaemic
US
stroke and cerebral sinovenous thrombosis in Denmark 1994-2006: a nationwide population-based study. Acta
paediatrica. 2011;100(4):543-9. doi: 10.1111/j.1651-2227.2010.02100.x. PubMed PMID: 21114523.

AN
155. Sreenan C, Bhargava R, Robertson CM. Cerebral infarction in the term newborn: clinical presentation and
M
long-term outcome. The Journal of pediatrics. 2000;137(3):351-5. doi: 10.1067/mpd.2000.107845. PubMed
PMID: 10969259.
ED
156. Ricci D, Mercuri E, Barnett A, Rathbone R, Cota F, Haataja L, Rutherford M, Dubowitz L, Cowan F.
Cognitive outcome at early school age in term-born children with perinatally acquired middle cerebral artery
PT
territory infarction. Stroke; a journal of cerebral circulation. 2008;39(2):403-10. doi:

CE
157. Laugesaar R, Kolk A, Tomberg T, Metsvaht T, Lintrop M, Varendi H, Talvik T. Acutely and
AC
retrospectively diagnosed perinatal stroke: a population-based study. Stroke; a journal of cerebral circulation.
158. Westmacott R, MacGregor D, Askalan R, deVeber G. Late emergence of cognitive deficits after unilateral
neonatal stroke. Stroke; a journal of cerebral circulation. 2009;40(6):2012-9. doi:

ACCEPTED MANUSCRIPT
159. van Buuren LM, van der Aa NE, Dekker HC, Vermeulen RJ, van Nieuwenhuizen O, van Schooneveld
MM, de Vries LS. Cognitive outcome in childhood after unilateral perinatal brain injury. Developmental medicine
and child neurology. 2013;55(10):934-40. doi: 10.1111/dmcn.12187. PubMed PMID: 23758403.
160. Golomb MR, MacGregor DL, Domi T, Armstrong DC, McCrindle BW, Mayank S, deVeber GA.
Presumed pre- or perinatal arterial ischemic stroke: risk factors and outcomes. Annals of neurology.
2001;50(2):163-8. PubMed PMID: 11506398.
T
161. Fitzgerald KC, Williams LS, Garg BP, Golomb MR. Epilepsy in children with delayed presentation of
IP
perinatal stroke. Journal of child neurology. 2007;22(11):1274-80. doi: 10.1177/0883073807307106. PubMed
CR
PMID: 18006956.
162. Golomb MR, Garg BP, Saha C, Azzouz F, Williams LS. Cerebral palsy after perinatal arterial ischemic
US
stroke. Journal of child neurology. 2008;23(3):279-86. doi: 10.1177/0883073807309246. PubMed PMID:
18305317.
AN
163. Bernard TJ, Rivkin MJ, Scholz K, deVeber G, Kirton A, Gill JC, Chan AK, Hovinga CA, Ichord RN,
M
Grotta JC, Jordan LC, Benedict S, Friedman NR, Dowling MM, Elbers J, Torres M, Sultan S, Cummings DD,
Grabowski EF, McMillan HJ, Beslow LA, Amlie-Lefond C, Thrombolysis in Pediatric Stroke S. Emergence of
ED
the primary pediatric stroke center: impact of the thrombolysis in pediatric stroke trial. Stroke; a journal of
cerebral circulation. 2014;45(7):2018-23. doi: 10.1161/STROKEAHA.114.004919. PubMed PMID: 24916908;

PT
PMCID: 4083478.
CE
AC
ACCEPTED MANUSCRIPT
Risk Factors for Childhood Arterial Ischemic Stroke
Arteriopathies
Focal or transient cerebral arteriopathy
Craniocervical arterial dissection
Fibromuscular dysplasia
Moyamoya disease
Primary CNS angiitis
T
Cardiac Disease
IP
Congenital heart disease
Cardiomyopathy
CR
Arrhythmia
Catheterization/surgery
US
ECMO
Inherited thrombophilia
AN
Protein C, S, Antithrombin deficiency
Factor V Leiden
M
Prothrombin G20210A
ED
MTHFR C677T
Lipoprotein(a) elevations
PT
Acquired thrombophilia
Antiphospholipid syndrome
CE
Drug-induced thrombophilia (i.e. asparaginase)

Sickle cell disease
AC
Malignancy
Congenital vascular syndromes
Inborn errors of metabolism
Mitochondrial disorders
Fabry Disease
Rheumatologic disease
Systemic lupus erythematosus
Systemic vasculitis (i.e. Takayasu arteritis, Churg Strauss)
ACCEPTED MANUSCRIPT
Captions
Table 1. Summary of the various causes and risk factors for childhood AIS.
Figure 1. Outline of a diagnostic algorithm for a child presenting with new AIS.
T
IP
CR
US
AN
M
ED
PT
CE
AC
ACCEPTED MANUSCRIPT
T
IP
CR
US
AN
Figure 1
M
ED
PT
CE
AC

J BCMD 2017 03 003

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

J BCMD 2017 03 003

Uploaded by

Copyright:

Available Formats

Accepted Manuscript

Pediatric arterial ischemic stroke: Epidemiology, risk factors, and

Ryan J. Felling, Lisa R. Sun, Emily C. Maxwell, Neil Goldenberg,

Division of Hematology, Department of Pediatrics

infarct, children, neonates, brain injury

implications on recurrence risk, outcomes, and treatment strategies.

significant increase in incidence between 1988 and 1999 (8).

that the frequency of perinatal AIS is likely underestimated.

Risk Factors and Etiology

children with a first AIS (Figure 1).

Perinatal and Presumed Perinatal AIS

infertility, primiparity, intrauterine growth restriction, oligohydramnios, gestational hypertension or pre-

of labor, complicated delivery (including forceps, vacuum, or emergency C-section), abnormal

future studies of perinatal AIS.

possibility that arteriopathies (congenital, infectious, or traumatic) might predispose neonates to

relatives should always prompt a thorough thrombosis evaluation.

of longitudinal evaluation of childhood intracranial arteriopathies. Recent imaging studies have

presentations, as described in the CASCADE criteria (13).

Understanding the pathophysiology of FCAs is an ongoing challenge to investigators in the field of

of the craniocervical or intracranial vessels is likely an under-recognized cause of arteriopathy in

carotid terminus. Pathologically, moyamoya disease is characterized by fibrocellular intimal thickening,

understanding the pathophysiology of arteriopathy (Bernard et al., communication).

neurologic morbidity in these patients.

already high-risk condition.

escalation of therapy or additional preventive measures under certain circumstances.

irradiation therapy and subsequent development of vasculopathy (119-121).

the above conditions.

Management of Pediatric AIS

with aggressive treatment of fevers and seizures.

understand which therapies are most effective.

imaging necessary for diagnosis.

technologies in neuroimaging and neurorehabilitation will lead to better understanding of the

doi: 10.1161/STROKEAHA.108.519066. PubMed PMID: 18802206.

2002;110(5):924-8. doi: 10.1542/peds.110.5.924.

doi: 10.1016/j.pediatrneurol.2008.09.018. PubMed PMID: 19218034.

Neurology. 2003;61(2):189-94. PubMed PMID: 12874397.

Clin Epidemiol. 1995;48(11):1343-8. PubMed PMID: 7490597.

neurology. 2006;21(5):415-8. PubMed PMID: 16901448.

Institute of Neurological Disorders and Stroke. Pediatrics. 2007;120(3):609-16. doi: 10.1542/peds.2007-0336.

PubMed PMID: 17766535.

PubMed PMID: 11753097.

22156694; PMCID: 3312781.

Classifying Arteriopathies. Stroke; a journal of cerebral circulation. 2016;47(10):2443-9. doi:

10.1161/STROKEAHA.116.013544. PubMed PMID: 27633024.

2011;69(1):130-40. doi: 10.1002/ana.22224. PubMed PMID: 21280083.

outcome. Pediatric neurology. 2014;51(6):760-8. doi: 10.1016/j.pediatrneurol.2014.07.031. PubMed PMID:

doi: 10.1161/01.STR.0000247921.97794.5e. PubMed PMID: 17261729.

10.1016/j.thromres.2004.08.004. PubMed PMID: 15507271.

2016;173:62-8 e1. doi: 10.1016/j.jpeds.2016.02.064. PubMed PMID: 27049002.

PubMed PMID: 19541515.

JAMA. 2005;293(6):723-9. doi: 10.1001/jama.293.6.723. PubMed PMID: 15701914.

neonatal edition. 2012;97(6):F411-6. doi: 10.1136/archdischild-2011-300973. PubMed PMID: 22445901.

motor impairment: a population-based study. Pediatrics. 2004;114(3):612-9. doi: 10.1542/peds.2004-0385.

PubMed PMID: 15342829.

Pediatrics. 2011;127(3):e722-9. doi: 10.1542/peds.2010-1490. PubMed PMID: 21339263.

Surg Pathol Clin. 2013;6(1):87-100. doi: 10.1016/j.path.2012.10.001. PubMed PMID: 26838704.

International Pediatric Stroke Study. Pediatrics. 2011;128(6):e1402-10. doi: 10.1542/peds.2011-1148. PubMed

10.1016/j.athoracsur.2009.03.030. PubMed PMID: 19699905; PMCID: PMC2840405.

Membrane Oxygenation. The Annals of thoracic surgery. 2015;100(5):1751-7. doi:

10.1016/j.athoracsur.2015.06.020. PubMed PMID: 26298170; PMCID: PMC4630110.

8749.2009.03377.x. PubMed PMID: 19583743.

European Paediatric Neurology Society. 2004;8(3):155-60. doi: 10.1016/j.ejpn.2004.02.001. PubMed PMID:

34. Fluss J, Garcia-Tarodo S, Granier M, Villega F, Ferey S, Husson B, Kossorotoff M, Muehlethaler V,