Pediatric Neurology 51 (2014) 760e768

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Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Topical Review

Perinatal Arterial Ischemic Stroke: Presentation, Risk Factors,

Evaluation, and Outcome
Laura L. Lehman MD a, Michael J. Rivkin MD a, b, c, *
a
Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts
b
Department of Psychiatry, Boston Children’s Hospital, Boston, Massachusetts
c
Department of and Radiology, Boston Children’s Hospital, Boston, Massachusetts

abstract
BACKGROUND: Perinatal arterial ischemic stroke is as common as large vessel arterial ischemic stroke in adults and
leads to significant morbidity. Perinatal arterial ischemic stroke is the most common identifiable cause of cerebral
palsy and can lead to cognitive and behavioral difficulties that are amortized over a lifetime. METHODS: The
literature on perinatal arterial ischemic stroke was reviewed and analyzed. RESULTS: Risk factors for perinatal
arterial ischemic stroke include those that are maternal, neonatal, and placental. The most common clinical signs
at presentation are seizures and hemiparesis. Evaluation should begin with thorough history acquisition and
physical examination followed by magnetic resonance imaging of the brain, with consideration of magnetic
resonance angiography of the head and neck, echocardiogram, and thrombophilia evaluation. Treatment beginning
early to include physical, speech, and occupational therapies including constraint-induced movement therapy and
close cognitive and developmental follow-up may be beneficial. Future treatments may include transcranial
magnetic stimulation, hypothermia, and erythropoietin. CONCLUSIONS: Perinatal arterial ischemic stroke comprises
a group of arterial ischemic injuries that can occur in the prenatal, perinatal, and postnatal periods in term and
preterm infants with different types of perinatal arterial ischemic stroke having different clinical presentations,
risk factors, and long-term outcomes.
Keywords: neonatal, perinatal, presumed perinatal, ischemic, stroke
Pediatr Neurol 2014; 51: 760-768
Ó 2014 Elsevier Inc. All rights reserved.

Introduction cerebral blood flow secondary to arterial or cerebral venous

Neonatal stroke remains incompletely understood.
Similar to stroke in older children and adults, neonatal stroke
may be either hemorrhagic or ischemic; however, the pre-
sentation and etiologies of stroke in neonates differ from
those of both older age groups and, in many cases, remain
unrecognized. A workshop convened by the National In-
stitutes of Health addressed ischemic perinatal stroke.
Ischemic perinatal stroke was defined as “a group of het-
erogeneous conditions in which there is a focal disruption of
Article History:
Received December 5, 2013; Accepted in final form July 25, 2014
* Communications should be addressed to: Dr. Rivkin; Department of
Neurology; Boston Children’s Hospital; Pavilion 154; 300 Longwood
Avenue; Boston, Massachusetts 02115.
E-mail address: michael.rivkin@childrens.harvard.edu
thrombosis or embolization, between 20 weeks of fetal life
through twenty-eighth postnatal day confirmed by neuro-
imaging or neuropathologic studies.”1 Thus, the clinical en-
tity of ischemic perinatal stroke includes focal or multifocal
ischemic injury to the central nervous system of either
arterial or venous etiology that can occur during the prenatal,
intrapartum, or postnatal period. This review focuses spe-
cifically on arterial ischemic stroke (AIS) in the neonate that
investigators have consistently defined as a pattern of
ischemic brain injury in an arterial distribution.2-4
AIS during childhood occurs most frequently in the
perinatal period. The incidence of AIS in the neonate is
similar to the incidence of large artery AIS in adults and is
17 times greater than the incidence of AIS in children.5 In
term neonates, AIS is the most common recognized cause of
cerebral palsy and is the second most common underlying
etiology of neonatal seizures.6,7

0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.031
 L.L. Lehman, M.J. Rivkin / Pediatric Neurology 51 (2014) 760e768
First, we will discuss the classification and the epide-
miology of perinatal AIS. Next, we will describe the known
maternal, placental, and neonatal risk factors associated
with perinatal AIS. Then, we will review the common clin-
ical presentations and imaging findings and discuss the
recommended evaluation and treatment. We will conclude
with a discussion of outcome after perinatal AIS.
Classification
As mentioned previously, perinatal AIS refers to a distinct
pattern of ischemic brain injury in an arterial distribution
that occurs during the prenatal, intrapartum, or neonatal
period. Perinatal AIS can be subclassified according to the
time of diagnosis as fetal, neonatal, or presumed perinatal
AIS. Fetal AIS is diagnosed before birth through the use of
fetal imaging methods or in stillbirth on the basis of
neuropathologic examination that reveals a pattern of
ischemic brain injury in an arterial distribution. Neonatal
AIS constitutes an acute presentation of encephalopathy
manifesting as seizure, altered mental status, and/or
neurological deficit between birth and the twenty-ninth
postnatal day for which a pattern of ischemic brain injury
in an arterial distribution is evident by clinical neuro-
imaging. Presumed perinatal AIS is diagnosed in individuals
>28 days of age with focal neurological deficits and a cor-
responding chronic infarct in arterial distribution in whom
it is presumed (but not proven) that the ischemic injury
occurred between the twentieth week of fetal life through
the twenty-eighth postnatal day but was not detected
during that period.1-4 Neonatal AIS can be further catego-
rized as a term or preterm clinical event depending on the
gestational age of the infant. Preterm neonatal AIS is
defined as an AIS occurring in a preterm infant variably
defined by investigators as less than 35 weeks to 37 weeks
of gestational age.5,8,9
Epidemiology
The incidence of neonatal AIS in term infants has been
reported to reside between one in 2300 and one in 5000
live births.7,10,11,12 AIS occurs even more frequently among
preterm newborns. Benders et al.9 found that preterm AIS
occurred at a rate of seven per 1000 infants born at or before
34 weeks of gestation. A male predominance occurs in term
neonatal AIS but has not been observed in preterm neonatal
AIS.2-4,12 Studies on the incidence of presumed perinatal
stroke are scarce. One study, which combined hemorrhagic
and ischemic presentations of presumed perinatal stroke
found an incidence of one in 2307 live births with a female
predominance.11
Risk factors
Risk factors for perinatal AIS comprise maternal,
neonatal, and placental conditions (Table 1). Maternal risk
factors include infertility, preeclampsia, prolonged rupture
of membranes, maternal smoking, intrauterine growth
retardation, maternal fever, thrombophilia, and cho-
rioamnionitis.5,13-16 The risk of neonatal AIS increases as the
number of the pregnant mother’s risk factors rises.5 Many
different studies have demonstrated different maternal risk
761
TABLE 1.
Risk Factors for Perinatal Arterial Ischemic Stroke
Type of Risk Factor Risk Factor
Maternal Thrombophilia
Infertility
Prolonged rupture of membranes
Preeclampsia
Smoking
Intrauterine growth retardation
Infection
Maternal fever
Fetal Thrombophilia
Congenital heart disease
Arteriopathy
Hypoglycemia
Perinatal asphyxia
Infection
Need of resuscitation
Apgar score of <7 at 5 minutes
Placental Chorioamnionitis
Placental infarcts
Placenta weighing less than tenth percentile
factors to be independently associated with neonatal AIS.
One study using multivariate analysis demonstrated that
neonatal AIS in the term infant was associated with
maternal fever during delivery.13 Another study determined
that maternal smoking was the only maternal risk factor
associated with neonatal AIS.14 In the International Pediat-
ric Stroke Study (IPSS) cohort, maternal risk factors were
uncommon except gestational hypertension and/or pre-
eclampsia, which occurred in 10% of mothers.17
Fewer studies exist that examine maternal risk factors
in preterm infants with neonatal AIS. Golomb et al.
examined infants with preterm neonatal AIS and found
that 30% of the mothers had a history of maternal
infection, 22% had a history of gestational bleeding, 17%
had a history of maternal smoking, and 9% had a history
of maternal drug use.2 Benders et al.,9 on the other hand,
was not able to demonstrate any relationship between
preterm neonatal AIS and any known maternal risk
factor.
Even fewer studies have examined maternal risk factors
in presumed perinatal AIS. Golomb et al.18 found that most
of the children diagnosed with presumed perinatal AIS had
maternal histories of preeclampsia, maternal infection,
bleeding during pregnancy, or gestational diabetes.
Moreover, in a study examining maternal-infant pairs
including infants with either presumed perinatal or
neonatal AIS, 78% of the dyads possessed at least one
thrombophilia risk factor. In this cohort, factor V Leiden
heterozygosity, protein C deficiency, and antiphospholipid
antibodies carried significant risk of stroke compared with
controls.16
Neonatal risk factors include congenital heart disease
(CHD), prothrombotic abnormalities, 5-minute Apgar
score of <7, hypoglycemia, and infection.11,13,16,19-22 Me-
chanical force applied to the newborn’s head and neck
during labor may also lead to injury of craniocervical ar-
teries increasing risk of arterial dissection and stroke.23 A
recent study using multivariate analysis determined that
hypoglycemia, an Apgar score of <7 at 5 minutes, and
762 L.L. Lehman, M.J. Rivkin / Pediatric Neurology 51 (2014) 760e768
early-onset sepsis and/or meningitis were independently
associated with neonatal AIS.13 Similarly, Kirton et al.17
using neonatal data from the IPSS in which 92% of the in-
fants were born at term found that among neonates with
AIS, 30% received perinatal resuscitation, 23% had systemic
infection, and less than 20% demonstrated prothrombotic
or cardiac abnormalities.
Perinatal AIS occurs in the setting of CHD. Neonates with
CHD have been found to sustain arterial stroke in patterns of
arterial occlusive or watershed injury. Furthermore, AIS has
been found to occur in the preoperative and intraoperative
and/or postoperative periods. Further, it is not infrequently
clinically silent in its occurrence.24 Characteristics of CHD
and its management such as the presence of an intracardiac
right-to-left shunt, preoperative ballon atrial septostomy,
transposition of the great arteries, or single ventricle
physiology have been associated with neonatal AIS.19,25,26
Further, operative features such as duration of bypass, age
at surgical correction, and need for reoperation may also be
associated with the occurrence of AIS in neonates with
CHD.27 Diagnostic procedures such as cardiac catheteriza-
tion and the more recent use of ventricular assist device as a
bridge to cardiac transplant from extracorporeal membrane
oxygenation have been associated with the occurrence of
AIS.28-30 Finally, evidence of subtle white matterebased
cerebral injury attributable to the prenatal or perinatal
period has been reported in adolescents with d-trans-
position of the great arteries.31
Thrombophilia and genetic factors remain associated with
AIS in the neonatal period. Prothrombotic risk factors
including elevated lipoprotein (a), MTHFR mutation, factor V
Leiden, prothrombin gene mutation, and protein C de-
ficiencies have all been associated with neonatal AIS.32,33 In a
study by Gunther et al.,32 thrombophilia was evident in 68%
of infants with neonatal AIS compared with 24% of controls
with an odds ratio of 6.7. Along with prothrombotic genetic
risk factors, other genetic risk factors may contribute to
neonatal AIS. A recent article by Gelfand et al.34 found that
patients with neonatal AIS were more likely to have the
apolipoprotein E ε4 allele than controls but because of small
sample size lacked statistical significance. Apolipoprotein E
ε4 is a gene expressed in the central nervous system and
involved in lipid transport, the metabolism of which has
been associated with cerebral palsy and adult stroke.
Preterm neonates who develop AIS have similar risk
factors to term infants. In a patient study of 31 preterm
infants with neonatal AIS, a multivariate analysis deter-
mined that twin-twin transfusion, abnormal fetal heart rate
pattern, and hypoglycemia were independent risk factors
for the occurrence of AIS. Although, only 11 of the 31 neo-
nates had a thrombophilia evaluation, two of the 11 were
found to be factor V Leiden heterozygotes, five harbored an
MTHFR mutation (two homo and three hetero), whereas
one had an increased lipoprotein (a) level.9
Little is known about the risk factors in children found to
have a presumed perinatal AIS. Nevertheless, the occur-
rence of an inherited thrombophilia has been evident to be
more common among children with presumed perinatal
AIS compared with those with neonatal AIS.35 Conversely,
perinatal asphyxia appears more frequently in children
with neonatal AIS compared with those with presumed
perinatal AIS.11
Abnormal placental pathology has become a focus of
interest as a cause of perinatal AIS. An evaluation of
placental pathology in infants with cerebral palsy and
neurological impairment found that severe fetal cho-
rioamnionitis, extensive avascular villi, and diffuse cho-
rioamniotic hemosiderosis were independently associated
with neurological impairment.36 Severe fetal placental
vascular lesions including fetal thrombotic vasculopathy,
chronic villitis with obliterative fetal vasculopathy, cho-
rioamnionitis with severe fetal vasculitis, and meconium-
associated fetal vascular necrosis are also significantly
correlated with neurological impairment and cerebral
palsy.37 Few studies exist that specifically examine placental
pathology in relation to perinatal AIS. However, a recent
study of placental pathology in 12 neonates with either AISs
or cerebral sinovenous thrombosis demonstrated that all
five neonates with AIS had placental abnormalities. Of the
five neonates with arterial ischemic stroke, three had
chronic villitis, three had distal villous immaturity, two had
a placental infarct, and two had a placental weight less than
the tenth percentile.38 Placental pathology has also been
found to be significantly more common in infants with
neonatal AIS as compared to those with presumed perinatal
AIS.11 Interestingly, among preterm neonates, no difference
in placental pathology was present between those with AIS
and controls.9
Clinical presentation
Newborns who sustain AIS present 58-68% of the time
during the neonatal period.39,40 The remainder presents after
28 days of age usually because of detection of a focal
neurological abnormality which, in turn, leads to discovery of
an old cerebral infarct that is classified as presumed perinatal
AIS. The most common presenting feature of neonatal term
infants with AIS is seizure. Seizures constitute the initial sign
in 69-90% of the term newborns with neonatal AIS.17,39,40 The
first seizure occurrence after 12 hours of life, especially one
with focal features, has been reported to distinguish those
days AIS rather than generalized hypoxic-ischemic brain
injury.41 Further, most of the seizures associated with
neonatal AIS occur within the first 3 days of life.13,39,42 Other
common presentations include encephalopathy, apnea, and
tone abnormalities. In a cohort of 248 neonates, 63% pre-
sented with diffuse neurological signs including change in
the level of consciousness (39%) and abnormal tone (38%).
Notably, focal neurological signs were present in only 30% of
patients, 95% of whom demonstrated a lateralizing hemi-
paresis. Respiratory and feeding difficulties were present in
26% and 24%, respectively.14 Similar characteristics were
found by Chabrier et al.41 who found that 46% of 100 neo-
nates with neonatal AIS presented with abnormal tone and
36% with decreased level of consciousness.
Preterm neonates with AIS present differently from term
infants. Preterm infants with neonatal AIS are commonly
asymptomatic and are diagnosed by routine head ultra-
sound.9,39 Seizure occurrence is less common as compared
to term infants with neonatal AIS. Golomb et al.43 found
that most of the preterm infants with neonatal AIS pre-
sented with respiratory difficulties or apnea (83%), whereas
30% presented with seizure, 26% with abnormal feeding,
and 22% with abnormal tone.
 L.L. Lehman, M.J. Rivkin / Pediatric Neurology 51 (2014) 760e768 763

Presumed perinatal AIS usually presents after 2 months
of age with a median age of presentation of 6 months.18,39
Most infants (81-86%) with presumed perinatal AIS pre-
sent with early hand preference or fisting.8,15 Less common
presentations include seizures (14-15%) and gaze prefer-
ence (5%).11,17,18,39
Imaging
Clinical suspicion of neonatal AIS is confirmed by neu-
roimaging. Cranial ultrasound is the most convenient but
also the least sensitive of available neuroimaging modal-
ities.44,45 Cranial computed tomography offers higher image
resolution than ultrasound but exposes the infant to x-
irradiation. Magnetic resonance imaging (MRI) provides the
highest anatomic resolution and the best sensitivity to
detect acute ischemia but requires transport of the patient
to an MRI scanning suite (Figs 1 and 2).46 Specific sequences
important to obtain when imaging the neonate with MRI
include diffusion-weighted imaging (DWI), T1- and T2-
weighted imaging (T1W and T2W), and susceptibility
weighted imaging. A magnetic resonance angiography
(MRA) of the head and neck should be considered to look
for craniocervical arteriopathy because it can easily be
added to the initial MRI evaluation. Vascular imaging has
not been studied as much in neonatal stroke as it has in
older children and adults. Nonetheless, patient reports and
series have demonstrated the ability of MRA to detect cer-
vicocephalic arterial dissection and asymmetry of cerebro-
vascular trees in neonates found to have AIS.23,47-49
Different MRI sequences are helpful to identify perinatal
stroke depending on the timing of the imaging from initial
injury. DWI is used to see cytotoxic edema and in neonates
is sensitive within hours of the initial injury, similar to
adults. Visualization of the lesion using DWI is best
observed within the first 2-4 days from the time of the
initial injury.50,51 Dudink et al. studied term infants with
neonatal stroke in the first postnatal weeks with MRI to find
that T2W images revealed a high signal intensity in affected
cortical gray matter and white matter during the first week
of life, whereas T1W imaging revealed a low signal intensity
in the involved cortical gray matter. From 1 week to 1
month after birth, cortical gray matter signal intensity was
high on T1W imaging and low on T2W imaging. After 1-
2 months the infarcted area evolved into areas of tissue loss
and cysts (Fig 3).51
In all types of perinatal AISs, the majority are unilateral,
occur in the left hemisphere and in the middle cerebral
artery (MCA) territory. In a recent study of preterm and
term neonatal AIS and presumed perinatal AIS, Lee et al.
found that 87% of strokes were unilateral. The majority
occurred on the left side (53%) compared with those on the
right (35%) alone. MCA territory was exclusively affected in
74% of patients.39 Other studies have confirmed the pre-
dominance of left hemispheric (58-64%) and MCA territory
locations (75-90%) of AIS found in preterm, term neonates,
and those identified as presumed perinatal AISs.9,13,18
The location of AIS within the MCA territory varies in
term and preterm neonates. Term neonates usually
demonstrate cortical branch strokes (59%) within the MCA
territory while lenticulostriate branch infarcts are
commonly observed in preterms (39%).9,13 Main branch
MCA strokes occur with approximately equal frequency in
term and preterm infants. Interestingly, the arterial
involvement in the preterm infant was evident to change
with gestational age. Most of the infants with preterm AIS,
<28-32 weeks of gestational age, had lenticulostriate
involvement compared with older (32-36 weeks of gesta-
tional age) preterm infants with AIS, in whom the majority
had cortical branch infarcts.9 These results correlate with
findings that most of the term neonatal MCA territory AIS
reflects cortical branch involvement.13

FIGURE 1.
Comparison of head ultrasound (HUS) and brain magnetic resonance imaging (MRI) of neonatal arterial ischemic stroke in a 1-day-old term infant who
presented with a right focal seizure. (A) HUS reveals hyperechogenicity in the left cerebral hemisphere (indicated by white arrow) concerning for ischemic
injury. (B) Axial MRI diffusion-weighted trace image of the same patient observed in (A) reveals well-defined hyperintensity (indicated by white arrow) in
the left middle cerebral artery (MCA) territory. (C) Diffusion-weighted image apparent diffusion coefficient map of matching slice observed in (B) reveals
corresponding hypointensity (indicated by white arrow) in the left MCA territory.
764 L.L. Lehman, M.J. Rivkin / Pediatric Neurology 51 (2014) 760e768

FIGURE 2.
Comparison of cranial computed tomography (CCT) and brain magnetic resonance imaging (MRI) for demonstration of neonatal arterial ischemic stroke in a
1-day-old term infant who presented with a right focal seizure. (A) An axial CCT image reveals hypodensity (white arrow) in the left middle cerebral artery
(MCA) territory consistent with acute infarction. (B) Axial MRI diffusion-weighted trace image of the same patient revealed in (A) reveals clearly demarcated
area of infarct as a region of hyperintensity (white arrow) in the left MCA territory. (C) Diffusion-weighted image apparent diffusion coefficient map reveals
region of signal hypointensity and restricted diffusion (white arrow) to match area of signal hyperintensity observed in (B).

Evaluation recurrent event. Occurring at an approximate rate of 2%,

recurrent events have been associated with prothrombotic
Patient evaluation after perinatal AIS focuses on identi- disorders, CHD, and arteriopathy.52,53 Therefore, evaluation
fication of etiologies that may increase the risk of a should include laboratory testing for thrombophilia, an

FIGURE 3.
Comparison of magnetic resonance imaging (MRI) appearance of a patient with acute neonatal arterial ischemic stroke (AIS) compared with MRI of a patient
with presumed perinatal AIS. (A) T2-weighted (T2-W) axial image obtained in a 1-day-old term infant who presented with seizure reveals hyperintensity
(thick arrow) in gray matter cortex and underlying white matter with loss of gray and/or white matter differentiation in the left middle cerebral artery
territory (thick arrow) consistent with acute infarction compared with the normal right side with dark cortex (thin arrow) and normal differentiation of the
white and gray matter. (B) T1-weighted axial image, obtained in the same patient at the same time as image in (A), reveals signal hypointensity in cortical
gray matter (white arrow) matching the area of hyperintensity observed in (A) consistent with a diagnosis of acute neonatal AIS. (C) T2-W image obtained in
a 3-month-old infant with an unremarkable neonatal history who presented at 3 months of age with a prematurely appearing right-hand preference reveals
an area of hyperintensity and cystic change (thick arrow) with cystic septations (thin arrows) typically of chronic infarction.
 L.L. Lehman, M.J. Rivkin / Pediatric Neurology 51 (2014) 760e768
echocardiogram to evaluate for intracardiac thrombus,
right-to-left shunt or structural features contributing to
cardioembolic stroke, and vascular imaging of both head
and neck to evaluate for craniocervical arteriopathy.
The hemostatic system in the neonate undergoes rapid
physiologic change during the first year of life.54 Protein S
and protein C reach adult levels at 6 and 12 months of life,
respectively. If the levels are slightly low and the infant is
otherwise asymptomatic, a repeat level should be obtained
later in the first year of life. In addition, a child should be
evaluated for factor V Leiden dysfunction, homocysteine
elevation, prothrombin gene mutation 20210, and lipopro-
tein (a) elevation which have all been associated with
neonatal stroke.32,33,55 Antithrombin 3 deficiency has been
associated with stroke in older children and should also
be included in evaluation of thrombophilia in a child with
a neonatal stroke.56 The thrombophilia evaluation should
also include testing either the mother or the child for
antiphospholipid antibodies including lupus anticoagulant,
anticardiolipin, and anti-b2 glycoprotein antibodies
because these antibodies have also been associated with
perinatal AIS.16 Table 2 lists thrombophilia laboratory tests
associated with stroke in children and neonates.
CHD is a known risk factor for stroke in the neonatal
period, but there is no published literature on the preva-
lence of cardiac thrombus or right-to-left shunt in perinatal
AIS. It may be helpful in the case of perinatal stroke without
known CHD to evaluate for a cardioembolic cause of peri-
natal AIS stroke with echocardiography. A bubble study
should be performed to evaluate for a right-to-left shunt
that may be missed by Doppler study alone.57
Vascular imaging with an MRA of the head and neck will
assess for craniocervical arteriopathy. Arteriopathy in
childhood stroke has been evident to have a 5-year recur-
rence rate of 66%.58 With research significant for only pa-
tient descriptions, arteriopathy has been reported in
neonatal AIS including moyamoya disease and dissection
because of traumatic delivery.23,25
Treatment
Because recurrence rates are low, treatment of perinatal
AIS in the acute setting has been largely supportive. Data are
lacking to support prophylactic treatment with an antith-
rombotic after stroke in neonates. The American Heart As-
sociation guidelines state that anticoagulation may be
helpful in patients with perinatal AIS who have either a
prothrombotic state or CHD.59 Similarly, the CHEST
TABLE 2.
Thrombophilia Laboratory Tests
Thrombophilia Laboratories
Antithrombin functional assay
Protein C functional assay
Protein S functional assay
Factor V Leiden functional assay or factor V Leiden gene mutation
Prothrombin gene mutation
Serum homocysteine level
Serum lipoprotein (a)
Serum lupus anticoagulant
Anti-b2 glycoprotein 1 antibodies, IgG and IgM
Anti-cardiolipin antibodies, IgG, IgA, and IgM
765
guidelines recommend use of anticoagulation after stroke
only for the neonate who has a documented cardioembolic
source or who is homozygous for protein C deficiency.60 In
this regard, data from the IPSS registry on neonatal stroke
revealed that 21% of patients with a symptomatic neonatal
stroke were treated with antithrombotic therapy, mostly
with anticoagulation. A univariate analysis revealed that
there was an association between antithrombotic treatment
and presence of either thrombophilia or cardiac disease.17
Because a majority of neonates with stroke present with
seizures, antiepileptic medication should be considered to
prevent further episodes of seizures. Studies on the impact
of seizure on outcome in neonatal stroke do not exist.
However, the association of poststroke seizure with poorer
prognosis and greater in-hospital mortality is concerning in
adults.61,62 In addition, animal models have demonstrated
that poststroke seizures significantly increase ischemic
lesion volume.63 These results may be applicable to neo-
nates with AIS who present with seizures and who have
recurrent clinical or subclinical seizures, thereafter. Kirton
et al.17 found that most of the neonates with neonatal AIS
were treated with antiepileptics (67%) initially. However,
only 2% were discharged from the hospital on antiepileptic
medication, suggesting that treatment duration with anti-
epileptic medication is usually short.
Early implementation of physical, occupational, and
speech therapy may be helpful for maximizing outcome after
neonatal stroke. Research in the efficacy of early therapy is
minimal. Constraint-induced movement therapy (CIMT), a
type of occupational therapy, consists of constraining the
unaffected arm to allow the patient to focus on using the
affected arm. CIMT has been revealed to improve enduring
motor function in adults and reveals considerable promise in
its application to children who have sustained a stroke.64-66
CIMT has been demonstrated to be feasible in children less
than 18 months of age with unilateral cerebral palsy.67,68
Another emerging therapy for perinatal stroke is gait
training using various forms of supported walking including
treadmills, ramps, and ground. Gait training is affective in
cerebral palsy with children of younger ages at the time of
therapy demonstrating greater improvements. Yang et al.69
recently demonstrated feasibility of gait training in children
with perinatal stroke less than 2 years of age.
Besides CIMT, recent research has demonstrated that
transcranial magnetic stimulation (TMS), hypothermia, and
erythropoietin merit further consideration as potential
treatments for infants with neonatal AIS. In adults with
stroke, repetitive TMS has been revealed to improve motor
function.70,71 A recent study by Kirton et al.72 demonstrated
that TMS is safe in treatment of pediatric stroke and
improved hand function temporarily. Similarly, therapeutic
hypothermia may improve outcome after neonatal AIS. Its
use has been associated with absence of neonatal seizures in
neonates with AIS and may improve outcome after stroke.73
Rodent models of adult AIS have demonstrated that hypo-
thermia decreases infarct size and improves outcome.74
Finally, treatment with erythropoietin in neonatal rat
models decreases cerebral volume loss, increases both neu-
rogenesis and oligodendrogenesis from precursor cells, and
improves outcome after stroke.75,76 In adults, erythropoietin
significantly improved circulating endothelial progenitor
cells and 90-day clinical outcome after acute AIS.77
766 L.L. Lehman, M.J. Rivkin / Pediatric Neurology 51 (2014) 760e768
Outcome
Death after neonatal AIS is uncommon. The mortality rate
after neonatal AIS is 0.16 per 100,000 live births.78 Recur-
rence occurs in only 2% of neonates, the majority of whom
have prothrombotic disorders, CHD, or arteriopathy.52
Long-term sequelae from neonatal AIS can include mo-
tor, cognitive, or behavioral difficulties, as well as epilepsy.
Between 48% and 59% of neonates with AIS have long-term
motor deficits.39,79,80 Imaging can be helpful in predicting
motor outcome. MRI evidence of AIS involving basal
ganglia, cerebral cortex, and posterior limb of the internal
capsule in term neonates has been reported to correlate
with subsequent hemiparesis, whereas an involvement of
any one or two of those areas is associated with a more
favorable motor outcome.81,82 More recently, Kirton et al.83
found that involvement of descending corticospinal tract on
MRI in patients with neonatal AIS correlated with hemi-
paresis as a long-term consequence.
Behavioral and cognitive deficits are not infrequent. Lee
et al.39 found that 11% of children with neonatal AIS had
behavioral disorders and 21% had language delay. Behav-
ioral disorders were defined as attention problems, hyper-
activity, or behavioral problems, whereas speech delay was
defined as a physician diagnosis of speech or language
delay. Cognitive deficits, not easily detected at younger ages
of follow-up, may become more apparent at school age.
Westmacott et al. performed cognitive assessments at both
preschool and school age on children who had neonatal AIS.
The children with neonatal AIS did not differ significantly
from controls at preschool age. However, when the same
children were tested at school age, 69% revealed significant
reduction in one or more IQ index measures.84 Notably,
children with perinatal stroke have demonstrated a worse
performance on follow-up measures of cognitive function
than those who sustained stroke at later ages in
childhood.85
Neonates with AIS commonly present with seizure.
Initially, seizures can be repeated and refractory to treat-
ment. In most cases, seizures remit and most of these
children will not have seizures again in the future. However,
between 38% and 46% of neonates with AIS will develop
epilepsy.40,80
The outcome of children with presumed perinatal AIS
appears to differ from that found in neonatal AIS. The vast
majority of patients with presumed perinatal AIS (95%) have
a hemiparesis with 41% requiring limb casting or splinting.18
Motor outcome can be predicted by basal ganglia involve-
ment, whereas nonmotor outcomes are associated with
cortical involvement.26 Around half of the patients with
presumed perinatal AIS will have a cognitive or behavioral
difficulty.18 Epilepsy is not uncommon in children with
presumed perinatal AIS. A recent study by Fitzgerald et al.
found that 38% of children with presumed perinatal AIS
developed epilepsy. Risk factors for development of epi-
lepsy included seizure at presentation and infantile
spasms.86
Conclusions
Perinatal AIS comprises a group of arterial ischemic in-
juries that can occur during the prenatal, perinatal, and
postnatal periods in term and preterm infants. It includes
neonatal AIS and presumed perinatal AIS. These different
types of perinatal AIS have different clinical presentation,
risk factors, and long-term outcomes. Evaluation should
include a search for etiologies that would place the infant at
increased risk for stroke recurrence. Treatment consists of
physical, occupational, and language-based therapies to
maximize developmental outcome. However, the roles for
more recently developed therapies in this important clinical
group such as CIMT are promising and carry the possibility
of more effective therapy in the near future.
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