NEUROLOGICAL PROGRESS

Treatment of Childhood Arterial Ischemic

Stroke
Timothy J. Bernard, MD,1 Neil A. Goldenberg, MD,1,2 Jennifer Armstrong-Wells, MD, MPH,3
Catherine Amlie-Lefond, MD,4 and Heather J. Fullerton, MD, MAS3,5

Traditional risk factors associated with adult arterial ischemic stroke (AIS; ie, hypertension, hyperlipidemia, diabetes, smoking,
and atherosclerosis) are relatively rare in children. Childhood AIS is instead associated with a variety of conditions including
cerebral arteriopathies, congenital heart disease, infection, head and neck trauma, sickle cell anemia, and prothrombotic abnor-
malities. Although the pathophysiology and outcomes of adult AIS differ significantly from those in childhood AIS, therapeutic
management remains similar, largely because of the paucity of evidence from devoted pediatric observational studies and clinical
trials. The purpose of this article is to review the current guidelines and evidence in the treatment of childhood AIS, within the
context of that which exists in adult AIS. Medical management of hypoxia, hyperglycemia, fever, blood pressure, and increased
intracranial pressure has been insufficiently investigated in childhood stroke, resulting in a lack of guidance in these areas.
Although acute antithrombotic management in childhood AIS has received relatively greater attention in published recommen-
dations, it is based almost exclusively on consensus and expert opinion, and differs considerably among existing pediatric guide-
lines. Rehabilitation therapy in childhood AIS has great potential for meaningful improvements in long-term outcomes, espe-
cially given the plasticity of the young brain; however, little guidance for rehabilitative measures is provided by published
recommendations. Ongoing and future multicenter cohort study efforts, and ultimately devoted pediatric clinical trials, will be
essential to establish comprehensive evidence-based guidelines for the treatment of childhood AIS.
Ann Neurol 2008;63:679 – 696

The diagnosis of an acute arterial ischemic stroke (AIS)
requires the combination of a clinical syndrome con-
sistent with a stroke and a corresponding radiographic
abnormality (usually on magnetic resonance diffusion-
weighted images) in a known arterial distribution.
Childhood AIS is a subset of pediatric stroke, encom-
passing AIS patients aged 29 days to 18 years. The in-
cidence of childhood AIS has been estimated at 0.63 to
2.0 per 100,000 person-years in North America and
has significant attendant morbidity and mortality.1,2
Recurrence is common, occurring in approximately 7
to 20% of all children with AIS within 5 years (Fig
1).2– 4 Causative factors of childhood AIS differ signif-
icantly from adult AIS. The traditional risk factors as-
sociated with adult AIS (ie, hypertension, hyperlipid-
emia, diabetes, smoking, and atherosclerosis) are
relatively rare in childhood stroke.
Instead, childhood AIS is associated with a variety
of conditions including cerebral arteriopathies, vascu-
lar anomalies, congenital heart disease, infection, head
and neck trauma, sickle cell anemia, genetic/meta-
bolic disease, infections, and prothrombotic abnor-
malities.5–14 Arteriopathies, in particular, confer a
high recurrence risk that has been reported to be 66%
at 5 years.2 Although arteriopathy is common, occur-
ring in as many as 80% of children with AIS, the
causative agent and pathogenesis are uncertain.15 A
retrospective review of varicella in childhood AIS sug-
gests the possibility of a parainfectious causative
agent, because recent varicella infection (within 1
year) is found in three times as many children with as
compared with without childhood AIS.16 Second only
to arteriopathy in prevalence, prothrombotic abnor-
malities are present in 30 to 50% of childhood AIS
cases, suggesting a potentially important role of hy-
percoagulability.7–9,11 However, a single prothrom-
botic condition confers only a modest increased risk
for AIS, and hence does not offer a full explanation
for a stroke in a child. Metabolic and genetic diseases
such as homocystinuria or Fabry’s disease and con-

From the 1Department of Pediatrics, Section of Pediatric Neurol-
ogy, University of Colorado and The Children’s Hospital; 2Depart-
ment of Medicine, Section of Hematology/Oncology/Bone Marrow
Transplantation, and the Center for Cancer and Blood Disorders,
University of Colorado and The Children’s Hospital, Denver, CO;
3
Department of Neurology, Division of Child Neurology, Univer-
sity of California, San Francisco, San Francisco, CA; 4Department
of Neurology, Medical College of Wisconsin, Milwaukee, WI; and
5
Department of Pediatrics, University of California, San Francisco,
San Francisco, CA.
Received Jan 11, 2008, and in revised form Mar 14. Accepted for
publication Mar 21, 2008.
T.J.B. and N.A.G. contributed equally to this text.
Published online May 21, 2008, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21406
Address correspondence to Dr Bernard, The Children’s Hospital,
Denver, 13123 East 16th Avenue, Aurora, CO 80045.
E-mail: timothy.bernard@uchsc.edu

© 2008 American Neurological Association 679

Published by Wiley-Liss, Inc., through Wiley Subscription Services
Fig 1. Childhood arterial ischemic stroke (AIS) outcomes from published cohort studies in multiple countries, including Canada,
France, Switzerland, Germany, United Kingdom, and the United States. (A) Percentage of children with persistent neurological
deficits at follow-up. (B) Overall mortality. The country of origin is provided for each cohort together with follow-up duration in
parentheses. (C) Five-year cumulative recurrence risk.

genital syndromes such as PHACES (posterior fossa
malformations, facial hemangioma, arterial cerebro-
vascular anomalies, cardiovascular anomalies, and eye
anomalies) can cause rare, but distinct, presentations
of childhood AIS.14 In other relatively uncommon
cases, cerebral angiography or biopsy can confirm the
diagnosis of cerebral angiitis.17 Although in some in-
stances of AIS, such as sickle cell anemia, vasculitis,
and congenital heart disease, the causative factor of
the stroke is known, the pathophysiology remains un-
clear in the majority of cases. Nevertheless, the strik-
ingly different risk-factor profile for childhood AIS
suggests that childhood AIS is a different disease than
adult AIS.
The high incidence of poor outcomes in childhood
AIS demonstrates the need for improved therapeutic
intervention. Published outcomes in childhood AIS
vary depending on follow-up duration and cohort
characteristics, but recent studies have demonstrated a
mortality rate of 2 to 11% and persistent neurological
deficit in 68-73% of patients (see Fig 1).2– 4,18 –21 In
addition to the high morbidity of childhood AIS, a re-

680 Annals of Neurology Vol 63 No 6 June 2008

cently published US experience reported that the aver-
age cost for the first year of treatment for childhood
AIS is $31,678.22 Long-term costs, including ongoing
rehabilitation, school services, and disability, have yet
to be studied.
Currently, treatment principles in childhood AIS
are largely extrapolated from evidence in adult AIS
because of the paucity of pediatric-specific data. Two
guidelines exist to aid the pediatric subspecialist in
the treatment of childhood AIS: those of the Ameri-
can College of Chest Physicians (ACCP) in the
United States and the Royal College of Physicians
(RCP) in the United Kingdom.23,24 Other than in
the area of sickle cell–related AIS, these management
guidelines are based largely on consensus and expert
opinion (Table 1). Much of their focus is on anti-
thrombotic therapy.
The purpose of this article is to review the current
guidelines and evidence in the treatment of childhood
AIS, within a background of that which exists in adult
AIS.
Intensive and Supportive Care Measures
Supportive measures in childhood AIS are directed at
protecting the ischemic penumbra and are largely based
on adult trials, consensus statements, and general prin-
ciples for management of an acutely ill child. Specific
recommendations regarding treatment of hypoxia, hy-
perthermia, and severe hypertension guide the standard
of care in adult AIS and are likely to benefit pediatric
AIS patients. Still, management of oxygenation, glu-
cose, temperature, and blood pressure has not been
studied extensively in childhood stroke.
Oxygenation
Maintenance of airway, breathing, and circulation are
the first priority in any acutely ill child. The adult
stroke literature suggests that mildly or moderately
hypoxic acute AIS patients (defined by pulse oximetry
as ⬍92% oxygen saturation) should receive supple-
mental oxygen, whereas severely hypoxic patients,
with loss of respiratory drive or the presence of car-
diorespiratory instability, should be intubated and
mechanically ventilated.25,26 The role of oxygen sup-
plementation in well-oxygenated AIS patients is more
controversial.27 Providing high-flow oxygen therapy
via face mask to adult AIS patients with normal ox-
ygen saturations has been associated with transient
improvements in magnetic resonance diffusion-
weighted imaging lesion volume and clinical exami-
nation as compared with patients maintained in room
air, but the long-term benefit of oxygen has yet to be
established.27,28 In fact, one single-center, placebo-
controlled study suggested that 3L/min nasal cannula
oxygen may worsen 1-year outcomes in mild or mod-
erate strokes.29 Studies of oxygenation in childhood
AIS are lacking, but a single consensus guideline from
the RCP advises that oxygen saturation should be
maintained within normal limits (Table 2).24
Treatment of acute childhood AIS with oxygen has
not been studied, and its use in children is extrapolated
from adult stroke literature.
Glucose
Although there is strong evidence that hyperglycemia
and hypoglycemia are associated with poor outcomes
and extension of stroke in adult AIS, there is minimal
evidence in childhood stroke.30 –32 Adult stroke guide-
lines suggest treating hypoglycemia and hyperglycemia,
whereas childhood guidelines do not address the issue
(see Table 2).25 Nevertheless, treatment of hyperglyce-
mia in childhood AIS has been recommended in pedi-
atric stroke texts.33 This is based in part on adult AIS
experience, as well as observations that in critically ill,
nondiabetic children, there is a greater mortality rate
and a longer length of stay in patients with hypergly-
cemia.34,35 Although glycemic control likely improves
outcomes of AIS patients, the degree of morbidity
caused by hyperglycemia remains uncertain, especially
in childhood stroke.25
Treatment of hyperglycemia and hypoglycemia in
the setting of childhood AIS has not been studied, and
current practice in children is extrapolated from adult
stroke and pediatric critical care literature.
Temperature
Hyperthermia leads to a hypermetabolic state in which
substrate (eg, oxygen, glucose) demand is increased; in the
setting of impaired substrate delivery (such as ischemia),
this may lead to heightened supply-demand imbalance,
and hence further neuronal injury. Hyperthermia is
clearly associated with poor prognosis in animal models of
AIS and in prospective cohort studies evaluating morbid-
ity and mortality in adult AIS.36,37 It is unclear whether
treatment of hyperthermia improves prognosis in adult
AIS, although adult stroke guidelines do suggest aggressive
management of hyperthermia.25 In children, hyperther-
mia is associated with longer hospital stay and lower Glas-
gow Coma Scale in patients with traumatic brain injury,
but parallel studies have not been conducted in childhood
AIS.38 Induced hypothermia is a potential treatment strat-
egy for adult AIS, and it improves outcomes of neonates
with hypoxic ischemic encephalopathy.39 – 41 Although
there is lack of direct evidence of pyrexia worsening out-
comes in childhood stroke, various guidelines or expert
texts suggest maintaining euthermia in childhood AIS (see
Table 2).24 Given the benefit of hypothermia to the as-
phyxiated neonatal brain, temperature management may
ultimately prove to be a key factor in the management of
childhood AIS.
Treatment of pyrexia in the setting of childhood AIS
has not been studied, and current practice in children
Bernard et al: Childhood AIS Treatment 681
 Table 1. Level of Evidence Categorization Schemes
RCP Pediatric Guidelines24
A: “At least one meta-analysis,
systematic review or RCT rated as
1⫹⫹ (high quality meta-analyses,
systematic reviews of RCTs, or
RCTs with a very low risk of bias ),
and directly applicable to the target
population; or, a systematic review
of RCTs or a body of evidence
consisting principally of studies rated
as 1⫹ (well-conducted meta-
analyses, systematic reviews of
RCTs, or RCTs with a low risk of
bias), directly applicable to the
target population and demonstrating
overall consistency of results.”
B: “A body of evidence including
studies rated as 2⫹⫹ (high quality
systematic reviews of case control or
cohort studies; high quality case
control or cohort studies with a very
low risk of confounding, bias or
chance and a high probability that
the relationship is causal), directly
applicable to the target population,
and demonstrating overall
consistency of results; or,
extrapolated evidence from studies
rated as 1⫹⫹ (see above), or 1⫹
(see above).”
C: “A body of evidence including
studies rated as 2⫹ (Well-conducted
case control or cohort studies with a
low risk of confounding, bias or
chance and a moderate probability
that the relationship is causal),
directly applicable to the target
population and demonstrating
overall consistency of results; or
extrapolated evidence from studies
rated as 2⫹⫹ (see above).”
D: “Evidence level 3 (non-analytic
studies, eg case reports, case series)
or 4 (expert opinion); or,
extrapolated evidence from studies
rated as 2⫹ (see above).”
RCP ⫽ Royal College of Physicians; ACCP ⫽ American College of Chest Physicians; AHA ⫽ American Heart Association; RCT ⫽
randomized, controlled trial.
is extrapolated from adult stroke and pediatric critical
care literature.
Blood Pressure
Extrapolation of blood pressure management from
adult to childhood AIS is challenging because of the
682 Annals of Neurology Vol 63 No 6
ACCP Pediatric AHA Adult Guidelines25,90
Guidelines23
“Grade 1 recommendations Class I: “Conditions for which there
are strong and indicate is evidence for and/or general
that the benefits do, or do agreement that the procedure or
not, outweigh the risks, treatment is useful and effective.”
burden, and costs.”
“Grade 2 suggests that Class II: “Conditions for which
individual patients’ values there is conflicting evidence and/
may lead to different or a divergence of opinion about
choices the usefulness/efficacy of a
procedure or treatment.”
A: RCTs without important Class IIa: “Weight of evidence or
limitations opinion is in favor of the
procedure or treatment.”
B: RCTs with important Class IIb: “Usefulness/efficacy is less
limitations (inconsistent well established by evidence or
results, methodological opinion.”
flaws)
C⫹: No RCTs but strong Class III: “Conditions for which
RCT results can be there is evidence and/or general
unequivocally extrapolated, agreement that the procedure or
or overwhelming evidence treatment is not useful/effective
from observational studies and in some cases may be
harmful.”
C: Clear observational Level of Evidence A: “Data derived
studies from multiple randomized clinical
trials.”
Level of Evidence B: “Data derived
from a single randomized trial or
nonrandomized studies.”
Level of Evidence C: “Expert
opinion or case studies.”
age-related changes in baseline reference values for
blood pressure in children, and because of the diffi-
culty in obtaining reliable blood pressure measure-
ments in anxious or upset children. The adult literature
remains mixed on the subject of hypertension. Outside
of cases in which thrombolytics are used, multiple
June 2008
 Table 2. Acute Medical Management of Adult and Childhood Arterial Ischemic Stroke
Acute therapy RCP Pediatric
Guidelines24
Oxygen Oxygen saturation should
be maintained within
normal limits. (D)
Temperature Temperature should be
maintained within
normal limits. (D)
Glucose None.
Blood pressure None.
Decompressive surgery Early neurosurgical
referral should be
considered in children
with stroke who have
depressed or
deteriorating conscious
level or other signs of
increased intracranial
pressure.
(Strong Consensus)
RCP ⫽ Royal College of Physicians; ACCP ⫽ American College of Chest Physicians; AHA ⫽ American Heart Association.
adult guidelines suggest permissive hypertension unless
the systolic blood pressure is more than 220mm Hg or
the diastolic blood pressure is more than 120mm
Hg.25 Reduction of blood pressure greater than
20mmHg has been associated with worse neurological
outcomes and larger infarcts, leading to the suggestion
ACCP AHA Adult Guidelines25,90
Pediatric
Guidelines23
None Hypoxic patients with stroke should
receive supplemental oxygen.
(Class I, Level of Evidence C)
None. It is generally agreed that sources of
fever should be treated and
antipyretic medications should be
administered to reduce temperature
in febrile patients with stroke.
(Class I, Level of Evidence C)
None. It is generally agreed that hypoglycemia
should be treated in patients with
acute ischemic stroke.
(Class I, Level of Evidence C)
None. It is generally agreed that patients with
markedly increased blood pressure
may have their blood pressure
lowered. A reasonable goal would be
to reduce blood pressure by 15%
during the first 24 hours after onset
of stroke. The level of blood pressure
that would mandate such treatment
is unknown, but consensus exists that
medications should be withheld
unless the systolic blood pressure is
⬎220mm Hg or the diastolic blood
pressure is ⬎120mm Hg.
(Class I, Level of Evidence C)
None. Decompressive surgery for malignant
edema of the cerebral hemisphere
may be life-saving, but the impact of
morbidity is unknown. Both the age
of the patient and the side of the
infarction (dominant vs nondominant
hemisphere) may affect decisions
about surgery. Although the surgery
may be recommended for treatment
of seriously affected patients, the
physician should advise the patient’s
family about the potential outcomes,
including survival with severe
disability.
(Class IIa, Level of Evidence B)
Decompressive surgical evacuation of a
space-occupying cerebellar infarction
is a potentially life-saving measure,
and clinical recovery may be good.
(Class I, Level of Evidence B)
that even extreme cases of hypertension should be re-
duced by only 15% in the first 24 hours.25,42 How-
ever, despite evidence that abrupt reduction in blood
pressure may extend the stroke penumbra, there is of-
ten no independent association with poor outcome and
antihypertensive medicines themselves.43 One antihy-
Bernard et al: Childhood AIS Treatment 683
pertensive, nimodipine, has demonstrated greater mor-
tality rates and increased poor outcomes, whereas dem-
onstrating decreased infarct size in human and animal
models.44 – 46 As is the case for glycemic control, blood
pressure control in childhood AIS is not addressed in
current guidelines, although one expert text suggests
aiming for mild hypertension with a systolic blood
pressure greater than 75% for age in childhood AIS
(see Table 2).33 Devoted pediatric investigation is
needed in this area.
Treatment of hypertension and hypotension in the
setting of childhood AIS has not been studied, and
current practice in childhood AIS is extrapolated from
adult stroke literature.
Increased Intracranial Pressure
Acute management of large-distribution AIS in chil-
dren and adults often involves management of in-
creased intracranial pressure (ICP) secondary to edema
and/or mass effect on the ventricles. Because of the rel-
atively small space between the cranial vault and brain
parenchyma, children typically have less of an anatomic
buffer than adults for significant brain edema, and they
require close monitoring for signs and symptoms of in-
creased ICP during the first 72 to 96 hours after a
large infarct. A recent pooled analysis of adult AIS pa-
tients with large middle cerebral artery stroke and early
edema (⬍45 hours) demonstrated that decompressive
surgical intervention decreased mortality and improved
outcomes, as compared with conservative medical man-
agement.47 In a meta-analysis combining the data of
93 subjects from three small, randomized, controlled
trials (DECIMAL, DESTINY, HAMLET), mortality
for conservative management in adult AIS patients
with early brain edema was 71% as compared with
22% for decompressive surgical intervention.47 How-
ever, 35% of surgically managed adult AIS patients
with early brain edema are unable either to walk or
perform activities of daily living without assistance, as
compared with 7% of patients receiving conservative
management.48 The American Heart Association
(AHA) recommends that “although the [de-
compressive] surgery may be recommended for treat-
ment of seriously affected patients, the physician
should advise the patient’s family about the potential
outcomes, including survival with severe disability.”25
Although some case reports document favorable out-
come after decompressive surgery in large middle cere-
bral artery childhood AIS, evidence and guidelines are
lacking in the childhood stroke.49 The RCP does rec-
ommend that early neurosurgical referral should be
considered in children with stroke who have depressed
or deteriorating conscious level or other signs of in-
creased ICP (see Table 2).24
Treatment of increased ICP in the setting of child-
hood AIS has not been studied, and current practice
684 Annals of Neurology Vol 63 No 6 June 2008
in childhood AIS is extrapolated from adult stroke
literature.
Hyperacute Therapies
Clot Lysis and Mechanical Removal
Tissue plasminogen activator (tPA) is used acutely in
adult AIS as a profibrinolytic agent, lysing intracerebral
clots and thereby restoring blood flow to compromised
regions of brain. Presumably, thrombolysis offers the
principal advantage of salvaging ischemic tissue that
has not yet infarcted. tPA is an intrinsic activator of
the fibrinolytic system and can be used as an acute
thrombolytic agent, converting endogenous plasmino-
gen to plasmin.23 Based on adult AIS randomized,
controlled, clinical trial findings of reduced morbidity
and mortality in patients treated with intravenous tPA,
adult AIS patients are now routinely given systemic
tPA when presenting within 3 hours of stoke onset.50
A dose of 0.9mg/kg (maximum, 90mg) is used, with
10% of the dose given as a bolus over the first minute,
and the remaining dose given as a 1-hour infusion.
Other hyperacute therapies used in adults include in-
traarterial (IA) administration of tPA or other throm-
bolytics and endovascular clot retrieval devices. These
endovascular options extend the time window for treat-
ment up to 8 hours for AIS involving the anterior cir-
culation, and even longer in cases involving the poste-
rior circulation.25,51,52
In the National Institute of Neurological Diseases
and Stroke trial, intravenous tPA was associated with a
10-fold increased risk for symptomatic intracerebral
hemorrhage: 6.4% in treated patients, as compared
with 0.6% of untreated patients.50 Despite this in-
creased risk, the treatment group experienced improved
neurological outcome at 3 months. Two randomized,
multicenter, controlled trials have evaluated the efficacy
of IA thrombolysis in adult AIS patients with middle
cerebral artery occlusion and have been reported, PRO-
ACT I and PROACT II.53,54 Although PROACT II
demonstrated a 10.9% hemorrhage rate in patients
treated with IA urokinase as compared with 3.1% of
the intravenous unfractionated heparin control group,
recanalization was improved from 18% to 66% in the
urokinase group. Rankin score at 90 days was also sig-
nificantly improved in the patients who received IA
treatment. Recently, retrieval devices, such as the
MERCI L5 Retriever, have demonstrated recanaliza-
tion rates as high as 57%, and are even greater when
coupled with thrombolytic agents.55
There have been no RCTs performed on the use of
tPA or IA therapies in childhood AIS, and it remains
unclear whether the cost/benefit ratio would similarly
tip in favor of treatment. This will require devoted pe-
diatric study, rather than extrapolation from adult evi-
dence, given the following factors: (1) principal risk
factors for AIS differ considerably between children
and adults; (2) mortality and morbidity appear to dif-
fer considerably for childhood versus adult AIS (ie,
children likely have better spontaneous recovery); and
(3) optimal tPA doses are likely to differ between chil-
dren and adults, given laboratory evidence of signifi-
cant differences in baseline fibrinolytic parameters be-
tween the two populations.23,56 –58 It is interesting to
note in the latter regard that, although some individual
fibrinolytic proteins and indices (eg, ratios of tPA/plas-
minogen activatory inhibitor-1) have suggested reduced
fibrinolytic function in children compared with adults,
truly functional global assessments of fibrinolytic ca-
pacity have recently suggested enhanced fibrinolytic ca-
pacity in children relative to adults.56 Given the uncer-
tainty surrounding fibrinolytic activity in children
relative to adults and the lower levels of systemic tPA
in pediatric patients, pediatric dosing requirements
may differ from adult standards. One theoretical ad-
vantage of mechanical embolectomy over thrombolytic
use in children is that these developmental changes in
fibrinolysis are less relevant.
Multiple case reports and one case series have re-
ported the use of systemic and IA thrombolytic therapy
in childhood AIS, with mixed results.59 – 67 In fact, Jan-
jua and colleagues68 found that 46 of 2,904 children
(1.6%) with ICD-9 codes for stroke between 2000 and
2003 in the National Inpatient Sample in the United
States received a procedure code for thrombolytic ther-
apy, suggesting that practitioners may be using tPA for
the treatment of childhood stroke. However, a case se-
ries from the International Pediatric Stroke Study dem-
onstrated that approximately half of children who re-
ceived systemic or IA thrombolytic therapy did so
outside of the timeline established by AHA guidelines
in adult AIS.59
In contrast with the extensive research and detailed
recommendations in the adult literature, pediatric sub-
specialists have minimal guidance in treating childhood
AIS with thrombolytics (Table 3). A multicenter col-
laborative clinical trial approach with stringent uniform
exclusion criteria will be required to address whether
the benefits of hyperacute thrombolytics in AIS, and
the time window for this intervention, also apply to
children.
The use of IA tPA, IA devices, and systemic tPA in
acute childhood AIS is based on evidence from a few
case reports and a single case series, as well as extrap-
olation from the adult literature.
Antiplatelet Therapy
Acute Treatment
Whereas hyperacute strategies such as tPA are used to
improve outcome after AIS, antithrombotic agents are
a standard treatment in both children and adults for
prevention of stroke recurrence. Aspirin is the most
widely used antiplatelet therapy in childhood AIS.
Other antiplatelet agents, such as dipyridamole, ticlo-
pidine, clopidogrel, and glycoprotein IIb-IIIa antago-
nists, are infrequently used in childhood AIS.69 The
antithrombotic effect of aspirin results largely from
irreversible inhibition of the cyclooxygenase-1 enzyme
in platelets, leading to impaired platelet aggregation
and activation, although recent studies have suggested
an additional effect of noncyclooxygenase-1 path-
ways.23,70
Two large multicenter trials have evaluated the effi-
cacy of aspirin in adult AIS, when given within 48
hours of symptom onset.71,72 When analyzed together,
these trials demonstrate a significant protective effect of
aspirin against in-hospital AIS recurrence (160 and
300mg, respectively), providing an absolute risk reduc-
tion of 7 per 1,000 adult AIS patients.71–73 Hemor-
rhagic transformation or hemorrhagic stroke is in-
creased by only 2 in 1,000, whereas other bleeding
complications rarely lead to adverse outcomes.73 Based
on these trials, the AHA recommends the administra-
tion of aspirin 325mg within 24 to 48 hours of symp-
tom onset in adult AIS, unless the patient has received
thrombolytic therapy or has other contraindications
(see Table 3).25
In acute childhood AIS, there are no trials that eval-
uate the efficacy of aspirin or other antiplatelet thera-
pies. Extrapolating from the adult literature and guide-
lines, the RCP recommends initial treatment with
aspirin 5mg/kg/day in the setting of acute AIS in child-
hood, excluding sickle cell patients and patients with
evidence of hemorrhage (see Table 3).24
Secondary Prevention
Large adult studies have demonstrated the equivalence
of aspirin and anticoagulation for prevention of recur-
rent stroke in AIS. The WARSS (Warfarin–Aspirin Re-
current Stroke Study) trial was a 48-center, placebo-
controlled, blinded, randomized trial comparing
warfarin (international normalized ratio, 1.4 –2.8) and
aspirin (325mg/day) for the prevention of recurrent
noncardioembolic stroke, and found no significant dif-
ference in either efficacy or adverse effects.74
Adverse effects of aspirin in adult AIS secondary pre-
vention are generally limited to hemorrhage, gastritis,
and rare anaphylactic reactions.75 In pediatric patients,
however, Reye’s syndrome is a specific concern. Reye’s
syndrome is characterized by mitochondrial dysfunc-
tion, leading to noninflammatory liver failure and en-
cephalopathy.76,77 Typically, the disease has a viral
prodrome 3 to 5 days before onset, often associated
with influenza or varicella.66 Death is the outcome in
nearly 30 to 40% of cases. Metabolic abnormalities,
such as Medium-Chain Acyl-CoA Dehydrogenase De-
ficiency, are commonly responsible for Reye’s syn-
Bernard et al: Childhood AIS Treatment 685
 Table 3. Antithrombotic Management of Adult and Childhood Arterial Ischemic Stroke
RCP Pediatric ACCP Pediatric AHA Adult Guidelines25,90
Guidelines24 Guidelines23

Acute systemic No specific No specific Intravenous rtPA (0.9mg/kg; maximum

thrombolysis guideline, but guideline, but dose, 90mg) is recommended for
the following the following selected patients who may be treated
comment: comment: within 3 hours of onset of ischemic
“There is “The use of stroke.
currently no thrombolytic (Class I, Level of Evidence A)
evidence to agents in
support use of children with
thrombolytic AIS, however,
agents such as has been rare,
tissue and the risk/
plasminogen benefit ratio is
activator (tPA) unknown at
in the acute this time.”
treatment of
arterial
ischaemic stroke
in children.”
Acute intraarterial None. None. Intraarterial thrombolysis is an option
thrombolysis for treatment of selected patients who
have major stroke of ⬍6 hours’
duration because of occlusions of the
MCA and who are not otherwise
candidates for intravenous rtPA.
(Class I, Level of Evidence B)
Acute, nonthrombolytic Aspirin (5mg/kg/ For children with The oral administration of aspirin
management of day) should be AIS, we suggest (initial dose, 325mg) within 24 to 48
idiopathic AIS given once there treatment with hours after stroke onset is
is radiological UFH or recommended for treatment of most
confirmation of LMWH for patients.
arterial ischemic 5-7 days and (Class I, Level of Evidence A)
stroke, except in until
patients with cardioembolic
evidence of stroke or
intracranial vascular
hemorrhage on dissection has
imaging and been excluded.
those with sickle (Grade 2C)
cell disease.
(Strong
Consensus)
RCP ⫽ Royal College of Physicians; ACCP ⫽ American College of Chest Physicians; AHA ⫽ American Heart Association; AIS ⫽
arterial ischemic stroke; rtPA ⫽ recombinant tissue plasminogen activator; MCA ⫽ middle cerebral artery; UFH ⫽ unfractionated
heparin; LMWH ⫽ low-molecular-weight heparin.

drome.78 There is an association between Reye’s syn-
drome and aspirin usage that dates back to the
1980s.79,80 Since general discontinuation of aspirin in
pediatrics in the early 1980s, the incidence of Reye’s
syndrome has greatly declined.79,81 Consequently,
childhood AIS patients taking aspirin should have a
yearly flu shot and close monitoring during flu-like ill-
nesses.
Aspirin is typically the first-line treatment for sec-
ondary prevention of recurrent childhood AIS.69 In
fact, both the RCP and the ACCP guidelines suggest
aspirin as secondary prevention in childhood AIS,
when sickle cell disease, dissection, and cardioembolic
sources have been excluded (Table 4). Dosing recom-
mendations vary between groups; the ACCP guidelines
suggest 2 to 5mg/kg/day, whereas the RCP guidelines
recommend lower doses (1–3mg/kg/day). A single,
nonrandomized, prospective study comparing aspirin
(4mg/kg) and low-dose low-molecular-weight heparin
(LMWH) in 135 children with AIS demonstrated sim-
ilar AIS recurrence and bleeding risks between the two
agents.19,82 These pediatric cohort study findings have
never been confirmed in a randomized, controlled trial
in childhood AIS.

686 Annals of Neurology Vol 63 No 6 June 2008

Table 4. Secondary Prevention in Adult and Childhood Arterial Ischemic Stroke
Secondary RCP Pediatric ACCP Pediatric AHA Adult Guidelines90
Prevention Guidelines24 Guidelines23

Secondary Patients with cerebral For all children with For patients with noncardioembolic
prevention arteriopathy other AIS, we suggest ischemic stroke or TIA, antiplatelet
of idiopathic than arterial treatment with agents rather than oral
AIS dissection or aspirin, 2–5mg/kg/ anticoagulation are recommended to
moyamoya syndrome day, after reduce the risk for recurrent stroke
or those with sickle anticoagulation and other cardiovascular events.
cell disease should be therapy has been (Class I, Level of Evidence A)
treated with aspirin discontinued. Aspirin (50–325mg/day), the
(1–3mg/kg/day) (Grade 2C) combination of aspirin and extended-
(Strong Consensus) release dipyridamole, and clopidogrel
are all acceptable options.
(Class IIa, Level of Evidence A)
Secondary Providing there is no For children with AIS For patients with ischemic stroke or
prevention hemorrhage on brain and vascular TIA and extracranial arterial
of AIS in imaging, dissection, we dissection, use of warfarin for 3 to 6
dissection anticoagulation should suggest treatment months or use of antiplatelet agents
be considered in for 5 to 7 days is reasonable.
children with with UFH or (Class IIa, Level of Evidence B).
confirmed extracranial LMWH followed Beyond 3 to 6 months, long-term
arterial dissection by therapy with antiplatelet therapy is reasonable for
associated with arterial LMWH or VKAs most stroke or TIA patients.
ischemic stroke. for 3 to 6 months. Anticoagulant therapy beyond 3 to 6
Anticoagulation (Grade 2C) months may be considered among
should be considered patients with recurrent ischemic
until there is evidence events.
of vessel healing, or (Class IIb, Level of Evidence C)
for a maximum of 6
months.
(Strong Consensus)
Secondary Anticoagulation should For children with AIS For patients with ischemic stroke or
Prevention be considered in and cardioembolic TIA who have cardioembolic AIS,
of Cardio- children with cardiac stroke, we suggest either warfarin (INR, 2.0–3.0) or
embolic AIS sources of embolism, treatment for 5 to 7 antiplatelet therapy may be
following discussion days with UFH or considered for prevention of recurrent
with the cardiologist LMWH followed by events depending on the cardiac
managing the patient therapy with causative factor.
(Strong Consensus) LMWH or VKAs (Class I-II, Level of Evidence A-C)
for 3 to 6 months.
(Grade 2C)
Secondary None. None. For cases of cryptogenic ischemic stroke
prevention in or TIA and positive APL antibodies,
the setting of antiplatelet therapy is reasonable.
APL (Class IIa, Level of Evidence B)
antibodies For patients with ischemic stroke or TIA
who meet the criteria for the APL
antibody syndrome with venous and
arterial occlusive disease in multiple
organs, miscarriages, and livedo
reticularis, oral anticoagulation with a
target INR of 2 to 3 is reasonable.
(Class IIa, Level of Evidence B)
Secondary None. None. Patients should be evaluated fully for
prevention alternative mechanisms of stroke. In
in the the absence of venous thrombosis,
setting of long-term anticoagulants or
inherited antiplatelet therapy is reasonable.
thrombophilia (Class IIa, Level of Evidence C)
RCP ⫽ Royal College of Physicians; ACCP ⫽ American College of Chest Physicians; AHA ⫽ American Heart Association; AIS ⫽
arterial ischemic stroke; UFH ⫽ unfractionated heparin; LMWH ⫽ low-molecular-weight heparin; VKA ⫽ vitamin K antagonist;
INR ⫽ international normalized ratio; TIA ⫽ transient ischemic attack; APL ⫽ antiphospholipid.

Bernard et al: Childhood AIS Treatment 687

 The use of aspirin for secondary prevention of acute
childhood AIS is based on evidence from case reports
and cohort studies, as well as extrapolation from the
randomized, controlled trials in the adult literature.
Anticoagulant Therapy
Acute Treatment
Heparins, including unfractionated heparin and
LMWH, are the principal agents used in the acute
phase of anticoagulant therapy for AIS. Heparins en-
hance the activity of antithrombin, an intrinsic anti-
coagulant that serves as a key inhibitor of thrombin.
Young infants, particularly neonates, have lower levels
of antithrombin than adults, decreasing the biological
effects of heparin, and thereby increasing the dosing
requirements for young infants and neonates. Unfrac-
tionated heparin doses are age dependent, with
younger children requiring greater average doses
(20U/kg/hr) than older children and adults; similar
observations have been made for LMWHs.83,84 Bolus
dosing of unfractionated heparin is typically avoided
in AIS. In children, heparin therapy is monitored
most accurately by anti–factor Xa activity. For unfrac-
tionated heparin, the therapeutic range is 0.35 to 0.7
anti–factor Xa activity U/ml, whereas for LMWH,
the therapeutic range is 0.5–1.0U/ml.23 Side effects
of unfractionated heparin include bleeding, osteopo-
rosis, and heparin induced thrombocytopenia (HIT),
the latter occurring in 2.3% of critically ill pa-
tients.23,85 Risks for osteoporosis and HIT appear to
be substantially lower for LMWH than for unfrac-
tionated heparin.
Based on the high rates of prothrombotic abnormal-
ities, cardioembolic stroke and dissection in childhood
AIS, and the accumulating safety data, ACCP guide-
lines recommend treatment with unfractionated hepa-
rin or LMWH for 5 to 7 days and until cardioembo-
lism or vascular dissection have been excluded.
However, this recommendation remains controversial,
and the RCP recommends initial treatment of child-
hood AIS with aspirin 5mg/kg until an indication for
anticoagulation is found (see Table 3).23,24
Secondary Prevention
When aspirin is not preferred, LMWH and warfarin
are the primary anticoagulants used as subacute ther-
apy for secondary prevention of childhood AIS. War-
farin acts through antagonism of vitamin K, thereby
interfering with ␥-carboxylation of the vitamin K–de-
pendent procoagulant factors II, VII, IX, and X, as
well as proteins C and S. Warfarin skin necrosis is a
rarely observed but a potentially severe and prevent-
able complication, occurring in patients with protein
C deficiency during the initiation of warfarin therapy
without concomitant therapeutic heparin.86 The ma-
688 Annals of Neurology Vol 63 No 6 June 2008
jor adverse effect in pediatric patients taking warfarin
is bleeding, occurring in 0.5 to 5% of patients per
year.87,88 In one large series, managing 319 patients
receiving prophylactic warfarin for multiple reasons,
only 2 serious complications were noted: a subdural
hemorrhage and a hematoma with subsequent anemia
requiring transfusion.88 Long-term warfarin use may
cause osteoporosis because vitamin K is essential for
bone mineralization, and patients on long-term war-
farin have associated decreased bone density.89 In
children, this may be a particularly important consid-
eration because of the potential of multiple years of
therapy if the decision is made to provide life-long
anticoagulation.
Unfractionated heparin, LMWH, and warfarin are
all agents utilized by child neurologists and hematol-
ogists for secondary stroke prevention in childhood.69
The RCP and ACCP guidelines specifically recom-
mend anticoagulation over antiplatelet therapy in two
childhood AIS subtypes: arterial dissection and car-
dioembolic stroke (see Table 4).23,24 This limited rec-
ommendation is extrapolated from the adult trials,
described earlier, suggesting no increased benefit (and
potential harm) for anticoagulation compared with
aspirin outside the setting of arterial dissection and
cardioembolic stroke (atrial fibrillation, cardiomyopa-
thy, mural thrombus, and prosthetic heart valves).90
Hence, AHA guidelines recommend anticoagulation
for some cardioembolic events and state that antico-
agulation is reasonable in AIS with some inherited
thrombophilias and should be used in antiphospho-
lipid antibody syndrome (see Table 4).90
It is notable that meta-analysis data in adult AIS
indicate that the number needed to treat to prevent
one case of recurrent adult AIS is 10 for anticoagula-
tion, as compared with 135 for aspirin.91 This poten-
tial benefit of anticoagulation appeared to be out-
weighed by the relative increase in bleeding
complications. When these findings are extrapolated
to children, it is important to recognize that the rate
of bleeding complications for anticoagulation for
other disease states (principally, acute venous throm-
boembolism) appears to be substantially lower than
that observed in adults. Whether the risk for intracra-
nial hemorrhage associated with anticoagulation in
AIS is lower among children as compared with adults
is unclear and warrants further investigation via ran-
domized, controlled trials in childhood AIS.
In pediatric stroke, retrospective studies have sug-
gested that LMWH appears to be safe in childhood
AIS, without a high risk for intracranial hemorrhage
or HIT.82,92 Strater and colleagues19 retrospectively
reviewed 86 consecutive subjects receiving LMWH
(enoxaparin 1–1.5mg/kg/dose once daily or dalteparin
75–125 anti–factor Xa U/kg/dose once daily) without
any adverse events, including local or systemic hem-
orrhage or HIT. Burak and coauthors92 reported
eight patients receiving a conventional enoxaparin
regimen (1mg/kg/dose given twice daily [up to
120mg/day]), who had only minimal side effects: one
episode of epistaxis and one oozing at an intravenous
site.
The use of anticoagulation for treatment of acute
childhood stroke and secondary prevention of child-
hood stroke is based on evidence from case reports and
cohort studies, as well as extrapolation from the ran-
domized, controlled trials in the adult literature.
Therapeutic Intervention in Selected Cases:
Moyamoya, Sickle Cell Disease, and Other Rare
Disorders
The mechanisms of childhood AIS in moyamoya,
sickle cell disease, vasculitis, and genetic/metabolic dis-
orders are unique and, therefore, require distinct ther-
apeutic approaches.
Moyamoya is a progressive occlusive vasculopathy
of the distal internal carotids and its proximal
branches (Fig 2). Its idiopathic form is typically re-
ferred to as moyamoya “disease,” whereas moyamoya
“syndrome” includes secondary forms due to sickle
cell disease, trisomy 21, neurofibromatosis type 1, ra-
diation injury, or atherosclerosis. Moyamoya syn-
drome is usually treated with surgical intervention be-
cause there is a high risk for not only recurrent AIS
but also intracranial hemorrhage caused by abnormal
collateral vessels, limiting antithrombotic options.
Neurosurgical approaches at revascularization includ-
ing indirect bypass procedures, such as encephalodu-
roarteriomyosynangiosis and encephaloduroarterio-
synangiosis, have demonstrated collateralization and
resolution of symptoms in as many as 84% of pa-
tients.93,94 Direct bypass procedures, such as superfi-
cial temporal artery branch-to-middle cerebral artery
branch bypass, have also shown effective collateraliza-
tion and resolution of symptoms but are technically
more challenging than encephaloduroarteriosynangio-
sis and encephaloduroarteriomyosyangiosis.95 Some neu-
rosurgeons have used a combination of these tech-
niques.96 There are no randomized prospective trials
comparing surgical techniques, and hence the best strat-
egy for revascularization remains uncertain (Table 5).
Sickle cell disease results in both small-vessel infarc-
tions and large-vessel AIS due to moyamoya syndrome.
For acute AIS in the setting of sickle cell disease, both
RCP and ACCP guidelines recommend urgent eryth-
rocyte exchange transfusion to reduce hemoglobin S
levels to less than 30% of total hemoglobin.23,24 In ad-
dition, primary prevention of AIS in pediatric sickle cell
has been guided by the findings of the Stroke Preven-
tion Trial in Sickle Cell Anemia trial. In this multi-
center, randomized, controlled trial, 130 children with
increased velocity of intracranial arterial blood flow (a
consequence of arterial narrowing) as measured by
transcranial Doppler were randomized to primary AIS
prophylaxis involving a regular exchange transfusion
program designed to reduce hemoglobin S to less than
30% of total hemoglobin versus no intervention.97,98
In the control group, the yearly stroke risk remained
10%, whereas that of the experimental group was re-
duced to 1%. Therefore, for primary stroke prevention
in sickle cell disease, RCP and ACCP guidelines also
recommend that patients older than 2 years who have
sickle cell disease be screened yearly with transcranial
Doppler and placed on a chronic transfusion regimen
if found to have increased velocities (see Table 5).23,24
Unfortunately, the end point of this highly intensive
therapy (which typically requires surgical placement of
a long-term, large-caliber, indwelling central venous ac-
cess device) is unclear.99
Treatment of other rare rheumatological, metabolic,
and genetic diseases, such as CNS angiitis, Fabry’s dis-
ease, homocystinuria, or CADASIL (Cerebral Autoso-
mal Dominant Arteriopathy with Subcortical Infarcts
and Leukoencephalopathy), requires specific interven-

Fig 2. Moyamoya in a 7-year-old girl with a history of craniopharyngioma treated with cranial irradiation. Note the narrowing of
the right distal internal carotid artery and the proximal middle cerebral artery (black arrows) on the anteroposterior (A) and lat-
eral (B) conventional angiogram, as well as the extensive collateralization (white arrows). The left side has a similar appearance.
The magnetic resonance imaging T2 sequence demonstrates right middle cerebral artery territory atrophy and hyperintense signal
change (gray arrows), suggestive of previous, and likely chronic, ischemia.

Bernard et al: Childhood AIS Treatment 689

 Table 5. Special Cases of Pediatric Arterial Ischemic Stroke: Moyamoya and Sickle Cell
RCP Guidelines24 ACCP Guidelines23

AIS and sickle cell In children with sickle cell disease and For children with sickle cell disease who
ischemic stroke: (1) urgent exchange are 2 years old, we recommend
(Strong Consensus) screening for stroke using transcranial
Doppler imaging. If transcranial
Doppler imaging is unavailable, we
recommend intermittent screening
with MRI.
(Grade 1C)
Arterial transfusion should be undertaken to For children with sickle cell disease who
reduce hemoglobin S to ⬍30% and have ischemic stroke, we recommend
increase hemoglobin to 10–12.5gm/dl; (2) therapy with IV hydration and
if the patient has had a neurological event exchange transfusion to reduce
in the context of severe anemia (eg, splenic hemoglobin S levels to 30% total
sequestration or aplastic crisis), or if hemoglobin (Grade 1C).
exchange transfusion is going to be delayed
for more than 4 hours, urgent top-up blood
transfusion should be undertaken.
In children with sickle cell disease [and a For children with sickle cell disease who
history of childhood AIS]: (1) regular blood have ischemic stroke, after an initial
transfusion (every 3–6 weeks) should be exchange transfusion, we suggest a
undertaken to maintain the hemoglobin S% long-term transfusion program
⬍ 30% and the hemoglobin level between (Grade 2C).
10 and 12.5gm/dl; (2) transfusion may be
stopped after 2 years in patients who
experienced stroke in the context of a
precipitating illness (eg, aplastic crisis) and
whose repeat vascular imaging is normal at
this time; (3) after 3 years a less intensive
regimen maintaining hemoglobin S ⬍ 50%
may be sufficient for stroke prevention; and
(4) those who cannot receive regular blood
transfusions because of alloimmunization,
autoantibody formation, lack of vascular
access, or noncompliance with transfusion
or chelation may be considered for
treatment with hydroxyurea.(C)
AIS and Children with moyamoya syndrome None.
moyamoya (including those with sickle cell disease)
should be referred for evaluation to a center
with expertise in evaluating patients for
surgical revascularization. (D)
RCP ⫽ Royal College of Physicians; ACCP ⫽ American College of Chest Physicians; AIS ⫽ arterial ischemic stroke; MRI ⫽ magnetic
resonance imaging; IV ⫽ intravenous.

tions that target the underlying disorder. For example, Rehabilitation

Fabry’s disease, a type of lysosomal storage disease, is
treated with enzyme replacement therapy.100
Treatment of AIS in the setting of moyamoya syn-
drome is based on data from case reports and case se-
ries, and usually involves surgical revascularization. Pri-
mary and secondary prevention of AIS in the setting of
sickle cell disease is based on randomized controlled
trials in children with sickle cell anemia. Treatment of
other rare rheumatological, genetic, and metabolic dis-
eases warrant therapies targeted at the underlying con-
dition.
In addition to acute treatment and secondary preven-
tion of childhood AIS, rehabilitation has the potential
to favorably impact long-term morbidity, as well as
quality of life and emotional health. In a recent survey
of both parents and children, the most important goal
in stroke therapy from a child’s perspective was to not
be perceived as “different” from their peers, both in
appearance and function.101 Historically, multidisci-
plinary efforts from child life specialists, psychologists,
and occupational, physical, and speech therapists have
been integral to childhood stroke rehabilitation. The

690 Annals of Neurology Vol 63 No 6 June 2008

RCP accordingly recommends such a multidisciplinary
approach to rehabilitative therapies in childhood AIS,
utilizing a biopsychosocial model.24 Other adjunctive
therapies have shown promise in animal models in re-
cent years and are now being studied in both adults
and children with stroke, including constraint-induced
movement therapy (CIMT) and transcranial magnetic
stimulation. These approaches offer hope for safely
achieving meaningful improvements in motor outcome
months to years after stroke.
Constraint-Induced Movement Therapy
Early work in primates supported the theory of “forced
use” in neurorehabilitation; that is, allowing the deaf-
ferented (paretic) arm to be retrained by constraining
the less affected arm.102–105 Data suggesting the effec-
tiveness of CIMT in stroke and traumatic brain injury
in humans have been encouraging to date.106 –120 The
Extremity Constraint Induced Therapy Evaluation
(EXCITE) trial randomized adults with subacute AIS
to CIMT with intensive physical therapy versus inten-
sive physical therapy alone, for a treatment period of 2
weeks.120 The CIMT regimen consisted of wearing a
safety mitt on the less affected limb for approximately
90% of waking hours over a 2-week period, whereas
also undergoing intensive therapy on the affected limb
for 6 hours per day. The CIMT group showed a sig-
nificantly greater improvement in motor function of
the paretic arm than the control group, which persisted
for at least 1 year.
The use of CIMT in children is especially pertinent,
given the plasticity and potential for cerebrocortical re-
organization in the young brain. Many case series and
observational studies in children have reported on
CIMT in both stroke and hemiplegic cerebral palsy, al-
though with varying results.101,121–131 Two randomized,
controlled clinical trials of CIMT in children with cere-
bral palsy with asymmetric motor impairment have been
performed.126,130 These studies show improvement not
only in acquisition of motor skills, but also improve-
ment in the quality of those skills, as well as subjective
quality-of-life gains. Follow-up studies have suggested
that repeated courses of CIMT may be beneficial to help
maintain retention of these motor skills.123
Transcranial Magnetic Stimulation
Transcranial magnetic stimulation (TMS) is a relatively
safe, noninvasive technique to stimulate the cerebral
cortex.132,133 At higher frequencies, TMS increases the
excitability in the corticospinal system.134 –136 It is the-
orized that damage from stroke may cause lower excit-
ability of the motor cortex; thus, adjunctive target ex-
citability from TMS may facilitate relearning and
restoration of motor function. Although TMS alone
has not been shown to be efficacious in adults, the
pairing of this modality with CIMT or behavioral ther-
apy may be beneficial.137,138 Recently, a small, ran-
domized, controlled trial in pediatric AIS patients with
chronic hemiparesis showed dose-dependent improve-
ments in hand strength with the use of TMS as com-
pared with no TMS. Further studies of TMS as an
adjunctive approach in the treatment of pediatric AIS
are under way.139
Future Directions in Therapy
Because of the paucity of data regarding treatment of
childhood AIS, we lack clear treatment strategies for
acute, subacute, and rehabilitative care. Extrapolation
from adult literature is suboptimal given the clear dif-
ference in risk factors and pathogenesis. The relative
rarity of childhood stroke presents a major obstacle to
performing clinical trials. Risk stratification methods
will be needed to identify populations at the greatest
risk for poor outcomes and recurrence to reduce the
required sample size. Recent studies identifying vascu-
lopathy as a strong predictor of recurrence both exem-
plify the need for secondary stroke prevention trials in
children and present an opportunity to target a high-
risk population. Multicenter studies that utilize com-
mon definitions will be needed. Likewise, through col-
laborative investigations into the pathogenesis of the
arteriopathies associated with childhood stroke, more
effective standard therapeutic options targeting the un-
derlying mechanisms may be developed. Currently,
members of the International Pediatric Stoke Study are
embarking on these efforts.
At the same time, new agents must be explored via a
rational approach. For example, because research on
neuroprotective agents, such as glutamate receptor an-
tagonists and estrogen, is translated from animal mod-
els to adult human treatment trials, evaluation in chil-
dren will be important.140,141 However, investigators
will have to take into account developmental changes
in cellular metabolism and the response to oxidative
stress.142 Similarly, although many promising neuro-
protective agents, such as NXY-059, have failed to ben-
efit adult stroke patients, we cannot simply conclude
they would also lack efficacy in children.143 Of partic-
ular interest in childhood stroke, given the association
between arteriopathy and varicella, will be the research
in the area of antiviral, antimicrobial, and anti-
inflammatory treatments, such as the recent trial eval-
uating mezlocillin plus sulbactam over 4 days in acute
adult AIS patients.144 Finally, the potential roles of hy-
pothermia and stem cell infusion, which have shown
promise in neonatal hypoxic ischemic encephalopathy
and adult ischemic brain injury, should undoubtedly
be explored in pediatric AIS.40,145–149
Conclusions
Intensive supportive management, antithrombotic ther-
apy, and rehabilitation techniques are critical compo-
Bernard et al: Childhood AIS Treatment 691
nents in the management of children with AIS, to op-
timize outcomes. Although the pathophysiology and
outcomes of adult AIS differ significantly from those in
childhood AIS, therapeutic management currently re-
mains similar, largely because of the paucity of evi-
dence from devoted pediatric observational studies and
clinical trials. Medical management of hypoxia, hyper-
glycemia, fever, blood pressure, and increased ICP has
been insufficiently investigated in childhood stroke, re-
sulting in a lack of guidance in these areas for the gen-
eralist treating clinician and pediatric stroke specialist
alike. Although it has received relatively greater atten-
tion in published recommendations, acute antithrom-
botic management in childhood AIS is based almost
exclusively on consensus and expert opinion, and fre-
quently extrapolates from class 1 evidence in adult AIS.
Not surprisingly, considerable variability exists both
among current pediatric guidelines and in actual clini-
cal practice. Significant questions remain as to a role
for hyperacute therapy, such as thrombolytics, and the
indications for anticoagulation versus antiplatelet ther-
apy. Rehabilitation therapy in childhood AIS yields
long-term improvement in outcome that has potential
to be greater than that observed in adults, given greater
brain plasticity at a young age, and evidence is emerg-
ing that newer adjunctive modalities may provide ad-
ditional benefit in restoration of motor function. Ded-
icated pediatric studies are critically necessary to
establish key evidence informing multifaceted manage-
ment in childhood AIS.
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