Acute Hospital Management of Pediatric

Stroke
Taryn-Leigh Surtees,* Rachel Pearson,†,z Dana B. Harrar,x Sarah Lee,║
Catherine M. Amlie-Lefond,{ and Kristin P. Guilliams*,#

The field of pediatric stroke has historically been hampered by limited evidence and small
patient cohorts. However the landscape of childhood stroke is rapidly changing due in part to
increasing awareness of the importance of pediatric stroke and the emergence of dedicated
pediatric stroke centers, care pathways, and alert systems. Acute pediatric stroke manage-
ment hinges on timely diagnosis confirmed by neuroimaging, appropriate consideration of
recanalization therapies, implementation of neuroprotective measures, and attention to sec-
ondary prevention. Because pediatric stroke is highly heterogenous in etiology, management
strategies must be individualized. Determining a child’s underlying stroke etiology is essen-
tial to appropriately tailoring hyperacute stroke management and determining best approach
to secondary prevention. Herein, we review the methods of recognition, diagnosis, manage-
ment, current knowledge gaps and promising research for pediatric stroke.
Semin Pediatr Neurol 43:100990 © 2022 Elsevier Inc. All rights reserved.

Introduction Stroke Recognition

troke impacts »2/100,000 children (non-neonates)
S annually.1 The acute management of pediatric stroke is
rapidly evolving, following advances in the management of
Timely diagnosis of stroke is challenging in children, with the
median time from symptom onset to diagnosis of arterial
ischemic stroke (AIS) in children being over 20 hours.27
adult stroke as well as emerging pediatric-specific data. Here Delays occur both before and after the presentation for medi-
we review the overarching goals of acute management of the cal care. Diagnostic delays within the medical system may
child with suspected stroke: timely diagnosis, rapid evalua- result from the difficulty in distinguishing stroke from the
tion for hyperacute treatment, neuroprotection, and second- myriad stroke mimics that occur in children.8 Stroke mimics,
ary stroke prevention. some of which are also urgent diagnoses, are far more com-
mon than stroke in children with acute onset focal neuro-
From the *Department of Neurology, Washington University in St. Louis, logic deficits.812 On the other hand, children with stroke
y
St. Louis, MO. often present with concurrent headache12 or seizure,13,14
Neurology Division, Children’s Hospital Orange County, Orange, CA.
z and distinguishing a migraine with associated hemiparesis or
Department of Pediatrics, University of California, Orange, CA.
x
Department of Neurology, Children’s National Medical Center, George a seizure with post-ictal paresis from AIS can be challeng-
Washington University School of Medicine, Washington, DC. ing.15 Screening tools to increase stroke recognition are pro-
║
Division of Child Neurology, Department of Neurology, Stanford Stroke moted in the community and widely used by frontline
Center, Palo Alto, CA. providers. Unfortunately, such screening tools have variable
{
Departments of Neurology and Neurological Surgery, Seattle Children’s
utility in separating stroke from its mimics in children.16,17
Hospital, Seattle, WA.
#
Departments of Pediatrics and Radiology, Washington University in St.
Louis, St. Louis, MO.
Funding: This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declarations of interest: none.
Pediatric Stroke Alerts, Care
Address reprint requests to: Kristin Guilliams, MD, MSCI Pediatric Pathways, and Stroke Centers
Neurology, Washington University, 660 South Euclid Ave., Campus
Box 8111, St. Louis, MO 63110-1093, USA. E-mail: Similar to adult stroke care, stroke alerts and care pathways
kristinguilliams@wustl.edu have become an integral part of acute pediatric stroke care and

https://doi.org/10.1016/j.spen.2022.100990 1
1071-9091/11/© 2022 Elsevier Inc. All rights reserved.
2 T.-L. Surtees et al.

their implementation is recommended by the American Heart Acute Neuroimaging

Association/American Stroke Association (AHA/ASA) Scientific
Statement on management of pediatric stroke.1 A systematic Due to the high incidence of stroke mimics in childhood,
approach intends to identify patients with acute stroke at the diagnosis requires urgent confirmatory neuroimaging, which
earliest possible time point given the time-sensitivity of hyper- may also be used to identify children with a high risk of
acute intervention and the importance of limiting brain injury decompensation, or stroke recurrence such as vasculitis or
and preventing early complications by initiating neuroprotec- craniocervical artery dissection.
tive measures as soon as possible. A survey of 47 pediatric Many centers use a limited sequence magnetic resonance
institutions found that most (98%) had stroke care pathways, image (MRI) as first-line imaging and revert to non-contrast
although this likely reflects response bias.18 While there are computed tomography (CT), with or without CT angiogra-
no standardized criteria for pediatric stroke alerts, elements phy, if MRI is contraindicated or unavailable within an
typically include a screening process to identify patients with acceptable timeframe.30,20,18,21,31,24,32,25 While no standard
the acute neurologic deficits followed by a single-call activa- exists for optimal time to first image in a pediatric stroke
tion system to mobilize a stroke team and activate a care path- code, many centers set a goal time to MRI of 60 minutes
way (Fig. 1).1921 The Pediatric National Institutes of Health from code.18 Perfusion imaging can identify appropriate
Stroke Scale (PedNIHSS), an adaptation of the adult NIHSS adult patients for late-window thrombectomy, but its utility
with developmentally appropriate modifications for children in children is not established.33,34 Moreover, perfusion imag-
ages 2 and up, is used to quantify neurologic deficit. While ing presents challenges for the pediatric population, includ-
the PedNIHSS has good interrater reliability, data are limited ing large ionizing radiation dose with CT perfusion, lack of
regarding the association of early PedNIHSS long-term familiarity with these protocols among pediatric radiologists
outcomes.22,23 Nonetheless, it is a helpful tool to quantify and and radiology technicians, and unknown standardized bolus
track the degree of neurological deficit. injection rate or IV requirements for children.35
Arterial ischemic strokes are identified in 9-17% of pediat- CT does not require sedation, and will detect intracranial
ric stroke alerts (Table 1),20,24,25,26,27 versus »75% in the hemorrhage, hydrocephalus, marked edema and some mass
adult population.28 An additional 18%-30% of pediatric lesions. It is poorly sensitive for early AIS,36 but is preferred
stroke alerts identify other acute neurological emergencies in an unstable patient or when intracranial hemorrhage is
including intracranial hemorrhage and neoplasms, central suspected. Head and neck CT angiography is sensitive for
nervous system infections, and hydrocephalus.20,24,26,27 arterial stenosis and occlusion but requires contrast and ion-
Therefore, pediatric stroke alerts/care pathways facilitate care izing radiation,37 so MR angiography is typically preferred in
for multiple neurologic emergencies. Inpatient stroke alerts children when possible. Pediatric-specific CT protocols and
identify acute stroke more frequently than those activated in experienced technologists capable of adjusting contrast dose
the emergency department,29 possibly reflecting increased parameters for smaller children can help reduce exposure in
stroke risk factors among hospitalized children, such as acute many cases where the benefit of making a swift diagnosis
systemic illness and predisposing underlying conditions. outweighs the potential risks.38
Despite stroke being more common among inpatients, inpa- MRI is an optimal study for suspected acute childhood
tient strokes tend to have longer delays to diagnosis com- AIS. A rapid stroke MRI protocol including diffusion
pared to those presenting to the emergency department.30 weighted imaging (DWI)/apparent diffusion coefficient
This may stem from the more complex clinical circumstances (ADC) for detection of ischemia, susceptibility or gradient
surrounding inpatient strokes and barriers to assessment echo for detection of blood, axial T2 or axial T2 FLAIR
including inability to obtain an accurate exam in sedated sequences, and time-of-flight MRA of the head and neck can
patients, patients too unstable to obtain imaging, and symp- be performed in approximately 15-20 minutes. Shortening
toms misattributed to other diagnoses. scan time, in conjunction with strategies such as child-life

Figure 1 A schematic of the goals of acute pediatric stroke management.

Pediatric Acute Stroke Management 3

consultation and MRI-compatible audio-visual systems, has by a 60 minute infusion, TNK is administered as a rapid sin-
been shown to reduce the need for sedation in a significant gle bolus.58 However, there is no published data at this time
proportion of children.3942 MRI is also the optimal modal- reporting TNK use in children, and IV tPA remains the
ity to address other conditions that may mimic stroke, thrombolytic agent with the most data in pediatric stroke.
including demyelinating disease, neoplasm, meningoenceph- Mechanical thrombectomy (MT) is now standard of care
alitis, and hemiplegic migraine.4345 for adult patients with large vessel occlusion (LVO) present-
ing within 6 hours of last known well based on 5 large RCTs
published in 2015.59 In 2018, the DAWN and DEFUSE 3 tri-
als found MT efficacy for well-selected patients up to
Recanalization Strategies 24 hours from last known well with evidence of salvageable
The published literature on hyperacute treatment of pediatric penumbra, defined either by perfusion imaging or magnitude
stroke is limited to small cohorts and complicated by publi- of clinical deficit out of proportion to the core infarct.60,61
cation and selection biases.4648 To date no randomized con- While a 24-hour window for pediatric stroke diagnosis is
trolled trials have examined the use of hyperacute often feasible, questions remain about safety, efficacy, and
reperfusion therapies (intravenous alteplase (tPA) or mechan- age limitations for MT in children.4649 Moreover, the natu-
ical thrombectomy) in pediatric stroke, and the safety and ral history of LVO and the benefit of MT over medical man-
efficacy of these interventions remain debated.46,4750 agement have not yet been prospectively investigated in
Few children with AIS undergo intravenous children, though a recent retrospective study found that chil-
thrombolysis,46,50,51 partially due to delays in stroke diagno- dren with LVO not treated with thrombectomy had poor
sis. When given within 4.5 hours of symptom onset, throm- outcomes.62 Small numbers and lack of equipoise present
bolysis with tPA appears to be safe in the pediatric barriers to a randomized pediatric thrombectomy trial, thus
population, with an estimated 2.1% rate of symptomatic decision-making for pediatric LVO is largely based on retro-
intracranial hemorrhage (sICH) in retrospective studies using spective and adult data. Multiple case reports and the multi-
Bayesian modeling—lower than the reported rates of post- center retrospective Save ChildS Study cite favorable
tPA sICH in adults.52,53 For children who receive IV tPA, the outcomes after MT; however, these data are limited by publi-
ideal effective dose is unknown, and children typically cation, recall and selection biases and therefore must be
receive the standard adult tPA dose of 0.9 mg/kg.51,1 Chil- interpreted cautiously, as positive outcomes may be over-
dren have increased levels of Plasminogen Activator Inhibi- reported.46 Further, whereas in adult patients a clinical-core
tor-1 (PAI1) and lower levels of endogenous tPA compared or perfusion imaging mismatch is required to qualify for
with adults; thus, it has been theorized that the effective dose treatment in late time windows, there is no consensus on
of tPA may be higher for children than adults.51,1,54,55 Tenec- which selection criteria are relevant in children. Recent stud-
teplase (TNK), a synthetic thrombolytic agent previously ies suggest that clinical-diffusion mismatch or imaging evi-
used for the treatment of adult ST-elevation myocardial dence of favorable collaterals may be promising biomarkers
infarction, is now being used for thrombolysis in adult stroke of favorable response to reperfusion in children, though fur-
patients. Though larger trials are ongoing, existing random- ther prospective study is warranted.63,64
ized studies indicate that TNK is noninferior to tPA for select Technical considerations, potentially underreported adverse
adult patients with acute stroke, and is currently recom- effects, and distinct stroke pathophysiology limit extrapolation
mended as an alternative to IV tPA by the AHA/ASA and of adult outcomes after thrombectomy to children. Femoral
other international guidelines.5658 TNK is a potentially artery diameter and intracranial and cervical vessel diameters in
appealing thrombolytic agent in children as it has higher smaller children may pose catheter limitations and increase the
fibrin specificity than tPA and is more resistant to PAI1.58 risk of vasospasm or vessel injury.65,66 Pediatric intracranial ves-
Further, whereas IV tPA is given in an initial bolus followed sels approach adult size by 5 years of age,67 but MT has been

Table 1 Frequency of Stroke Diagnosis and Other Neurologic Emergencies among Stroke Alerts.
% of Stroke % of Stroke
% of Stroke Alerts That Alerts That
N (# of Stroke Alerts That Were Were Other
Alerts During Were Ischemic Hemorrhagic Neurologic
Study Study Period Study Period) Stroke Strokes Emergencies

Wharton et al. J of Ped 2011-2018 385 15% 6% 17%

2020
Catenaccio et al. J 2014-2017 120 15% 2% N/A
Child Neurol 2020
DeLaroche et al. 2014-2016 (1.5 36 19% 11% N/A
Pediatr neurol years)
Harrar et al. J Pediatr 2014-2016 (2.5 65 9% 2% 18%
2020 years)
4 T.-L. Surtees et al.

reported in children less than one year old.68 Results from the cerebral arteriopathy is common and collaterals may be more
Save ChildS Study suggest that the risk of sICH after pediatric robust, head position may be beneficial. In the absence of
MT is low (less than 2%)69 though these patients underwent pediatric specific data, it is reasonable to recommend main-
relatively early revascularization at a median of 4 hours from taining patients flat for a limited period after stroke onset
symptom onset. Despite these limitations, a Scientific Statement unless there are simultaneous ICP concerns.
from the AHA/ASA on the management of stroke in children
suggests MT should be considered at experienced centers for
larger children with persistent, disabling deficits due to radio-
graphically confirmed large vessel occlusion.1
Blood Pressure
In the absence of strong evidence-based guidance, centers Both hypotension and hypertension may occur after acute
should decide whether or not they will offer MT to children pediatric stroke.75 Adult stroke guidelines recommend treat-
and pre-specify criteria and workflow to avoid in-the- ment of hypotension/hypovolemia to maintain brain and sys-
moment decision and coordination as much as possible. temic perfusion, and to provide early treatment of
Lauzier et al. highlights differing criteria at 2 pediatric stroke hypertension when required by comorbid conditions (ie,
centers who perform MT, as well as offers factors to consider acute coronary event, aortic dissection, postfibrinolysis
for developing pediatric MT pathways.70 Each center and sICH).57 In adults who do not receive recanalization therapy,
healthcare team will need to assess their own strengths and the use of urgent antihypertensive therapy is controversial.76
capabilities to determine how to deliver optimal care, includ- “Permissive hypertension” refers to allowing, but not striving,
ing the possibility of transferring to another facility. The for blood pressure >95th percentile, as this may reflect
transfer of pediatric stroke patients to adult MT centers has autoregulatory mechanisms facilitating perfusion. However,
been shown to be geographically feasible, with the over- the upper limits of permissible hypertension are not defined
whelming majority of pediatric hospitals within a 60 minute for children. Limitations and barriers to understanding the
drive of the nearest adult thrombectomy center.71 The logis- role of hypertension in pediatric stroke are nicely delineated
tics of patient transfer, including a plan for inter-hospital in a review by Kupferman et al.77
physician communication and arrangement of transport
should be pre-established and well-coordinated so as to
avoid delays in care.
Anemia
In a child with cerebral arteriopathy with or without stroke,
Neuroprotection decreased blood flow is the primary threat to cerebral oxygen
While a minority of pediatric stroke patients are candidates delivery.78 When there is superimposed anemia resulting in
for recanalization therapy, all may benefit from the early decreased arterial oxygen content (CaO2 = 1.36*hemoglobin
implementation of measures to minimize cell death and * SpO2 + PaO2*0.003), increased blood flow is needed to
infarct expansion, and prevent secondary injury, as well as maintain cerebral oxygen delivery.7981 At this time, only
early recurrence. A few such measures are outlined briefly sickle cell disease has specific transfusion recommendations,
below: although not all recommendations use an identical transfu-
sion threshold. The American Society of Hematology recom-
mends a simple transfusion to increase hemoglobin (Hb)
above 8.5 gm/dL prior to exchange transfusion, and to main-
Head Positioning tain Hb >9 gm/dL after AIS.82 The ASA recommends simple
Cerebral perfusion pressure depends on the position of the transfusion if the Hb is less than 10 gm/dL,1 and the British
head relative to the heart, and upright positioning must Society of Hematology recommends a post-exchange transfu-
account for hydrostatic gradients.72 Flat positioning eliminates sion target of 10 gm/dL.83 Although there are no specific tar-
this gradient and allows for blood pressure at the circle of Wil- gets in non-sickle cell patients, maintaining Hb of 10 gm/dL
lis to approximate that generated by the left ventricle. For in a child with impaired cerebral oxygen delivery seems rea-
some patients, particularly those perfusing the penumbra at sonable. Avoiding unnecessary bloodwork, particularly in
the lower limit of their cerebral autoregulation, this small dif- smaller children, may help maintain adequate Hb as well.
ference in pressure may significantly impact cerebral blood
flow. In Head POST, a large cluster-randomized crossover trial
randomizing stroke patients (ischemic and hemorrhagic) by
site to either flat or upright position for 24 hours did not find
Temperature Management
a difference in 90-day outcomes between groups.73 However, Temperature management is a well-established neuroprotec-
while pragmatic, the broad inclusion criteria likely introduced tive strategy in neonates with hypoxic-ischemic encephalopa-
noise of patients who had adequate collateral flow at any posi- thy and adults after cardiac arrest. However, the role of
tion.74 Furthermore, a significant proportion of patients had temperature management in patients with AIS is unestab-
delayed randomization (median 14 hours, with 25% random- lished. While fever has been associated with the adverse out-
ized beyond 35 hours) and inability to tolerate lying flat con- comes in adult stroke,8486 the impact of treatment with
found interpretation of the results. In pediatric stroke, where antipyretic agents such as paracetamol or acetaminophen is
 Pediatric Acute Stroke Management
Table 2 Early treatment and secondary prevention considerations by childhood stroke etiology.
Estimated Special Considerations
Stroke Recurrence Hyperacute Therapy Proposed approaches to Duration of for Secondary
etiology Risk Considerations* Secondary Prevention Therapy Prevention Trials and Studies
120,121,122
Arteriopathy 18-66%
Risk highest in
the first year123
Focal cerebral 3%-25%124 Theoretical concern for vascu- Aspirin** (typically dosed at Long-term antiplatelet Ongoing pediatric trials:
arteriopathy- lar injury with MT when 3-5 mg/kg/day) or therapy126; specific FOCAS127, PASTA: role
inflammatory type (FCA- introducing catheter into anticoagulation duration of corticosteroids in
i) inflamed artery1 plus not determined. FCAi
Could consider high dose
steroid pulse +/-taper124
plus
Consider acyclovir if active
VZV infection125
Craniocervical artery 9-12.5%128,129 Concern for subarachnoid Initiate aspirin or At least 6 weeks of anticoagu- Avoid ballistic movements of CADISS: adult study of
dissection (CAD) hemorrhage with thromboly- anticoagulation.1,132 lation.133 Consider aspirin the neck, vigorous mas- anticoagulation vs
sis of intracranial arterial dis- A common anticoagulation thereafter. Total duration of sage, or chiropractic aspirin in CAD
section but intervention may approach is with heparin antithrombotic therapy not manipulation. TREAT-CAD: adult non-
still be considered.130,131,132 infusion followed by low established.1,134 Consider avoiding all sports inferiority trial of
Caution when considering molecular weight for at least 1 month after aspirin vs vitamin K
MT125 heparin133 dissection per one adult antagonists136
guideline.135
Rotational arteriopathy Very high Consider surgical interven- If dissection, anticoagulation Avoid head rotation with use
causing recurrent recurrence tion at experienced center for 6-12 months139 of cervical collar until sur-
posterior circulation risk137,138 (C1-C2 cervical fusion, gical intervention achieved
139
strokes (typically V3 exploration/debridement,
segment) or decompression) if evi-
dence of dynamic arterial
compression with contra-
lateral head turn on cathe-
ter angiography or CTA138
Plus
If evidence of dissection, ini-
tiate anticoagulation139
Primary CNS Recurrence rate Concern for vascular injury Antithrombotic therapy (aspi- Antithrombotic therapy for Consider lumbar puncture
vasculitis unknown. Higher risk with MT when introducing rin, heparin, or warfarin) 2 years.142 prior to initiation of antith-
for progressive dis- catheter into inflamed artery1 plus Duration of immunosuppres- rombotic therapies.142
ease if presence of Rheumatology consult; sive therapy may depend on
neurocognitive dys- consider initiating risk for/evidence of disease
function, multifocal immunosuppression140,141 progression.140,140,141
MRI lesions, and dis-
tal stenosis.140
Moyamoya 35% at 1 year122 tPA contraindicated due to Initiate aspirin Long-term aspirin Avoid hyperventilatory activi-
risk of hemorrhage of Definitive management with ties as able. Correct dehy-
friable collateral vessels51 direct or indirect revascu- dration, and anemia.
Concern for vascular injury larization surgery
with MT when introducing
catheter into chronically
stenosed artery1

5
 6
Table 2 (Continued )
Estimated Special Considerations
Stroke Recurrence Hyperacute Therapy Proposed approaches to Duration of for Secondary
etiology Risk Considerations* Secondary Prevention Therapy Prevention Trials and Studies

Cardioembolic 13-27% at 10 Anticoagulation typically pre- Initiate anticoagulation Duration of therapy depen-
years143,144 ferred over antiplatelet dent on on-going cardiac
therapy in children1 risk factors.
If recurrent stroke while on
aspirin, consider changing
to clopidogrel or
anticoagulants.127
Thrombophilia Approximately 6-7% Hematology consult APASS: adult trial; aspirin vs
Thrombophilia may con- Aspirin or anticoagulation warfarin in APS147
tribute to stroke risk For APS, some evidence for TRAPS: adult trial; rivaroxaban
in conjunction with anticoagulation over aspi- vs VKA for prevention of
additional risk factors rin in adults.145 thromboembolic events in
Direct oral anticoagulants APS146
less favorable than warfa-
rin in adults.146
Cryptogenic 4.5%123 Aspirin 2 years Adult trials suggest benefit of RESPECT, REDUCE, CLOSE:
PFO closure over aspirin in adult PFO closure trials148
younger patients (18-60
years) with non-lacunar
stroke and high-risk PFO
features.148
In children, if PFO identified,
relevance and benefit of
closure remains
uncertain.1,149

*Initiation of antithrombotic/antiplatelet therapies is typically deferred for 24 hours in patients receiving tPA per adult recommendations.
**Reye syndrome has not been reported with the use of low-dose aspirin for pediatric stroke.

T.-L. Surtees et al.

Pediatric Acute Stroke Management 7

less clear. A randomized controlled trial comparing treatment Electroencephalographic (EEG)

with paracetamol versus placebo within 12 hours of symp- Monitoring for Ischemia
tom onset in adults with AIS or intracerebral hemorrhage
and a body temperature of 36⁰C-39⁰C found no difference Detection After Pediatric AIS
in functional outcome at three months.87 However, a post- In addition to detecting post-stroke seizures, EEG may iden-
hoc analysis found paracetamol treatment was associated tify new or ongoing cerebral ischemia, thereby facilitating
with improved outcomes in patients with a baseline tempera- other neuroprotective strategies. The EEG background
ture of 37°C-39°C. Current AHA/ASA guidelines recommend undergoes a predictable series of changes in the setting of
treatment of hyperthermia >38°C.76 A retrospective analysis decreasing blood flow,100 which can predict delayed cerebral
of 98 children with AIS found that 37.8% had fever within ischemia onset in adults with aneurysmal subarachnoid hem-
5 days of presentation; however, there was no association orrhage. This application of EEG in children is emerging.
with infarct size, poor outcome, or death at 3 months.75 Huguenard et al describe the use of postoperative quantita-
There are no randomized studies investigating the role of tive EEG (qEEG) after pial synangiosis for moyamoya disease
fever in pediatric stroke. and its potential to detect ischemia and change clinical man-
agement in half of their cohort.101 Similarly, Appavu et al
report qEEG features that may serve as non-invasive bio-
markers for ischemia and a way to evaluate the interaction
between systemic hemodynamics and the cerebral perfu-
Blood Glucose sion.102 More work is needed to understand the role of EEG
Hyperglycemia after AIS is a risk factor for poor outcome in in poststroke neuromonitoring.
adults,88,89 and current AHA/ASA guidelines state that it is
reasonable to treat hyperglycemia to maintain blood glucose
levels between 140-180mg/dL.76 Nevertheless, best practices
for blood glucose management after AIS remain elusive.
Increased ICP
GIST-UK, an RCT of insulin infusion to maintain a blood Patients with large volume AIS or hemorrhagic stroke are at
glucose concentration of 4-7mmol/L (72-126mg/dL) com- risk for edema and increased ICP. Osmotic therapy for clini-
pared to no glycemic control found no difference in death or cal deterioration from post-ischemic cerebral swelling is con-
disability at 90 days.90 Similarly, narrow glycemic control sidered reasonable in adult guidelines.103 Brief moderate
(target 80-130mg/dL) compared to standard control (target hyperventilation to a PCO2 of 30-34 mm Hg is acceptable
80-179mg/dL) in the first 72 hours post-stroke does not only as a bridge to more definitive therapy.103 Hypothermia,
appear to provide benefit.91 Hyperglycemia following child- barbiturates, and corticosteroids are not recommended.103
hood stroke has been associated with the poor neurologic If cerebral edema is refractory to medical management,
outcome.75 decompressive craniectomy may be considered. Pooled
results of RCTs in adults show a significant mortality (but
not morbidity) reduction when decompressive craniectomy
is performed within 48 hours of malignant MCA infarc-
tion.104 It is unknown whether decompressive craniectomy
Seizures and Status Epilepticus similarly confers mortality benefit in children. Among 4292
patients in the International Pediatric Stroke Study (IPSS)
Seizures are common after pediatric AIS and are often the registry, 38 underwent decompressive craniectomy, 29 of
presenting symptom.13,14 The reported incidence of acute whom had an anterior circulation AIS.105 The mortality rate
seizures in pediatric AIS varies widely, ranging from 17 to was 8%, and 85% of those with an anterior decompression
58%,14,92,93 with the incidence in younger children consis- for AIS had moderate-to-severe deficits in follow-up. The
tently higher than in older children.13,93 Seizures may AHA/ASA Scientific Statement stipulates that in those “with
increase metabolic demand,94 and potentially worsen ische- large-volume infarcts (more than half of the MCA territory),
mia if demand exceeds blood supply. Indeed, in a mixed treatment teams should consider either performing early pro-
cohort of critically-ill children, a maximum hourly seizure phylactic hemicraniectomy within the first 24 hours or
burden over 12 minutes was associated with significant neu- implementing serial imaging within the first 72 hours to
rologic decline.95 Given this, the most recent AHA/ASA sci- monitor swelling and the need for surgical intervention”.96
entific statement on the management of stroke in neonates
and children recommends that clinicians ‘consider electroen-
cephalographic screening or monitoring for children with
altered mental status’.96 Seizures, especially when prolonged Special Considerations for
or recurrent, have also been associated with future develop-
ment of epilepsy in children with AIS.14,93,97,98 Nonetheless,
Children With Sickle Cell Anemia
the optimal duration of antiseizure medications post-hospi- Acute stroke management for children with sickle cell disease
talization or medication impact on outcome remain requires special consideration. Children with sickle cell dis-
unknown.99 ease still warrant standard workup106,107 including
8 T.-L. Surtees et al.

echocardiogram108 and vessel imaging109, but also benefit centers capable of timely triage, diagnosis, and management
from red blood cell transfusion. If the hemoglobin is of acute pediatric stroke, typically supported by stroke triage
<8.5 gm/dL, or an exchange transfusion cannot be initiated protocols, stroke alerts, and stroke order sets to optimize
within 2 hours of presentation for medical care, then a simple pediatric-stroke readiness.118 Centers that have adopted
transfusion should be provided, based on current recom- these or similar measures report improved pediatric stroke
mendations from the American Society of Hematology.82 care.118,30 For example, Shack and colleagues found that
Otherwise, an automated exchange transfusion is preferred acute stroke protocols effected faster stroke diagnosis, expe-
to simultaneously raise total hemoglobin and lower hemoglo- dited treatment, and increased magnetic resonance imaging
bin S, while minimizing hyperviscosity risk. (MRI) as the initial imaging modality, thereby avoiding dual
imaging and radiation exposure.31 Similarly, others have
found that implementation of acute stroke protocols
decreased times to MRI.19,20 As pediatric stroke care contin-
Secondary Prevention ues to mature as a field, more research and guidance is
Antithrombotic therapy is often prescribed for secondary needed to inform best practices and standards of care
prevention in children, though the agent and the timing of throughout the entire hospitalization of a child with an acute
initiation vary based on patient, stroke characteristics, and stroke.
geography. An analysis of over 660 children in the IPSS regis-
try demonstrated higher rates of anticoagulant use for sec-
ondary stroke prevention in Europe, Canada, and Australia
as compared to the United States, where anticoagulants and
Conclusion
antiplatelets were used approximately equally.110 Anticoagu- Caring for a child with an acute stroke requires prompt recogni-
lation was more commonly employed for children with car- tion of symptoms, confirmation of diagnosis with neuroimag-
diac disease and dissection than other stroke etiologies.110 8/ ing, recanalization therapy for select patients with ischemic
17/2022 4:57:00 PMThese trends, however, are not equiva- stroke, optimizing cerebral oxygen delivery to minimize further
lent to evidence-based guidelines, as are available for adult cell death, and preventing recurrent strokes when possible. Inte-
ischemic stroke.111 To date there have been no RCTs yet grated, multidisciplinary care in the first few hours and days
completed for best practices in pediatric secondary stroke after a stroke can influence a child’s trajectory into the next
prevention. Table 2 lists considerations for hyperacute ther- phase of care for rehabilitation and recovery.
apy and secondary prevention for specific stroke etiologies.
There is growing interest in direct oral anticoagulants
(DOACs) for children. Anticoagulation with vitamin K antag-
onists (VKAs) is challenging in children, as VKAs require die- Declaration of Competing
tary modifications and frequent blood monitoring. Low Interest
molecular weight heparin (LMWH) necessitates blood moni-
The authors declare that they have no known competing
toring and subcutaneous injection. Pediatric-specific phar-
financial interests or personal relationships that could have
macodynamics and pharmacokinetics further complicate
appeared to influence the work reported in this paper.
achieving and maintaining a therapeutic effect.112 While not
yet studied for secondary stroke prevention in children,
DOACs are appealing given their ease of administration and
References
favorable safety profiles in adults. Recently, rivaroxaban has
1. Ferriero DM, Fullerton HJ, Bernard TJ, et al: Management of stroke in
shown promising safety and efficacy trends for thrombopro- neonates and children: A scientific statement from the American Heart
phylaxis in children with congenital heart disease and antico- Association/American Stroke Association. Stroke 50(3):e51-e96, 2019.
agulation for children with cerebral sinus venous https://doi.org/10.1161/STR.0000000000000183
thrombosis.113,114 Dabigatran, the only approved oral direct 2. Gabis LV, Yangala R, Lenn NJ: Time lag to diagnosis of stroke in children.
thrombin inhibitor, was found to be non-inferior to LMWH Pediatrics 110(5):924-928, 2002. https://doi.org/10.1542/peds.110.5.924
3. McGlennan C, Ganesan V: Delays in investigation and management of
and VKAs for secondary prevention of pediatric venous acute arterial ischaemic stroke in children. Dev Med Child Neurol 50
thromboembolism.115,112 Ongoing research is needed to (7):537-540, 2008. https://doi.org/10.1111/j.1469-8749.2008.03012.x
determine if DOACs should play a role in pediatric secondary 4. Rafay MF, Pontigon AM, Chiang J, et al: Delay to diagnosis in acute
stroke prevention. pediatric arterial ischemic stroke. Stroke 40(1):58-64, 2009. https://
doi.org/10.1161/STROKEAHA.108.519066
5. Srinivasan J, Miller SP, Phan TG, Mackay MT: Delayed recognition of
initial stroke in children: need for increased awareness. Pediatrics 124
Pediatric Stroke Centers (2):e227-e234, 2009. https://doi.org/10.1542/peds.2008-3544
6. Mallick AA, Ganesan V, Kirkham FJ, et al: Diagnostic delays in paediat-
Primary Stroke Centers (PSCs) and Comprehensive Stroke ric stroke. J Neurol Neurosurg Psychiatry 86(8):917-921, 2015.
Centers (CSCs) have improved adult stroke outcomes https://doi.org/10.1136/jnnp-2014-309188
7. Shack M, Andrade A, Shah-Basak PP, et al. A pediatric institutional
through evidence-based standardized guidelines for nearly acute stroke protocol improves timely access to stroke treatment. Dev
20 years.116,117 More recently, suggested criteria for pediatric Med Child Neurol. 2017;59(1):31-37. https://doi.org/10.1111/
stroke programs have emerged.118,119 These criteria identify dmcn.13214.
Pediatric Acute Stroke Management 9

8. Mackay MT, Yock-Corrales A, Churilov L, Monagle P, Donnan GA, 26. Catenaccio E, Riggs BJ, Sun LR, et al: Performance of a pediatric stroke
Babl FE: Accuracy and Reliability of Stroke Diagnosis in the Pediatric alert team within a comprehensive stroke center. J Child Neurol 35
Emergency Department. Stroke 48(5):1198-1202, 2017. https://doi. (9):571-577, 2020. https://doi.org/10.1177/0883073820920111
org/10.1161/STROKEAHA.116.015571 27. Wharton JD, Barry MM, Lee CA, Massey K, Ladner TR, Jordan LC:
9. Ladner TR, Mahdi J, Gindville MC, et al: Pediatric acute stroke Pediatric acute stroke protocol implementation and utilization over 7
protocol activation in a children’s hospital emergency department. years. J Pediatr 220:214-220, 2020,. https://doi.org/10.1016/j.
Stroke 46(8):2328-2331, 2015. https://doi.org/10.1161/STROKEAHA. jpeds.2020.01.067
115.009961 28. Hemmen TM, Meyer BC, McClean TL, Lyden PD: Identification
10. Wharton JD, Barry MM, Lee CA, Massey K, Ladner TR, Jordan LC: of nonischemic stroke mimics among 411 code strokes at the
Pediatric Acute Stroke Protocol Implementation and Utilization Over University of California, San Diego, Stroke Center. J Stroke Cer-
7 Years. J Pediatr 220:214-220, 2020,. https://doi.org/10.1016/j. ebrovasc Dis 17(1):23-25, 2008. https://doi.org/10.1016/j.
jpeds.2020.01.067 jstrokecerebrovasdis.2007.09.008
11. Harrar DB, Salussolia CL, Kapur K, et al: A stroke alert protocol 29. Barry M, Le TM, Gindville MC, Jordan LC: In-Hospital Pediatric Stroke
decreases the time to diagnosis of brain attack symptoms in a pediatric Alert Activation. Pediatr Neurol 88:31-35, 2018. https://doi.org/
emergency department. J Pediatr 216:136-141, 2020,. https://doi.org/ 10.1016/j.pediatrneurol.2018.08.003
10.1016/j.jpeds.2019.09.027 30. Shack M, Andrade A, Shah-Basak PP, et al: A pediatric institutional
12. Mackay MT, Chua ZK, Lee M, et al: Stroke and nonstroke brain attacks acute stroke protocol improves timely access to stroke treatment. Dev
in children. Neurology 82(16):1434-1440, 2014. https://doi.org/ Med Child Neurol 59(1):31-37, 2017. https://doi.org/10.1111/
10.1212/WNL.0000000000000343 dmcn.13214
13. Abend NS, Beslow LA, Smith SE, et al: Seizures as a presenting symp- 31. McKinney SM, Magruder JT, Abramo TJ: An Update on Pediatric
tom of acute arterial ischemic stroke in childhood. J Pediatr 159 Stroke Protocol. Pediatr Emerg Care 34(11):810-815, 2018. https://
(3):479-483, 2011. https://doi.org/10.1016/j.jpeds.2011.02.004 doi.org/10.1097/PEC.0000000000001653
14. Singh RK, Zecavati N, Singh J, et al: Seizures in acute childhood stroke. 32. Bernard TJ, Friedman NR, Stence NV, et al: Preparing for a “Pediatric
J Pediatr 160(2):291-296, 2012. https://doi.org/10.1016/j. Stroke Alert. Pediatr Neurol 56:18-24, 2016. https://doi.org/10.1016/j.
jpeds.2011.07.048 pediatrneurol.2015.10.012
15. Mackay MT, Yock-Corrales A, Churilov L, Monagle P, Donnan GA, 33. Powers WJ, Rabinstein AA, Ackerson T, et al: 2018 Guidelines for the
Babl FE: Differentiating childhood stroke from mimics in the emer- Early Management of Patients With Acute Ischemic Stroke: A Guide-
gency department. Stroke 47(10):2476-2481, 2016. https://doi.org/ line for Healthcare Professionals From the American Heart Associa-
10.1161/STROKEAHA.116.014179 tion/American Stroke Association. Stroke 49(3):e46-e110, 2018.
16. Yock-Corrales A, Babl FE, Mosley IT, Mackay MT: Can the FAST and https://doi.org/10.1161/STR.0000000000000158
ROSIER adult stroke recognition tools be applied to confirmed child- 34. Kerleroux B, Janot K, Dargazanli C, et al: Perfusion Imaging to Select
hood arterial ischemic stroke? BMC Pediatr 11:93, 2011. https://doi. Patients with Large Ischemic Core for Mechanical Thrombectomy.
org/10.1186/1471-2431-11-93 J Stroke 22(2):225-233, 2020. https://doi.org/10.5853/jos.2019.
17. Mackay MT, Churilov L, Donnan GA, Babl FE, Monagle P: Perfor- 02908
mance of bedside stroke recognition tools in discriminating childhood 35. Lee S, Amlie-Lefond CM: Target Practice: Aiming for Automated Perfu-
stroke from mimics. Neurology 86(23):2154-2161, 2016. https://doi. sion in Childhood Stroke. Stroke 52(10):3305-3307, 2021. https://doi.
org/10.1212/WNL.0000000000002736 org/10.1161/STROKEAHA.121.036218
18. Harrar DB, Benedetti GM, Jayakar A, et al: Pediatric acute stroke proto- 36. Srinivasan J, Miller SP, Phan TG, Mackay MT: Delayed recognition of
cols in the United States and Canada. J Pediatr 2021. https://doi.org/ initial stroke in children: need for increased awareness. Pediatrics 124
10.1016/j.jpeds.2021.10.048. S0022-3476(21)01048-9 (2):e227-e234, 2009. https://doi.org/10.1542/peds.2008-3544
19. DeLaroche AM, Sivaswamy L, Farooqi A, Kannikeswaran N: Pediatric 37. Zensen S, Guberina N, Opitz M, et al: Radiation exposure of computed
stroke clinical pathway improves the time to diagnosis in an emer- tomography imaging for the assessment of acute stroke. Neuroradiology
gency department. Pediatr Neurol 65:39-44, 2016. https://doi.org/ 63(4):511-518, 2021. https://doi.org/10.1007/s00234-020-02548-z
10.1016/j.pediatrneurol.2016.09.005 38. Brody AS, Frush DP, Huda W, Brent RL, American Academy of Pediat-
20. Harrar DB, Salussolia CL, Kapur K, et al: A stroke alert protocol rics Section on Radiology: Radiation risk to children from computed
decreases the time to diagnosis of brain attack symptoms in a pediatric tomography. Pediatrics 120(3):677-682, 2007. https://doi.org/
emergency department. J Pediatr 216:136-141, 2020,. https://doi.org/ 10.1542/peds.2007-1910
10.1016/j.jpeds.2019.09.027 39. Xu HS, Cavaliere RM, Min RJ: Transforming the Imaging Experience
21. Rivkin MJ, Bernard TJ, Dowling MM, Amlie-Lefond C: Guidelines for While Decreasing Sedation Rates. J Am Coll Radiol 17(1):46-52, 2020.
urgent management of stroke in children. Pediatr Neurol 56:8-17, https://doi.org/10.1016/j.jacr.2019.08.005
2016. https://doi.org/10.1016/j.pediatrneurol.2016.01.016 40. Durand DJ, Young M, Nagy P, Tekes A, Huisman TAGM: Mandatory
22. Ichord RN, Bastian R, Abraham L, et al: Interrater reliability of the Child Life Consultation and Its Impact on Pediatric MRI Workflow in
Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a an Academic Medical Center. J Am Coll Radiol 12(6):594-598, 2015.
multicenter study. Stroke 42(3):613-617, 2011. https://doi.org/ https://doi.org/10.1016/j.jacr.2014.12.015
10.1161/STROKEAHA.110.607192 41. Harned RK II, Strain JD: MRI-compatible audio/visual system: impact
23. Beslow LA, Kasner SE, Smith SE, et al: Concurrent validity and reliabil- on pediatric sedation. Pediatric Radiology 31(4):247-250, 2001.
ity of retrospective scoring of the Pediatric National Institutes of Health https://doi.org/10.1007/s002470100426
Stroke Scale. Stroke 43(2):341-345, 2012. https://doi.org/10.1161/ 42. Robertson RL, Silk S, Ecklund K, Bixby SD, Voss SD, Robson CD:
STROKEAHA.111.633305 Imaging Optimization in Children. J Am Coll Radiol 15(3):440-443,
24. Ladner TR, Mahdi J, Gindville MC, et al: Pediatric acute stroke proto- 2018. https://doi.org/10.1016/j.jacr.2017.10.017
col activation in a children’s hospital emergency department. Stroke 43. Mirsky DM, Beslow LA, Amlie-Lefond C, et al: Pathways for Neuroim-
46(8):2328-2331, 2015. https://doi.org/10.1161/STROKEAHA. aging of Childhood Stroke. Pediatr Neurol 69:11-23, 2017. https://
115.009961 doi.org/10.1016/j.pediatrneurol.2016.12.004
25. Tabone L, Mediamolle N, Bellesme C, et al: Regional pediatric acute 44. Aprahamian N, Harper MB, Prabhu SP, et al: Pediatric first time non-
stroke protocol: initial experience during 3 years and 13 recanalization febrile seizure with focal manifestations: is emergent imaging indi-
treatments in children. Stroke 48(8):2278-2281, 2017. https://doi.org/ cated? Seizure 23(9):740-745, 2014. https://doi.org/10.1016/j.
10.1161/STROKEAHA.117.016591 seizure.2014.06.003
10 T.-L. Surtees et al.

45. Massano D, Julliand S, Kanagarajah L, et al: Headache with focal neu- Stroke: An Analysis of the Save ChildS Study. Neurology 96(3):e343-
rologic signs in children at the emergency department. J Pediatr 165 e351, 2021. https://doi.org/10.1212/WNL.0000000000011107
(2):376-382, 2014. https://doi.org/10.1016/j.jpeds.2014.04.053 64. Lee S, Jiang B, Wintermark M, et al: Cerebrovascular Collateral Integ-
46. Barry M, Barry D, Kansagra AP, et al: Higher-Quality Data Collection Is rity in Pediatric Large Vessel Occlusion: Analysis of the Save ChildS
Critical to Establish the Safety and Efficacy of Pediatric Mechanical Study. Neurology 98(4):e352-e363, 2022. https://doi.org/10.1212/
Thrombectomy. Stroke 52(4):1213-1221, 2021. https://doi.org/ WNL.0000000000013081
10.1161/STROKEAHA.120.032009 65. Sun LR, Harrar D, Drocton G, Castillo-Pinto C, Gailloud P, Pearl MS:
47. Bhatia K, Kortman H, Blair C, et al: Mechanical thrombectomy in pedi- Endovascular therapy for acute stroke in children: age and size techni-
atric stroke: systematic review, individual patient data meta-analysis, cal limitations. J NeuroIntervent Surg 13(9):794-798, 2021. https://
and case series. J Neurosurg Pediatr 24(5):558-571, 2019. https://doi. doi.org/10.1136/neurintsurg-2021-017311
org/10.3171/2019.5.PEDS19126 66. Franken EA, Girod D, Sequeira FW, Smith WL, Hurwitz R, Smith JA:
48. Amlie-Lefond C, Wainwright MS: Response by Amlie-Lefond and Femoral artery spasm in children: catheter size is the principal cause.
Wainwright to Letter Regarding Article, “Organizing for Acute Arterial AJR Am J Roentgenol 138(2):295-298, 1982. https://doi.org/10.2214/
Ischemic Stroke in Children”. Stroke 51(2). https://doi.org/10.1161/ ajr.138.2.295
STROKEAHA.119.028380, 2020 67. He L, Ladner TR, Pruthi S, et al: Rule of 5: angiographic diameters of
49. Sporns PB, Wildgruber M, Kemmling A: Letter by Sporns et al cervicocerebral arteries in children and compatibility with adult neuro-
Regarding Article, “Organizing for Acute Arterial Ischemic Stroke in interventional devices. J NeuroIntervent Surg 8(10):1067-1071, 2016.
Children”. Stroke 51(2). https://doi.org/10.1161/STROKEAHA.119. https://doi.org/10.1136/neurintsurg-2015-012034
028320, 2020 68. Sun LR, Felling RJ, Pearl MS: Endovascular mechanical thrombectomy
50. Janjua N, Nasar A, Lynch JK, Qureshi AI: Thrombolysis for Ischemic for acute stroke in young children. J NeuroIntervent Surg 11(6):554-
Stroke in Children: Data From the Nationwide Inpatient Sample. 558, 2019. https://doi.org/10.1136/neurintsurg-2018-014540
Stroke 38(6):1850-1854, 2007. https://doi.org/10.1161/ 69. Sporns PB, Str€ater R, Minnerup J, et al: Feasibility, Safety, and Out-
STROKEAHA.106.473983 come of Endovascular Recanalization in Childhood Stroke: The Save
51. Rivkin MJ, deVeber G, Ichord RN, et al: Thrombolysis in Pediatric ChildS Study. JAMA Neurol 77(1):25-34, 2020. https://doi.org/
Stroke Study. Stroke 46(3):880-885, 2015. https://doi.org/10.1161/ 10.1001/jamaneurol.2019.3403
STROKEAHA.114.008210 70. Lauzier DC, Galardi MM, Guilliams KP, et al: Pediatric Thrombec-
52. Pacheco JT, Siepmann T, Barlinn J, et al: Safety and efficacy of recanali- tomy: Design and Workflow Lessons From Two Experienced
zation therapy in pediatric stroke: A systematic review and meta-analy- Centers. Stroke 52(4):1511-1519, 2021. https://doi.org/10.1161/
sis. Eur J Paediatr Neurol 22(6):1035-1041, 2018. https://doi.org/ STROKEAHA.120.032268
10.1016/j.ejpn.2018.07.013 71. Yu CY, Guilliams KP, Panagos PD, Kansagra AP: Pediatric hospital
53. Amlie-Lefond C, Shaw DWW, Cooper A, et al: Risk of Intracranial proximity to endovascular thrombectomy centers in the United States.
Hemorrhage Following Intravenous tPA (Tissue-Type Plasminogen Interv Neuroradiol 2021:159101992110593. https://doi.org/10.1177/
Activator) for Acute Stroke Is Low in Children. Stroke 51(2):542-548, 15910199211059334
2020. https://doi.org/10.1161/STROKEAHA.119.027225 72. Drummond JC: Blood Pressure and the Brain: How Low Can You Go?
54. Tarango C, Manco-Johnson MJ. Pediatric Thrombolysis: A Practical Anesth Analg 128(4):759-771, 2019. https://doi.org/10.1213/
Approach. Front Pediatr. 5:260, 2017. doi:10.3389/fped.2017.00260 ANE.0000000000004034
55. Parmar N, Albisetti M, Berry LR, Chan AKC: The fibrinolytic system in 73. Anderson CS, Arima H, Lavados P, et al: Cluster-Randomized, Cross-
newborns and children. Clin Lab 52(3-4):115-124, 2006 over Trial of Head Positioning in Acute Stroke. N Engl J Med 376
56. Campbell BCV, Mitchell PJ, Churilov L, et al: Effect of Intravenous (25):2437-2447, 2017. https://doi.org/10.1056/NEJMoa1615715
Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in 74. Aw A, G T, Md H, et al: HeadPoST: Rightly positioned, or flat out
Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND- wrong? Neurology 90(19). https://doi.org/10.1212/WNL.00000
IA TNK Part 2 Randomized Clinical Trial. JAMA 323(13):1257-1265, 00000005481, 2018
2020. https://doi.org/10.1001/jama.2020.1511 75. Grelli KN, Gindville MC, Walker CH, Jordan LC: Association of Blood
57. Powers WJ, Rabinstein AA, Ackerson T, et al: Guidelines for the Early Pressure, Blood Glucose, and Temperature With Neurological Out-
Management of Patients With Acute Ischemic Stroke: 2019 Update to come After Childhood Stroke. JAMA Neurol 73(7):829-835, 2016.
the 2018 Guidelines for the Early Management of Acute Ischemic https://doi.org/10.1001/jamaneurol.2016.0992
Stroke: A Guideline for Healthcare Professionals From the American 76. Powers WJ, Rabinstein AA, Ackerson T, et al: Guidelines for the Early
Heart Association/American Stroke Association. Stroke 50(12):e344- Management of Patients With Acute Ischemic Stroke: 2019 Update to
e418, 2019. https://doi.org/10.1161/STR.0000000000000211 the 2018 Guidelines for the Early Management of Acute Ischemic
58. Warach SJ, Dula AN, Milling TJ: Tenecteplase Thrombolysis for Acute Stroke: A Guideline for Healthcare Professionals From the American
Ischemic Stroke. Stroke 51(11):3440-3451, 2020. https://doi.org/ Heart Association/American Stroke Association. Stroke 50(12):e344-
10.1161/STROKEAHA.120.029749 e418, 2019. https://doi.org/10.1161/STR.0000000000000211
59. Goyal M, Menon BK, van Zwam WH, et al: Endovascular thrombectomy 77. Kupferman JC, Lande MB, Stabouli S, Zafeiriou DI, Pavlakis SG:
after large-vessel ischaemic stroke: a meta-analysis of individual patient Hypertension and childhood stroke. Pediatr Nephrol 36(4):809-823,
data from five randomised trials. The Lancet. 387(10029):1723-1731, 2021. https://doi.org/10.1007/s00467-020-04550-2
2016. https://doi.org/10.1016/S0140-6736(16)00163-X 78. Derdeyn CP, Videen TO, Yundt KD, et al: Variability of cerebral blood
60. Nogueira RG, Jadhav AP, Haussen DC, et al: Thrombectomy 6 to 24 volume and oxygen extraction: stages of cerebral haemodynamic
Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl impairment revisited. Brain 125(Pt 3):595-607, 2002. https://doi.org/
J Med 378(1):11-21, 2018. https://doi.org/10.1056/NEJMoa1706442 10.1093/brain/awf047
61. Albers GW, Marks MP, Kemp S, et al: Thrombectomy for Stroke at 6 to 79. Fields ME, Guilliams KP, Ragan DK, et al: Regional oxygen extraction
16 Hours with Selection by Perfusion Imaging. N Engl J Med 378 predicts border zone vulnerability to stroke in sickle cell disease. Neu-
(8):708-718, 2018. https://doi.org/10.1056/NEJMoa1713973 rology 90(13):e1134-e1142, 2018. https://doi.org/10.1212/
62. Bhatia KD, Briest R, Goetti R, et al: Incidence and Natural History WNL.0000000000005194
of Pediatric Large Vessel Occlusion Stroke: A Population Study. 80. Borzage MT, Bush AM, Choi S, et al: Predictors of cerebral blood flow
JAMA Neurology 79(5):488-497, 2022. https://doi.org/10.1001/ in patients with and without anemia. J Appl Physiol (1985) 120
jamaneurol.2022.0323 (8):976-981, 2016. https://doi.org/10.1152/japplphysiol.00994.2015
63. Sporns PB, Psychogios MN, Straeter R, et al: Clinical Diffusion Mis- 81. Hoiland RL, Bain AR, Rieger MG, Bailey DM, Ainslie PN: Hypoxemia,
match to Select Pediatric Patients for Embolectomy 6 to 24 Hours After oxygen content, and the regulation of cerebral blood flow. Am J
Pediatric Acute Stroke Management 11

Physiol Regul Integr Comp Physiol 310(5):R398-R413, 2016. https:// 100. Foreman B, Claassen J: Quantitative EEG for the detection of brain
doi.org/10.1152/ajpregu.00270.2015 ischemia. Crit Care 16(2):216, 2012. https://doi.org/10.1186/cc11230
82. DeBaun MR, Jordan LC, King AA, et al: American Society of Hematol- 101. Huguenard AL, Guerriero RM, Tomko SR, et al: Immediate Postopera-
ogy 2020 guidelines for sickle cell disease: prevention, diagnosis, and tive Electroencephalography Monitoring in Pediatric Moyamoya Dis-
treatment of cerebrovascular disease in children and adults. Blood ease and Syndrome. Pediatr Neurol 118:40-45, 2021. https://doi.org/
Advances 4(8):1554-1588, 2020. https://doi.org/10.1182/bloodad 10.1016/j.pediatrneurol.2021.02.004
vances.2019001142 102. Appavu BL, Temkit MH, Foldes ST, et al: Quantitative Electroencepha-
83. Davis BA, Allard S, Qureshi A, et al: Guidelines on red cell transfusion lography After Pediatric Anterior Circulation Stroke. J Clin Neurophy-
in sickle cell disease Part II: indications for transfusion. Br J Haematol siol 2020. https://doi.org/10.1097/WNP.0000000000000813. Publish
176(2):192-209, 2017. https://doi.org/10.1111/bjh.14383 Ahead of Print
84. Reith J, Jørgensen HS, Pedersen PM, et al: Body temperature in acute 103. Powers WJ, Rabinstein AA, Ackerson T, et al: 2018 Guidelines for the
stroke: relation to stroke severity, infarct size, mortality, and outcome. Early Management of Patients With Acute Ischemic Stroke: A Guide-
Lancet 347(8999):422-425, 1996. https://doi.org/10.1016/s0140- line for Healthcare Professionals From the American Heart Associa-
6736(96)90008-2 tion/American Stroke Association. Stroke 49(3):e46-e110, 2018.
85. Jørgensen HS, Reith J, Pedersen PM, Nakayama H, Olsen TS: Body https://doi.org/10.1161/STR.0000000000000158
temperature and outcome in stroke patients. Lancet 348(9021):193, 104. Vahedi K, Hofmeijer J, Juettler E, et al: Early decompressive surgery in
1996. https://doi.org/10.1016/s0140-6736(05)66135-1 malignant infarction of the middle cerebral artery: a pooled analysis of
86. Castillo J, Davalos A, Marrugat J, Noya M: Timing for fever-related three randomised controlled trials. Lancet Neurol 6(3):215-222, 2007.
brain damage in acute ischemic stroke. Stroke 29(12):2455-2460, https://doi.org/10.1016/S1474-4422(07)70036-4
1998. https://doi.org/10.1161/01.str.29.12.2455 105. Lehman LL, DeVeber G, Pergami P, et al: Characteristics and Outcome
87. den Hertog HM, van der Worp HB, van Gemert HMA, et al: The Para- in Children With Craniectomy Following Acute Ischemic Stroke in the
cetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, rando- International Pediatric Stroke Study. J Child Neurol 34(12):765-769,
mised, placebo-controlled, phase III trial. Lancet Neurol 8(5):434-440, 2019. https://doi.org/10.1177/0883073819855534
2009. https://doi.org/10.1016/S1474-4422(09)70051-1 106. Dowling MM, Quinn CT, Rogers ZR, Journeycake JM: Stroke in Sickle
88. Weir CJ, Murray GD, Dyker AG, Lees KR: Is hyperglycaemia an inde- Cell Anemia: Alternative Etiologies. Pediatric Neurology 41(2):124-
pendent predictor of poor outcome after acute stroke? Results of a 126, 2009. https://doi.org/10.1016/j.pediatrneurol.2009.02.011
long-term follow up study. BMJ 314(7090):1303-1306, 1997. https:// 107. Guilliams KP, Kirkham FJ, Holzhauer S, et al: Arteriopathy Influences
doi.org/10.1136/bmj.314.7090.1303 Pediatric Ischemic Stroke Presentation, but Sickle Cell Disease Influen-
89. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC: Stress hyper- ces Stroke Management. Stroke 50(5):1089-1094, 2019. https://doi.
glycemia and prognosis of stroke in nondiabetic and diabetic patients: org/10.1161/STROKEAHA.118.022800
a systematic overview. Stroke 32(10):2426-2432, 2001. https://doi. 108. Dowling MM, Quinn CT, Ramaciotti C, et al: Increased prevalence of
org/10.1161/hs1001.096194 potential right-to-left shunting in children with sickle cell anaemia and
90. Gray CS, Hildreth AJ, Sandercock PA, et al: Glucose-potassium-insulin stroke. Br J Haematol 176(2):300-308, 2017. https://doi.org/10.1111/
infusions in the management of post-stroke hyperglycaemia: the UK bjh.14391
Glucose Insulin in Stroke Trial (GIST-UK). Lancet Neurol 6(5):397- 109. Guilliams KP, Fields ME, Ragan DK, et al: Large-Vessel Vasculopathy
406, 2007. https://doi.org/10.1016/S1474-4422(07)70080-7 in Children With Sickle Cell Disease: A Magnetic Resonance Imaging
91. Johnston KC, Bruno A, Pauls Q, et al: Intensive vs Standard Treatment Study of Infarct Topography and Focal Atrophy. Pediatric Neurology
of Hyperglycemia and Functional Outcome in Patients With Acute 69:49-57, 2017. https://doi.org/10.1016/j.pediatrneurol.2016.11.
Ischemic Stroke. JAMA 322(4):326-335, 2019. https://doi.org/ 005
10.1001/jama.2019.9346 110. Goldenberg NA, Bernard TJ, Fullerton HJ, Gordon A, deVeber G:
92. Chadehumbe MA, Khatri P, Khoury JC, et al: Seizures are common in Antithrombotic treatments, outcomes, and prognostic factors in acute
the acute setting of childhood stroke: a population-based study. J childhood-onset arterial ischaemic stroke: a multicentre, observational,
Child Neurol 24(1):9-12, 2009. https://doi.org/10.1177/0883073 cohort study. Lancet Neurol 8(12):1120-1127, 2009. https://doi.org/
808320756 10.1016/S1474-4422(09)70241-8
93. Billinghurst LL, Beslow LA, Abend NS, et al: Incidence and predictors 111. Lansberg MG, O’Donnell MJ, Khatri P, et al: Antithrombotic and
of epilepsy after pediatric arterial ischemic stroke. Neurology 88 thrombolytic therapy for ischemic stroke: Antithrombotic Therapy
(7):630-637, 2017. https://doi.org/10.1212/WNL.000000000000 and Prevention of Thrombosis, 9th ed: American College of Chest
3603 Physicians Evidence-Based Clinical Practice Guidelines. Chest 141(2
94. Song JL, Kim JA, Struck AF, Zhang R, Westover MB: A model of meta- Suppl):e601S-e636S, 2012. https://doi.org/10.1378/chest.11-2302
bolic supply-demand mismatch leading to secondary brain injury. J 112. Branstetter JW, Kiskaddon AL, King MA, et al: Efficacy and Safety of
Neurophysiol 126(2):653-667, 2021. https://doi.org/10.1152/ Non-Vitamin K Antagonist Oral Anticoagulants in Pediatric Venous
jn.00674.2020 Thromboembolism Treatment and Thromboprophylaxis: A Systematic
95. Payne ET, Zhao XY, Frndova H, et al: Seizure burden is independently Review of the Literature. Semin Thromb Hemost 47(06):643-653,
associated with short term outcome in critically ill children. Brain 137 2021. https://doi.org/10.1055/s-0041-1725944
(Pt 5):1429-1438, 2014. https://doi.org/10.1093/brain/awu042 113. Bw M, Ad M, Ah VB, et al: Thromboprophylaxis for Children Post-
96. Ferriero DM, Fullerton HJ, Bernard TJ, et al: Management of Stroke in Fontan Procedure: Insights From the UNIVERSE Study. J Am Heart
Neonates and Children: A Scientific Statement From the American Assoc 10(22). https://doi.org/10.1161/jaha.120.021765, 2021 .
Heart Association/American Stroke Association. Stroke 50(3):e51-e96, e021765-e021765
2019. https://doi.org/10.1161/STR.0000000000000183 114. Connor P, Sanchez van Kammen M, Lensing AWA, et al: Safety and
97. Fox CK, Glass HC, Sidney S, Lowenstein DH, Fullerton HJ: Acute seiz- efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EIN-
ures predict epilepsy after childhood stroke. Ann Neurol 74(2):249- STEIN-Jr CVT). Blood Adv 4(24):6250-6258, 2020. https://doi.org/
256, 2013. https://doi.org/10.1002/ana.23916 10.1182/bloodadvances.2020003244
98. Fox CK, Mackay MT, Dowling MM, et al: Prolonged or recurrent acute 115. Brand~ao LR, Albisetti M, Halton J, et al: Safety of dabigatran etexi-
seizures after pediatric arterial ischemic stroke are associated with late for the secondary prevention of venous thromboembolism in
increasing epilepsy risk. Dev Med Child Neurol 59(1):38-44, 2017. children. Blood 135(7):491-504, 2020. https://doi.org/10.1182/
https://doi.org/10.1111/dmcn.13198 blood.2019000998
99. Guilliams KP, Dowling MM, Zafeiriou D, et al: Anti-seizure Medication 116. Lichtman JH, Allen NB, Wang Y, Watanabe E, Jones SB, Goldstein LB:
Practice Variation by Age of Pediatric Arterial Ischemic Stroke  Pedi- Stroke patient outcomes in US hospitals before the start of the Joint
atric Stroke Journal. Pediatr Stroke 1(1):1-16, 2020 Commission Primary Stroke Center certification program. Stroke 40
12 T.-L. Surtees et al.

(11):3574-3579, 2009. https://doi.org/10.1161/STROKEAHA.109. 133. Monagle P, Chalmers E, Chan A, et al: Antithrombotic therapy in neo-
561472 nates and children: American College of Chest Physicians Evidence-
117. Alberts MJ, Johnston SC: Does stroke center designation improve Based Clinical Practice Guidelines. Chest 133(6 Suppl):887S-968S,
patient outcomes? Family Practice News 41(7):25, 2011. https://doi. 2008. https://doi.org/10.1378/chest.08-0762
org/10.1016/S0300-7073(11)70343-7 134. Bernard TJ, Manco-Johnson MJ, Goldenberg NA: The roles of ana-
118. Bernard TJ, Rivkin MJ, Scholz K, et al: Emergence of the primary tomic factors, thrombophilia, and antithrombotic therapies in child-
pediatric stroke center: impact of the thrombolysis in pediatric hood-onset arterial ischemic stroke. Thromb Res 127(1):6-12, 2011.
stroke trial. Stroke 45(7):2018-2023, 2014. https://doi.org/10.1161/ https://doi.org/10.1016/j.thromres.2010.09.014
STROKEAHA.114.004919 135. Engelter ST, Traenka C, Grond-Ginsbach C, et al: Cervical Artery Dis-
119. Roach ES, Bernard T, deVeber G: Defining a Pediatric Stroke Center. section and Sports. Front Neurol 12:663830. https://doi.org/10.3389/
Pediatric Neurology 112:11-13, 2020. https://doi.org/10.1016/j. fneur.2021.663830, 2021
pediatrneurol.2020.08.008 136. Engelter ST, Traenka C, Gensicke H, et al: Aspirin versus anticoagula-
120. Amlie-Lefond C, Bernard TJ, Sebire G, et al: Predictors of cerebral arte- tion in cervical artery dissection (TREAT-CAD): an open-label, rando-
riopathy in children with arterial ischemic stroke: results of the Inter- mised, non-inferiority trial. Lancet Neurol 20(5):341-350, 2021.
national Pediatric Stroke Study. Circulation 119(10):1417-1423, https://doi.org/10.1016/S1474-4422(21)00044-2
2009. https://doi.org/10.1161/CIRCULATIONAHA.108.806307 137. Fox CK, Fullerton HJ, Hetts SW, et al: Single-center series of boys with
121. Wintermark M, Hills NK, deVeber GA, et al: Arteriopathy Diagnosis in recurrent strokes and rotational vertebral arteriopathy. Neurology 95
Childhood Arterial Ischemic Stroke: Results of the Vascular Effects of (13):e1830-e1834, 2020. https://doi.org/10.1212/WNL.0000000
Infection in Pediatric Stroke Study. Stroke 45(12):3597-3605, 2014. 000010416
https://doi.org/10.1161/STROKEAHA.114.007404 138. Rollins N, Braga B, Hogge A, Beavers S, Dowling M: Dynamic Arterial
122. Beslow LA, Jordan LC: Pediatric stroke: the importance of cerebral Compression in Pediatric Vertebral Arterial Dissection. Stroke 48
arteriopathy and vascular malformations. Childs Nerv Syst 26 (4):1070-1073, 2017. https://doi.org/10.1161/STROKEAHA.116.
(10):1263-1273, 2010. https://doi.org/10.1007/s00381-010-1208-9 016236
123. Fullerton HJ, Wu YW, Sidney S, Johnston SC: Risk of Recurrent Child- 139. Braga BP, Sillero R, Pereira RM, et al: Dynamic compression in verte-
hood Arterial Ischemic Stroke in a Population-Based Cohort: The bral artery dissection in children: apropos of a new protocol. Childs
Importance of Cerebrovascular Imaging. Pediatrics 119(3):495-501, Nerv Syst 37(4):1285-1293, 2021. https://doi.org/10.1007/s00381-
2007. https://doi.org/10.1542/peds.2006-2791 020-04956-1
124. Steinlin M, Bigi S, Stojanovski B, et al: Focal Cerebral Arteriopathy: Do 140. Benseler SM, Silverman E, Aviv RI, et al: Primary central nervous sys-
Steroids Improve Outcome? Stroke 48(9):2375-2382, 2017. https:// tem vasculitis in children. Arthritis Rheum 54(4):1291-1297, 2006.
doi.org/10.1161/STROKEAHA.117.016818 https://doi.org/10.1002/art.21766
125. Fearn ND, Mackay MT: Focal cerebral arteriopathy and childhood 141. Twilt M, Benseler SM: Childhood inflammatory brain diseases: patho-
stroke. Curr Opin Neuro 33(1):37-46, 2020. https://doi.org/10.1097/ genesis, diagnosis and therapy. Rheumatology 53(8):1359-1368,
WCO.0000000000000787 2014. https://doi.org/10.1093/rheumatology/ket398
126. Braun KPJ, Bulder MMM, Chabrier S, et al: The course and outcome of 142. Smitka M, Bruck N, Engellandt K, Hahn G, Knoefler R, von der Hagen
unilateral intracranial arteriopathy in 79 children with ischaemic M. Clinical Perspective on Primary Angiitis of the Central Nervous Sys-
stroke. Brain 132(2):544-557, 2008. https://doi.org/10.1093/brain/ tem in Childhood (cPACNS). Front Pediatr. 8:281, 2020. doi:10.3389/
awn313 fped.2020.00281
127. Park Y, Fullerton HJ, Elm JJ: A pragmatic, adaptive clinical trial design 143. Rodan L, McCrindle BW, Manlhiot C, et al: Stroke recurrence in chil-
for a rare disease: The FOcal Cerebral Arteriopathy Steroid (FOCAS) dren with congenital heart disease. Ann Neurol 72(1):103-111, 2012.
trial. Contemp Clin Trials 86:105852. https://doi.org/10.1016/j. https://doi.org/10.1002/ana.23574
cct.2019.105852, 2019 144. Pulcine E, Seed M, Brand~ao LR, et al: Hemorrhagic transformation and
128. Rafay MF, Armstrong D, Deveber G, Domi T, Chan A, MacGregor DL: stroke recurrence in children with cardiac disease receiving antithrom-
Craniocervical arterial dissection in children: clinical and radiographic botic therapy for secondary stroke prevention. J Thromb Haemost 19
presentation and outcome. J Child Neurol 21(1):8-16, 2006. https:// (10):2428-2439, 2021. https://doi.org/10.1111/jth.15428
doi.org/10.1177/08830738060210010101 145. Salehi Omran S, Hartman A, Zakai NA, Navi BB: Thrombophilia Test-
129. Fullerton HJ, Johnston SC, Smith WS: Arterial dissection and stroke in ing After Ischemic Stroke: Why, When, and What? Stroke 52(5):1874-
children. Neurology 57(7):1155-1160, 2001. https://doi.org/10.1212/ 1884, 2021. https://doi.org/10.1161/STROKEAHA.120.032360
wnl.57.7.1155 146. Pengo V, Hoxha A, Andreoli L, et al: Trial of Rivaroxaban in AntiPhos-
130. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al: Scientific Ratio- pholipid Syndrome (TRAPS): Two-year outcomes after the study clo-
nale for the Inclusion and Exclusion Criteria for Intravenous Alteplase sure. J Thromb Haemost 19(2):531-535, 2021. https://doi.org/
in Acute Ischemic Stroke: A Statement for Healthcare Professionals 10.1111/jth.15158
From the American Heart Association/American Stroke Association. 147. Antiphospholipid Antibodies and Subsequent Thrombo-occlusive
Stroke 47(2):581-641, 2016. https://doi.org/10.1161/STR.0000000 Events in Patients With Ischemic Stroke. JAMA 291(5):576, 2004.
000000086 https://doi.org/10.1001/jama.291.5.576
131. Metso TM, Metso AJ, Helenius J, et al: Prognosis and safety of anticoa- 148. Mojadidi MK, Zaman MO, Elgendy IY, et al: Cryptogenic Stroke and
gulation in intracranial artery dissections in adults. Stroke 38(6):1837- Patent Foramen Ovale. J Am Coll Cardiol 71(9):1035-1043, 2018.
1842, 2007. https://doi.org/10.1161/STROKEAHA.106.479501 https://doi.org/10.1016/j.jacc.2017.12.059
132. Debette S, Mazighi M, Bijlenga P, et al: ESO guideline for the manage- 149. Shih EK, Beslow LA, Natarajan SS, Falkensammer CB, Messe SR,
ment of extracranial and intracranial artery dissection. Eur Stroke J 6 Ichord RN: Prevalence of Patent Foramen Ovale in a Cohort of Chil-
(3). https://doi.org/10.1177/23969873211046475, 2021. XXXIX- dren With Cryptogenic Ischemic Stroke. Neurology 97(21):e2096-
LXXXVIII e2102, 2021. https://doi.org/10.1212/WNL.0000000000012892