Review
Paediatric stroke: pressing issues and promising directions
Lancet Neurol 2015; 14: 92–102
See Online for podcast
Calgary Pediatric Stroke
Program, Alberta Children’s
Hospital Research Institute,
Departments of Pediatrics and
Clinical Neurosciences,
University of Calgary, Calgary,
AB, Canada (A Kirton MD); and
SickKids Children’s Stroke
Program, Hospital for Sick
Children, Department of
Pediatrics, University of
Toronto, Toronto, ON, Canada
(G deVeber MD)
Correspondence to:
Dr Adam Kirton, Alberta
Children’s Hospital, Section of
Neurology, Calgary, AB T3B6A8,
Canada
adam.kirton@
albertahealthservices.ca
92
Adam Kirton, Gabrielle deVeber
Stroke occurs across the lifespan with unique issues in the fetus, neonate, and child. The past decade has seen
substantial advances in paediatric stroke research and clinical care, but many unanswered questions and controversies
remain. The pathobiology of perinatal stroke needs to be better understood if prevention strategies are to be realised.
Similarly, enhanced understanding of the mechanisms underlying childhood stroke, including cerebral arteriopathies,
could inform the development of mechanism-specific treatments. Emerging clinical trials, including studies of
neonatal sinovenous thrombosis and childhood arterial stroke, offer the hope of evidence-based treatment options in
the near future. Early recognition of stroke in children is a key educational target for both the public and health-care
professionals, and has translational potential to advance the application of neuroprotective, thrombolytic, and
antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after stroke onset,
improving outcomes and quality of life for affected children and their families.
Introduction following key issues for discussion: stroke mechanisms,
Stroke occurs throughout life but clinical considerations focusing on perinatal stroke and childhood arteriopathy;
vary depending on the life stage. Adult stroke defines the treatment updates, including antithrombotics, throm-
disease in the minds of lay people and professionals bolytics, and directions for clinical trials; plasticity
alike. Although important commonalities probably exist models of rehabilitation; and knowledge translation.
between young adult and adolescent stroke, virtually all
aspects of stroke in the elderly are different from those in Perinatal stroke: searching for disease biology
children. Atherosclerosis and accompanying modifiable Perinatal stroke accounts for a large proportion of
risk factors that dominate adult stroke mechanisms and paediatric stroke morbidity. The first week of life carries
treatment are nearly non-existent in paediatric stroke. the most focused period of risk for stroke5 and most
Highly powered clinical trials that increasingly inform survivors have lifelong morbidity. Motor deficits,
adult stroke management, including antiplatelet and typically hemiparetic cerebral palsy, predominate, but
anticoagulant strategies, chemical and mechanical cognitive or behavioural disorders and epilepsy are also
thrombolysis, stroke unit care, and many others do not common. Imaging-based classifications now recognise
yet exist in children. Population-based methodologies specific perinatal stroke disease states, including
have replaced less accurate administrative coding studies arterial and venous varieties with differing timing,
to better define incidence rates of childhood stroke, presentations, and locations of injury.6 Illustrative cases
emphasising that this disorder is not rare among of the three main subtypes of perinatal stroke are
childhood illnesses. Three such studies published since shown in figure 1.6
2009 have reported remarkably consistent rates of Little is understood about the pathophysiology of
stroke (1·3, 1·6, and 1·6 per 100 000 children per year), perinatal stroke, which means that few disease-specific
suggesting that these determinations are accurate.1–3 treatments and no prevention strategies are available.
Rates of perinatal stroke are even higher, occurring in at Unequivocal major risks such as congenital heart disease
least one in 3500 livebirths.4,5 or bacterial meningitis are present in about a third of
In the past few years, many important advances in the neonates with acute AIS. Case-control studies have
pathophysiology and management of paediatric stroke examined clinical risk factors, including maternal,
have been made. From a medical perspective, neonates obstetric, and neonatal variables, but little consistency
(aged ≤28 days since birth) and children (aged 1 month to has been noted across studies.7,8 The evidence increasingly
18 years) are different. Arterial ischaemic stroke (AIS) and suggests that many neonates with AIS will have risk
cerebral sinovenous thrombosis (CSVT) differ in many factors and presentations that overlap with those of
regards, although both harbour overlapping and global hypoxic ischaemic encephalopathy, and the two
incompletely understood predisposing disorders that can co-occur.9,10 This overlap adds further challenge to the
result in a final common pathway of thrombotic vascular identification of disease-specific risk factors. In a 2014
occlusion. Knowledge of the mechanisms underlying meta-analysis, clinical variables associated with hypoxia
paediatric stroke is rapidly expanding and remains crucial were frequently associated with neonatal stroke.11 Specific
to informing our approach to treatment. Treatment data, investigations of disease biology are a crucial addition to
likewise, are steadily accumulating and will support the clinical risk factor studies to improve understanding of
imminent development of much-needed paediatric stroke perinatal stroke pathogenesis.
clinical trials. Two such approaches include investigation of maternal
In this Review, we focus on some of the most pressing and newborn prothrombotic tendencies and examination
and recently productive aspects of research in the of pathological changes in the placenta. Many studies
specialty of ischaemic paediatric stroke. We identified the have shown associations of perinatal stroke with
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different prothrombotic states.12 One meta-analysis
identified thrombophilia as a contributing factor across
all-age paediatric AIS and CSVT, including perinatal
stroke.13 A seminal case-control study reported an odds
ratio of 6·70 (95% CI 3·84–11·67) for thrombophilia in
neonatal AIS.12 Most subsequent perinatal stroke studies
relying on clinical thrombophilia testing have reported
lower rates of association,10 emphasising the variability
in testing and laboratory challenges in the assessment of
haemostasis. Exactly how prothrombotic disorders
translate into thrombosis within high flow cerebral
arteries is unknown, but proximal embolic sources such
as the placenta have been suggested.5 Thrombophilia
alone is rarely suspected to be causative in either
perinatal or childhood stroke.5
Placental diseases can cause perinatal arterial stroke.
AIS lesions are often multifocal, even in the absence of
overt cardiac disease, which lends support to a proximal
embolic source.10 Recurrence rates are close to zero,
consistent with mechanisms present only prenatally
and perinatally. Investigators obtaining placentas for
pathological examination are presented with major
challenges because most strokes are diagnosed within
days after birth. However, some small studies have
directly correlated pathological placental disease with
perinatal stroke.14 Some clinical studies have lent further
support to placental inflammation, consistently
reporting associations with chorioamnionitis.14,15 Our
preliminary data suggest that specific inflammatory
biomarker profiles are present in neonates with acute
ischaemic stroke (unpublished). Large-scale placental
tissue banking studies are needed to establish the role
of placental disease in perinatal stroke. These studies,
in conjunction with neonatal and maternal biomarker
profiles, such as disordered inflammation, might help
to define disease biology and potentially identify the
maternal signatures needed for screening of at-risk
pregnancies to ultimately inform prevention strategies.
Advances in childhood cerebral arteriopathy
Among children with stroke, arteriopathy has emerged
as the predominant underlying mechanism, causing
53% of cases.14,16 Arteriopathy is the greatest predictor of
recurrence, emphasising its importance as a treatment
target for secondary stroke prevention.14,17,18 Amlie-Lefond
and colleagues19 characterised classic arteriopathy
subtypes in the International Paediatric Stroke Study
(IPSS) cohort. A fundamental dichotomy has emerged in
the discovery of arteriopathic mechanisms. Acquired,
acute arterial diseases related to childhood infections and
trauma occurring in healthy, school-aged children are
distinguished from more chronic, inherent arterial
disorders, many of which are either genetic or occur in
children with chronic systemic disorders.
The most common established arteriopathy in
childhood stroke is a unilateral intracranial arteriopathy
associated with basal ganglia stroke, originally reported
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A B C
Figure 1: Perinatal ischaemic stroke syndromes
(A) Symptomatic neonatal arterial ischaemic stroke diagnosed acutely with diffusion MRI showing recent arterial
infarction. (B) Arterial presumed perinatal ischaemic stroke presenting in late infancy with MRI showing focal
encephalomalacia secondary to remote arterial occlusion. (C) Periventricular venous infarction presenting in
infancy with hemiparetic cerebral palsy, with MRI showing focal venous infarction of the periventricular white
matter secondary to fetal germinal matrix haemorrhage.
with the term transient cerebral arteriopathy (TCA),
which is distinguished from moyamoya by its time
course, unilateral location, and an absence of long-term
progression. The arteriopathy is centred at the junction
of the distal internal carotid artery, proximal middle
cerebral artery, and proximal anterior cerebral artery.
TCA has a distinct banded appearance on initial
angiography (figure 2) and a dynamic timecourse with
progressive arteriopathy in the first 3–6 months, followed
by stabilisation or improvement.20 The original
investigators posited that the basis for this disorder is
inflammatory but could also include dissection. Whether
TCA can be diagnosed on initial imaging is controversial
because it is partly defined by its course of non-
progression after 6 months. However, one study reported
that among 79 consecutive children with basal ganglia
infarction and unilateral intracranial arteriopathy,21 94%
showed a typical TCA pattern of evolution over the
subsequent 6−12 months. TCA seems to be diagnosable
at stroke presentation with a high degree of certainty.
Many terminologies have been applied to similar
patterns of acquired cerebral arteriopathy in children. One
is focal cerebral arteriopathy.19 A second term based on the
presumed inflammatory mechanism is non-progressive,
angiography-positive childhood primary angiitis of the
CNS.22 Another syndrome with similar arterial imaging
but a presumed infectious cause is post-varicella
angiopathy, suggesting that TCA might sometimes have a
direct link to infectious mechanisms.23 Emerging results
from the Vascular Effects of Infection in Pediatric Stroke
(VIPS) study should shed light on the role of infections in
childhood cerebral arteriopathy.24 In some children
diagnosed with TCA, intracranial dissection has been
noted in autopsy studies.25
Overlapping these arteriopathy syndromes is
fibromuscular dysplasia. A study of paediatric
fibromuscular dysplasia and stroke identified
pathologically confirmed cases that occurred in infancy
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pathophysiology of this disorder and likewise the need for

A B
a more uniform arteriopathy classification, which is in
development (figure 2).27,28
Advances in new methodologies are beginning to
provide insight into the mechanisms of TCA. Specifically,
arterial wall imaging could improve the diagnosis and
characterisation of TCA and other acquired arteriopathies.
Arterial wall imaging with blood-sensitive sequences
remains useful to identify intracranial dissection
(figure 3).25 Arterial wall enhancement with high-
resolution, contrast-enhanced, vessel wall MRI could
support a diagnosis of vasculitis in both children and
adults (figure 3).29–31 However, arterial wall enhancement
can be confused with periarterial enhancement, which
C
has been reported in healthy children at some cerebral
arterial segments.32 Further refinement is needed in the
techniques and interpretation of wall imaging.
Genetically determined arteriopathies are increasingly
recognised as a cause of childhood AIS. By summarising
target cells for the various genetic defects in genetically
determined arteriopathies, Munot and colleagues33 have
Figure 2: Focal cerebral arteriopathy
(A) Diffusion MRI from a child with sudden-onset right hemiparesis showing acute infarction within deep and proposed an appealing targeted gene approach to
cortical middle cerebral artery territories. (B) Conventional angiography (left internal carotid injection) confirms studying TCA and other poorly understood childhood
focal arteriopathy affecting the distal internal carotid artery, and proximal middle cerebral artery and anterior arteriopathies (figure 4). Nowak-Göttl and colleagues34
cerebral artery. (C) Wall irregularities can be seen on the enlarged image, including alternating areas of focal
reported genetic variants of plasma glutathione
stricture and dilatation.
peroxidase in childhood arteriopathy. The RNF213 gene
seems to account for a substantial proportion of
A C moyamoya disease.35 Other genetic alterations in
moyamoya include 3p24·2–p26, 6q25, 8q23, 12p12, and
17q25.36 In 2014, a genetic arteriopathy caused by a
deficiency of adenosine deaminase 2 (ADA2) was
reported that features intermittent fevers, lacunar strokes
beginning in early childhood, and livedoid rash;
histopathological changes include compromised
endothelial integrity, endothelial cellular activation, and
B D inflammation.37 The list of additional genetically
determined arteriopathies continues to expand, including
COL4A1, ACTA2, and pericentrin (MOPD2) mutations,
and syndromes such as Alagille’s and PHACE. Functional
studies lend support to novel genetic discoveries that
suggest a role for extracellular matrix proteins such as
ADAMTS.38,39 A 2014 review40 adeptly summarises genetic
causes of childhood stroke, including arteriopathies. For
Figure 3: MRI of arterial wall in paediatric arterial ischaemic stroke
Patient 1 had focal cerebral arteriopathy with acute serum biomarkers suggesting active inflammation. Day 1 T1 health-care workers, the ability to distinguish between
MRI with gadolinium shows enhancement of the right middle cerebral artery (A). Arrow shows linear gadolinium acquired and inherent arteriopathies carries major
enhancement along the middle cerebral artery wall on the right that was not seen on the left (A). This finding was implications for acute management, chronic stroke
not present (arrows) on the same study repeated 3 weeks later after treatment with steroids (B). Patient 2 had
prevention, screening for systemic complications, and
acute arterial ischaemic stroke with conventional angiography suggesting focal disease of the left middle cerebral
artery and a possible central luminal filling defect (arrowhead, C). Focal T1 hyperintensity suggests the presence of counselling.
intramural blood consistent with intracranial dissection (D). Parts A and B reproduced from Mineyko and The list of predisposing and triggering mechanisms
colleagues,29 by permission of Wolters Kluwer Health. Parts C and D reproduced from Dlamini and colleagues,25 by for childhood AIS is expanding. Thrombophilia is the
permission of SAGE Publications.
prototypical predisposing risk factor for childhood
stroke, although usually in combination with another
with systemic arteriopathy and childhood cases that might causative factor.13 Acquired common childhood
have been misdiagnosed, based solely on the so-called disorders such as iron deficiency likewise predispose to
beading on angiography as seen in TCA.26 The range of stroke.41 Recently confirmed common triggers for
terms used to describe acquired cerebral arteriopathy childhood AIS include trauma and infection.42 A novel
draws attention to the present dearth of knowledge on the mineralising angiopathy in infants with basal ganglia

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stroke has been described, apparently triggered by
minor head trauma.43 Such examples underscore the
importance of considering the convergence and
interaction of many risk factors in childhood stroke
pathogenesis. Most of the associations described for
childhood stroke probably represent only potential risk
factors, usually working in combination with other
factors to produce stroke, rather than being independent
causative mechanisms.
Treatment dilemmas in childhood stroke
Despite advances reviewed here, for many children with
AIS and CSVT, a poor understanding of mechanisms
combines with a dearth of clinical trials to make evidence-
based treatment elusive. Consensus-based guidelines that
provide recently updated suggestions for best practice
include the Canadian Best Practice Guidelines (2010)44
and the American College of Chest Physicians Evidence-
Based Clinical Practice Guidelines (CHEST; 2012).45
For childhood AIS, guidelines consistently recommend
antithrombotic treatment, specifying anticoagulation for
cardiac disorders or arterial dissection. However,
controversies about anticoagulation versus aspirin persist
for other forms of childhood AIS. Moreover, the optimum
duration of aspirin use is poorly defined, although 2 years
as a minimum is suggested. In practice, anticoagulation
use varies widely because of these uncertainties. In the
IPSS, 43% of children received anticoagulation either
alone or in combination with aspirin (figure 5) and global
rates of anticoagulation ranged from 29% to 69%.18
Meanwhile, additional safety data have emerged for
anticoagulation as initial therapy in childhood AIS. One
centre treated 135 children with initial anticoagulation
per protocol and reported a 4% risk of symptomatic
intracranial haemorrhage.46 These data are in agreement
with a previous study of 37 children with non-moyamoya
arteriopathies who received initial anticoagulation for a
minimum of 4 weeks, with no major bleeds occurring
during 1329 patient-months.47 However, neither study
could establish efficacy for anticoagulation.
An improved biological understanding of the relative
fibrin versus platelet content of occlusive clots in different
scenarios of childhood stroke would inform selection of
antiplatelet or anticoagulation agents. This information
is not available at present. However, in adults,
histopathological examination of clots retrieved with
mechanical extraction devices has been successful. The
findings are of variable compositions, with a mixture of
fibrin, red blood cells, platelets, calcification, and in older
clots, endothelialisation.48 Fibrin-rich (red) clots tend to
be localised to regions with reduced flow or stasis,
whereas platelet-rich (white) clots are localised to regions
exposed to high-shear blood flow. Thrombus-specific
MRI contrast agents with affinity to either fibrin or
activated platelets are in development.49 Such agents
could supplement MRI techniques and inform treatment
approaches to childhood stroke.
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Accumulation of abnormal metabolites:
GLA (Fabry’s disease)
Homocysteinuria Media Adventitia
External elastic lamina
Internal elastic lamina
ELN
ABCC6-calcification of elastin fibres
Vascular smooth muscle cells Intima
ACTA2, pericentrin, NF1
Lumen
Vascular basement membrane
COL4A1
Abnormal response to endothelial injury:
SAMHD1, GLUT10, ATP7A, NF1
Fibroblasts
Abnormal vascular homoeostasis:
NOTCH signalling pathway: NOTCH3, JAG1
TGFβ pathway: HTRA1, SLC2AI0
Figure 4: Inherent arteriopathies
Schematic representation of the cross-sectional structure of an artery showing
target cells for genetic defects in genetically determined arteriopathies.
Reproduced with permission from Munot and colleagues.33
GLA=globotriaosylceramide. TGFβ=transforming growth-factor β.
A randomised clinical trial in childhood AIS that
compares antiplatelet and anticoagulant drugs for safety
and efficacy outcomes is needed to establish optimum
antithrombotic treatment. Low disease incidence and
other factors would mandate that such a trial include a
large number of international paediatric stroke centres.
Powerful global research consortia such as the IPSS
provide increasing opportunity to undertake this kind of
trial. Such a trial could potentially include young adults
because their pathophysiology might be similar enough to
that of children. A post hoc subgroup analysis from the
Warfarin-Aspirin Recurrent Stroke Study (WARSS)
reported a significant benefit of warfarin in reducing the
risk of recurrent stroke or death in the 2 years after an
initial stroke in non-hypertensive adults with cryptogenic
stroke (hazard ratio 0·45, 95% CI 0·22–0·96; p=0·04).50
After exclusion of cardioembolism, atherosclerosis, and
lipohyalinosis, cryptogenic stroke is responsible for the
remaining 40% of strokes in adults. Children with stroke
are generally non-hypertensive and many would fit the
adult criteria for classification as cryptogenic. To combine
children with AIS and young (<18–40 years) non-
hypertensive adults with cryptogenic stroke is a reasonable
approach that is worthy of exploration. In view of the 30%
reduction in recurrent stroke detected in the WARSS
subgroup analysis50 when aspirin and anticoagulants were
compared, several hundred patients per treatment arm
would be needed.
Acute recanalisation therapies continue to emerge in
childhood AIS, migrating from adult practice. Consistent
with previous guidelines, the CHEST guidelines advise
against the use of alteplase to achieve thrombolysis or
mechanical thrombectomy for children outside specific
research protocols.45 15 children receiving alteplase were
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Canada
(84, 7) 6 substantial neurological deficits (paediatric NIH Stroke
24 35
22 Asia
19 59 25 41
69 (29, 4)
Europe
34 38 (68, 2)
USA
(364, 18) 28
12
61 27
South America Australia
6
(48, 1) (47, 1)
40 54
Anticoagulant therapy (%)
Antiplatelet monotherapy (%)
No therapy (%)
Figure 5: Antithrombotic treatment practices in the International Paediatric Stroke Study
Acute antithrombotic therapy use in childhood-onset arterial ischaemic stroke by geographical region (number of
patients, number of centres). Anticoagulant therapy (red) includes patients who received anticoagulant therapy
with or without antiplatelet therapy. Reproduced with permission from Goldenberg and colleagues.18
studied in the IPSS: two died from stroke complications,
one fully recovered, and 12 had neurological deficits.51
Four had asymptomatic intracranial haemorrhage. A
paediatric safety and dose-finding study for intravenous
alteplase within 4·5 h of stroke onset was developed,
entitled the Thrombolysis in Pediatric Stroke study. This
study was halted because of insufficient recruitment, but
For the National Institute of yielded important data on the need for the development
Neurological Disorders and of acute stroke treatment centres for children.52
Stroke’s Stroke Trials Network
see http://www.ninds.nih.gov/
The role of endovascular therapy in adult stroke
research/clinical_research/ continues to be defined.53 Despite an absence of safety
NINDS_stroke_trials_network. data and no strong efficacy data in adults, and despite
htm recommendations against mechanical thrombectomy for
children outside specific research protocols,54 endovascular
treatment, including mechanical thrombectomy, has been
applied to children with AIS. 34 published cases of
paediatric endovascular treatment, including intra-arterial
alteplase, were reviewed in 2011.54 13 children aged
2–18 years underwent mechanical embolectomy, including
intra-arterial thrombolysis in nine patients. Mean time
from symptom onset to treatment was 14 h (range 2–72).
Recanalisation, reported in 28 children, was completed in
12 children but was partial or absent in the remaining 16
patients (57%). Clinical outcomes were not available in
most children. Complications occurred in 29% of children,
including haemorrhage and one dislodged coil. The
investigators suggest safety guidelines for endovascular
treatment in childhood stroke. They strongly urge that
only interventional teams with specific paediatric
experience treat children and that paediatric stroke
neurologists be included in decision making. They
emphasise the risks associated with the treatment of
children as small adults, because these devices were
designed for adult use. They recommend that endovascular
96
treatment be considered only for older children with
Scale scores 10–30), occlusion of a dominant cerebral
artery, and MRI diffusion evidence of substantial
preservation of brain tissue in that territory.
Procedures with only slight potential benefit and high
risks should be avoided in children with stroke because
natural outcomes in childhood stroke are probably better
than they are in adults. Investigators who compared
outcomes after brainstem stroke emphasised this point.55
Among 90 paediatric patients, 57% had good outcomes,
mortality was 8%, and the remaining 35% survived with a
modified Rankin Scale score of 4 or more, for an overall
poor outcome frequency of 43%.55 By comparison, in
adults enrolled in the Basilar Artery International
Cooperation Study,56 mortality was 39% and 31% survived
with a modified Rankin Scale score of 4 or more, for an
overall poor outcome rate of 70% (1·6 times greater than
that noted for children). Although such group comparisons
have unavoidable limitations, they seem to show that the
dismal prognosis of adult basilar artery stroke might not
be appropriate to guide management and research of the
same disease in children.
To summarise, present practice variability and adverse
outcomes in most children with stroke suggest an urgent
need for improved evidence for childhood stroke
treatment. To strengthen the evidence base, the
development of treatment trials is not only crucial but
also feasible with the availability of large research
networks, including the IPSS and the developing
National Institute of Neurological Disorders and Stroke’s
Stroke Trials Network in the USA. Such networks,
working together, could provide the capacity to enrol the
needed numbers of children and where appropriate,
young adults. Valid paediatric stroke severity and
outcome scales are now available,57,58 as is reassuring
preliminary safety data for anticoagulants in childhood
stroke. As noted previously, one specific candidate trial
supported by the WARSS subanalysis would be a
comparison of aspirin and anticoagulants for the
prevention of recurrent childhood AIS. Another example
is an anticoagulant trial in neonatal CSVT; a perinatal
stroke syndrome with wide treatment variability.
Neonatal CSVT: diagnostic challenges in a
potentially treatable disease
CSVT causes brain injury, long-term morbidity, and
death in newborn babies.59 Presentations are non-
specific, consisting of neonatal encephalopathy and
seizures beginning after the first few days of postnatal
life. Fortunately, modern management of newborn
babies with seizures or encephalopathy typically results
in prompt imaging, most often MRI, with increasing
addition of magnetic resonance venography. Diagnostic
sensitivity of MRI and magnetic resonance venography
is improving but imaging findings are often subtle and
easily missed (figure 6).60
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Even small clots in the deep venous system, such as the
straight sinus, can cause severe venous infarction and
haemorrhage in bilateral deep grey and white matter.
Outcomes are often poor and include a high rate of
epileptic encephalopathies.61,62 Haemorrhagic trans-
formation of deep CSVT parenchymal lesions can extend
to become large intraventricular haemorrhage, possibly
obscuring the causative deep system thrombosis on
imaging.63 The medical community is increasingly
accepting that a term baby with intraventricular
haemorrhage is harbouring deep system CSVT until
proven otherwise, especially if evidence of associated
thalamic infarction or bleeding is noted. Additional
imaging biomarkers include restricted diffusion or
haemorrhage in the distal deep venous territories of the
frontal white matter, the fan-shaped or flower-like
appearance of which has been termed the iris sign
(figure 6).61
Neonatal CSVT might be associated with mechanical
factors typified by occipital bone compression of the
superior sagittal sinus in supine lying.64 Simple
decompression with newborn head positioning can
alleviate this problem,65 emphasising the importance of
supportive, neuroprotective care in newborn stroke.
Prompt diagnosis of neonatal CSVT is essential because
it is a treatable disorder with a natural history of early
progression. Anticoagulation is increasingly accepted as
routine practice for neonatal CSVT without haemorrhage,
on the basis of a strong rationale, extrapolated from
routine anticoagulation practice in adult and childhood
CSVT and safety data in neonates.66 A substantial amount
of safety data likewise supports anticoagulation in
neonatal CSVT with thalamic haemorrhage.67 A single-
centre, protocol-driven study of neonates with CSVT
reported that about 30% of newborn babies managed
without anticoagulation had thrombus propagation in the
first week after diagnosis compared with only about 5% of
those receiving anticoagulation.66 No increased risk of
serious bleeding was recorded in the group receiving
anticoagulation, whereas the group who did not receive
anticoagulation had higher rates of infarction and worse
outcomes. Consistent with these results, present
guidelines support anticoagulation for neonatal CSVT
without haemorrhage, and for those with haemorrhage,
either initial anticoagulation or clinical observation with
early repeat imaging.45 At present, anticoagulation practice
in neonatal CSVT varies between countries.68 Equipoise
regarding anticoagulation in neonatal CSVT still exists,
suggesting both need and opportunity for a clinical trial
that is in development at present within the IPSS.
Rehabilitation: harnessing the plasticity of the
developing brain
As a focal injury of defined timing in an otherwise healthy
brain, perinatal and childhood stroke present an ideal
human model of developmental plasticity. Motor system

A B C D E

F G H I J

Figure 6: Deep neonatal cerebral sinovenous thrombosis

(Case 1: A–E) (A) CT in a term newborn baby with seizures showing hyperdensity in the caudothalamic groove (arrow). (B) Apparent diffusion coefficient MRI shows restricted diffusion (arrow).
(C) Susceptibility MRI shows haemorrhage in the frontal white matter (iris sign, arrow) (D) Sagittal T1 shows a linear hyperintensity within the straight sinus (arrow). (E) MRV shows no flow in the
same location (arrow). (Case 2: F–J) (F) CT from another term newborn baby with seizures shows large intraventricular but also thalamic haemorrhage (arrow). (G) Diffusion MRI shows widespread
thalamic ischaemia. (H) MRV shows no flow in the straight sinus (arrow). (I) Untreated, the child returned 2 weeks later with irritability, at which point CT venogram showed extension of the thrombus
throughout the major dural sinuses. (J) After 6 weeks of anticoagulation, the sinuses look healthy on MRV including the straight sinus (arrow). The child has refractory epilepsy and global delays.
MRV=magnetic resonance venography.

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RM1 LM1
W
Figure 7: Developmental plastic motor organisation after perinatal stroke
Control of the weak right hand (W) often relies on both contralateral
corticospinal pathways from the left (lesioned) primary motor cortex (LM1, solid
white line) and ipsilateral projections from the unlesioned right primary motor
cortex (RM1, solid orange line). These two inputs compete to establish synapses
with anterior horn spinal motor neuron pools (circles) during child development.
Additionally, each primary motor cortex can affect the other via interhemispheric
inhibition (dashed green arrows). The relative balance of control determines
motor outcome, with contralateral control associated with better function.
Interventions that promote the success of contralateral (or inhibit the success of
ipsilateral) upper motor neuron systems to compete for spinal motor neurons
should result in better motor function. Modified from Kirton,69 by permission of
Elsevier.
plasticity has been the focus of both human and animal
research.69,70 With this combined approach, motor system
development after unilateral perinatal injury is
increasingly understood.71–73 A key element to such models
is the degree of control of the hemiparetic side by the
ipsilateral (contralesional) hemisphere (figure 7).
Corticospinal innervation is bilateral at birth, with
subsequent withdrawal of ipsilateral projections resulting
in a mature system with contralateral control. Early injury
changes this balance, with increasing ipsilateral control
associated with worse motor function. This same basic
model has informed recovery models and new treatments
in adult stroke.74 Increasingly, elucidation of the
neurophysiological correlates of therapeutic effects has
become a reality. The potential now exists to define new
central targets that might be manipulated by the
application of modulating approaches to improve
function. Early application of such modulating treatments
is feasible if patients can be selected who are at greatest
98
risk for hemiparesis. Routine clinical imaging biomarkers
of acute neonatal stroke that are predictive of hemiparesis,
including diffusion changes in the descending
corticospinal tract (figure 8), might help identification of
candidates for early rehabilitation interventions.
Constraint-induced movement therapy (CIMT)
restrains the unaffected limb during motor training of
the affected limb. Evidence supports long-term efficacy
in adult stroke76 and congenital hemiplegia.77 Advanced
imaging studies, mostly in adult stroke, have shown that
response to CIMT might be associated with a shift in
motor control towards the lesioned hemisphere with
increased activation of perilesional areas.74 The same
might be true in congenital hemiplegia.74,78 An advanced
imaging study of perinatal stroke with an overall group
response to CIMT defined individual differences in
treatment response based on relative ipsilateral versus
contralateral corticospinal motor control.74,79 These results
suggest that individualised rehabilitation based on
measurable differences in plastic reorganisation could
become feasible.
Therapeutic effects depend on the induction of motor
learning in the brain. Non-invasive brain stimulation
technologies have shown the capacity to enhance
plasticity in induced motor learning in healthy adults.74,80
Neuromodulation approaches should therefore be
coupled with motor learning therapy for maximum
benefit. Randomised trial evidence suggests that
bimanual approaches such as hand-arm bimanual
intensive therapy have much the same efficacy as
CIMT.74,76,77,81 Novel approaches are geared towards the
combination of CIMT (to induce unimanual change)
with bimanual therapy (incorporating new skills into
more practical functions). The timing of therapy might
also be important. Animal and human studies suggest
crucial periods of early development when interventions
might be of maximum benefit.82 For perinatal stroke, an
ability to predict organisational plasticity and outcomes
at diagnosis using imaging could help with the earlier
selection of children for clinical trials.6,83
Non-invasive brain stimulation has enhanced the
development of stroke reorganisation models. It also has
the potential to modulate recovery towards improved
function. Both repetitive transcranial magnetic
stimulation and transcranial direct-current stimulation
have shown efficacy across many moderately powered,
blinded, sham-controlled randomised trials in adult
stroke motor recovery.69,84,85 One pilot trial in childhood
stroke showed beneficial effects of contralesional,
inhibitory repetitive transcranial magnetic stimulation86
and a larger trial in perinatal stroke is due to report
(NCT01189058).72 Effect sizes are small but are supported
by the demonstration of physiological changes with
advanced imaging. Clinical trials of non-invasive brain
stimulation for neurological disorders are increasing in
number exponentially. As a focal injury in the developing
brain, paediatric stroke represents an ideal human model
www.thelancet.com/neurology Vol 14 January 2015

of neuroplasticity. Just how a child’s age interacts with
other complex determinants of outcome remains a
complex issue needing further study.
Translation of knowledge to patients, parents,
physicians, and policy makers
The power of knowledge sharing to improve outcomes
for the families of children with paediatric stroke should
not be underestimated. Parental morbidity is a substantial
but under-investigated factor in childhood stroke.
A novel method was validated specifically to assess
parental outcomes in perinatal stroke.87 Uniquely
prominent issues seem to include maternal feelings of
guilt and blame. This is not surprising in view of the
absence of information on definitive causes in most
cases. Concerns by the mother that she exposed her
fetus to harm during pregnancy might underlie
maternal guilt. Such misplaced guilt could place an
unfair burden on parents already dealing with a
disabled child. Supportive education geared towards
this concern, both in person by clinicians and via
multimedia resources, might be a straightforward but
effective way to reduce this morbidity. Educational
interventions with similar benefits could include
counselling to reassure parents of the very low rates of
perinatal stroke recurrence88 in both affected children
and in subsequent pregnancies, thereby alleviating
unnecessary anxieties.
Online, open-access resources provided by reputable
organisations are increasingly available for families. A
Family Guide to Pediatric Stroke is a collaboration
between paediatric stroke experts and affected families
facilitated by the Canadian Stroke Network and Heart
and Stroke Foundation of Canada.89 Similar resources
exist in Australia and other countries. The International
Alliance for Pediatric Stroke is designed to bring
disparate paediatric stroke survivor support groups
together under one umbrella to share information and
peer support for paediatric stroke patients and their
families and to advance research priorities. New
information of potential relevance is vetted through a
board of paediatric stroke clinicians and researchers.
This important asset empowers families with accurate
information to counter the abundance of internet
misinformation.
Early recognition of stroke in children is a key
educational target for both the public and health-care
professionals. Delayed diagnosis is common (usually
>24 h), representing the single largest barrier to
advancing acute therapies in such children.90,91 Key issues
identified include poor awareness among parents, the
public, and both primary care and specialty physicians,
and the need for fundamental infrastructure (such as
imaging protocols) and care pathways. The development
of paediatric stroke centres aims to ease rapid diagnosis
and improve the feasibility of acute interventional trials.92
The diagnosis of presumed perinatal stroke syndromes
www.thelancet.com/neurology Vol 14 January 2015
Review
Figure 8: Acute pre-Wallerian degeneration in the corticospinal tract
Diffusion MRI of an infant with acute arterial ischaemic stroke shows restricted
diffusion in descending corticospinal tracts (arrow), a mark of Wallerian
degeneration resulting from infarction of more superior motor pathways. The
extent of this sign is associated with long-term hemiparesis in neonates and
children with arterial ischaemic stroke, and could serve as an imaging biomarker
to identify candidates for early rehabilitation.75
also represents a major target for improving diagnosis.
At present, diagnosis is delayed, in some cases up to a
year or more, from first parental concern because
primary care physicians might not be aware of the
importance of clear handedness (pathological
handedness) before the first birthday.93 Public and health- For more on childhood stroke
care awareness campaigns could be further developed; from the Australian Stroke
Foundation see http://
for example, “Two hands before One”. Early diagnosis strokefoundation.com.au/what-
will depend on improved awareness about paediatric is-a-stroke/childhood-stroke/
stroke, and will have immediate translational potential to For The International Alliance
advance the application of neuroprotective, thrombolytic, for Pediatric Stroke see http://
and antithrombotic interventions, and rehabilitation www.iapediatricstroke.org
strategies to the earliest possible timepoints after stroke
onset.82 Incorporation of aspects of paediatric stroke into
national stroke best practice guidelines, as has been
accomplished in Canada, should improve awareness
across broad populations.
Another emerging direction for childhood stroke is to
influence agents of change at a broader societal level. The
inadequate degree of public awareness, particularly
among major funding agencies, foundations, and
philanthropic organisations, carries implications for
research funding. Interest from major academic
institutions such as the American Heart Association and
American Stroke Association has improved, and
paediatric stroke now has major representation on
administrative and annual academic meeting schedules
and published guidelines.94 Funding for clinical studies
99
 Review
Search strategy and selection criteria
We searched PubMed for paediatric stroke articles published
between March 1, 2009, and June 1, 2014. We identified
1287 manuscripts in total with the search terms
(“pediatrics”[MeSH Terms] OR “pediatrics”[All Fields] OR
“pediatric”[All Fields]) AND (“stroke”[MeSH Terms] OR
“stroke”[All Fields]). We reduced the number to 935 by
restricting findings to human studies and then to 908,
including 151 reviews, by restricting findings to reports written
in English. We filtered the 757 non-reviews using the PubMed
article classification terms “classical article, clinical trial,
comparative study, or controlled clinical trial”, resulting in
164 reports. We then removed 124 heart-only, adult stroke,
and other non-relevant studies, which resulted in 41 reports.
We identified the following key issues: stroke mechanisms,
focusing on perinatal stroke and childhood arteriopathy;
treatment updates, including antithrombotics, thrombolytics,
and directions for clinical trials; plasticity models of
rehabilitation; and knowledge translation. For each topic, we
did further PubMed searches to supplement the initial search.
The search was updated on Sept 1, 2014, but no additional
material was added.
of paediatric stroke has started to flow from the National
Institute of Neurological Disorders and Stroke in the past
5 years. Cross-disciplinary education has advanced too,
including new guidelines combining childhood stroke
with paediatric heart disease,95 thrombosis,45 and
obstetrics and perinatal medicine.96 Perinatal and
childhood stroke are also important sources of
medicolegal litigation. Causation claims result in
enormous expenses and misappropriated damages that
might be reduced by improved knowledge translation.
Advocacy for childhood stroke has to take place at the
highest levels, including national and international
awareness initiatives and collaboration with organisations
capable of influencing governmental policy generation.
Conclusion
Paediatric stroke has no shortage of pressing issues. The
pathobiology of perinatal stroke needs to be elucidated if
prevention strategies are ever to be realised. Similarly,
enhanced understanding of the mechanisms underlying
childhood stroke, including cerebral arteriopathies, could
inform the development of new mechanism-specific
treatments. In addition to those topics highlighted in this
Review, understanding of other important primary
causes of stroke, including congenital heart disease,
sickle cell anaemia, and others, is evolving rapidly.
Antithrombotic interventions, from acute
recanalisation to secondary stroke prevention, are now
readily available and neuroprotective measures can
potentially limit stroke volumes. However, clinical trials
need to be undertaken to provide safety, dose-finding,
and efficacy data and enable evidence-based decision
100
making. To enable timely access to these treatments,
improved awareness and more rapid access to appropriate
imaging are crucial for neonates and children with acute
stroke. The same can be said for neonatal CSVT, for
which additional studies are urgently needed despite
improved recognition and early data on the safety of
anticoagulation. Study of the plasticity of the developing
brain and recovery of function after stroke is starting to
provide important insights into mechanisms of recovery
in the immature brain. Progress will be accelerated by
imminent further advances in basic science and
technology. The next step will be the development of
treatments tailored to modulate these mechanisms and
improve outcomes. As our understanding of outcomes
expands to include patient-related quality of life and
longer-term trajectories of recovery, treatments can be
assessed against increasingly relevant outcomes beyond
simple neurological complications and mortality.
Families should be at the heart of these expanding
research themes to match scientific progress with
relevant needs and to optimise the translation of
knowledge to those most affected. Real progress has
been made in recent years. Common among the
elements of progress is the drive to better understand the
biological roots of pathophysiology, treatments, outcome,
and recovery. The coupling of emerging investigational
technologies with integrated global research networks
promises to accelerate the rate of advances in childhood
stroke research. This will generate new avenues to
improve outcomes for children with stroke and their
families.
Contributors
AK and GdV contributed equally to the conception, scientific literature
review, figure generation, drafting, and editing of the Review.
Declaration of interests
AK and GdV have received occasional honoraria for invited
presentations at educational institutions and have provided expert
medicolegal opinions. AK and GdV hold many sources of research
funding but none were directly influential in the writing of this report.
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