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Articles

Childhood arterial ischaemic stroke incidence, presenting


features, and risk factors: a prospective population-based
study
Andrew A Mallick, Vijeya Ganesan, Fenella J Kirkham, Penny Fallon, Tammy Hedderly, Tony McShane, Alasdair P Parker, Evangeline Wassmer,
Elizabeth Wraige, Samir Amin, Hannah B Edwards, Kate Tilling, Finbar J O’Callaghan

Summary
Background Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective Lancet Neurol 2014; 13: 35–43
population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the Published Online
epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. December 2, 2013
http://dx.doi.org/10.1016/
S1474-4422(13)70290-4
Methods Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring
Department of Paediatric
over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million Neurology, Bristol Royal
children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, Hospital for Children, Bristol,
the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, UK (A A Mallick MB BCh);
parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases Neurosciences Unit, UCL
Institute of Child Health,
and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis London, UK (V Ganesan MD,
of case notes. Capture–recapture analysis was used to estimate completeness of ascertainment. Prof F J Kirkham MD,
F J O’Callaghan PhD);
Department of Child Health,
Findings We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic
Southampton University
stroke was 1·60 per 100 000 per year (95% CI 1·30–1·96). Capture–recapture analysis suggested that case ascertainment Hospitals NHS Trust,
was 89% (95% CI 77–97) complete. The incidence of arterial ischaemic stroke was highest in children aged under Southampton, UK
1 year (4·14 per 100 000 per year, 95% CI 2·36–6·72). There was no difference in the risk of arterial ischaemic stroke (Prof F J Kirkham); Department
of Paediatric Neurology,
between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18–2·12] for boys and 1·61 per 100 000 per year
St George’s Hospital, London,
[1·18–2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11–3·85; p=0·017) and black (2·28, 1·00–4·60; p=0·034) UK (P Fallon MBBS);
children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features Department of Paediatric
(most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and Neurology, King’s College
Hospital NHS Foundation
headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial
Trust, London, UK
ischaemic stroke was identified in 80 (83%) cases. (T Hedderly MBBS); Department
of Paediatric Neurosciences,
Interpretation Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation Evelina Children’s Hospital,
London, UK (T Hedderly,
of such differences might provide causative insights.
E Wraige MBBS); Department of
Paediatric Neurology, John
Funding The Stroke Association, UK. Radcliffe Hospital, Oxford, UK
(T McShane MD); Department
of Paediatric Neurology,
Introduction population-based study in the south of England using Addenbrooke’s Hospital,
Arterial ischaemic stroke is an important cause of acquired several ascertainment sources, with verification by Cambridge, UK (A P Parker MD);
brain injury in children, with long-term morbidity and personal examination of cases and case notes. Department of Paediatric
substantial health, economic, and personal costs.1–3 Risk Neurology, Birmingham
Children’s Hospital,
factors in children are markedly different from those Methods Birmingham, UK
associated with arterial ischaemic stroke in adults, and Study design (E Wassmer MBChB); and School
limited understanding of these risk factors has meant that Arterial ischaemic stroke was defined as acute of Clinical Sciences (S Amin MSc,
there is no evidence base to guide management.4 neurological symptoms secondary to acute focal cerebral H B Edwards MA, F J O’Callaghan)
and School of Social and
Most previous epidemiological studies of childhood infarction in an arterial distribution on brain imaging. Community Medicine
arterial ischaemic stroke have used retrospective database Separate episodes of arterial ischaemic stroke were (Prof K Tilling PhD), University
searches, usually based in one institution or in settings recorded if a new acute neurological deficit with further of Bristol, Bristol, UK
without universal health-care coverage, to identify cerebral infarction occurred after the index arterial Correspondence to:
cases.5 Also, in most previous studies assessment of ischaemic stroke; these were deemed recurrent arterial Dr Finbar J O’Callaghan,
Neurosciences Unit, Institute of
racial differences was not possible because the studies ischaemic strokes. Child Health, University College
were done in racially homogeneous populations. There All children were treated in the UK’s National Health London, London WC1N 3LU, UK
are few data from these studies on completeness of Service (NHS). Because the NHS is a comprehensive, f.o’callaghan@ucl.ac.uk
ascertainment of cases or diagnostic accuracy. We publicly funded health service with universal coverage
investigated the epidemiology and characteristics of that is free at the point of use, it is an ideal system for
childhood arterial ischaemic stroke in a prospective undertaking epidemiological and population-based

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studies. Children aged 29 days to less than 16 years at the summarised in panel 1. The IPSS also reports the
onset of arterial ischaemic stroke were eligible for proportion of children in whom infection is a risk factor,
inclusion. Perinatal and neonatal stroke are typically but these infections are also listed under acute systemic
regarded as distinct from later childhood stroke, with disorders, acute head and neck disorders, or chronic
different causative factors, presenting features, outcomes, head and neck disorders. Because there is increasing
and recurrence rates.6 Health care in the UK for people evidence that simple, common childhood infections can
aged 16 years and older is often provided by adult services increase the risk of arterial ischaemic stroke, a further
rather than within paediatric services and, therefore, age risk factor category of recent (not present at stroke onset)
up to 16 years is typically used as the upper limit in infection (within 4 weeks preceding the onset of arterial
epidemiological studies of uncommon paediatric ischaemic stroke) was also used.8 Categories were not
disorders.7 The study area encompassed all counties and mutually exclusive, although a single infection was not
metropolitan regions in the southern part of England and included in the recent infection category if it met the
the British Crown Dependencies of Jersey and Guernsey. definition of acute systemic disorders, acute head and
The northern borders of the study area were Here- neck disorders, or chronic head and neck disorders.
fordshire, Worcestershire, West Midlands Metropolitan Individual patients were included in multiple categories
County, Warwickshire, Northamptonshire, Cambridge- if several risk factors were present. Laboratory and
shire, and Norfolk (figure 1). The study area included radiological investigations were at the discretion of the
5·99 million children, representing about 50% of all treating clinicians, although national guidelines were
children within the UK. available and encourage a uniform approach.9 Details of
Presenting features and risk factors were categorised investigations were recorded.
according to the scheme previously published by the The study was granted multicentre ethical approval from
International Paediatric Stroke Study (IPSS),4 as Southampton and South West Hampshire Research Ethics
Committee (B) and site-specific approval at all NHS Trusts
within the study area.

Procedures
Children with onset of arterial ischaemic stroke between
July 1, 2008, and June 30, 2009, were notified to the study
researchers. Cases were identified by three groups of
sources: paediatric neurology, paediatric, and other. The
paediatric neurology sources consisted of a lead
paediatric neurologist at each of the tertiary paediatric
neurology centres in the study area, all other paediatric
neurologists working in the study area, trainee members
of the British Paediatric Neurology Association, and
parallel surveillance with the British Paediatric Neurology
Surveillance Unit (a rare disease surveillance system that
targets all consultant members of the British Paediatric
Neurology Association). The paediatric sources consisted
of a lead paediatrician at each hospital within the study
area and all consultant members of the Royal College of
Paediatrics and Child Health working within the study
area. The other sources group consisted of a radiologist
(typically with an interest in paediatrics or neuroradiology)
Birmingham at each hospital, a physiotherapist at each hospital, at
Cambridge least one neurosurgeon at each paediatric neurosurgical
centre, direct notification from parents or carers, and
Oxford
surveillance with the Paediatric Intensive Care Audit
Bristol London Network (a system that collects data on all children
Southampton
admitted to paediatric intensive care units in the UK).
All the health professionals involved were sent a
monthly electronic reminder requesting reports of any
cases seen in the preceding month or to state that no
cases had been seen. The researchers reviewed the
Figure 1: Map of Great Britain showing the study area
clinical records and radiological investigations of notified
All acute National Health Service Trusts within the study area (dark shading)
were included. Channel Islands are not shown in the figure but were also cases to verify eligibility for inclusion and to categorise
included in the study area. the presenting features and risk factors. Recurrence of

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Panel 1: International Paediatric Stroke Study scheme for categorisation of childhood arterial ischaemic stroke risk factors

Arteriopathy • Protein S deficiency


• Focal cerebral arteriopathy • Protein C deficiency
• Moyamoya disease • Prothrombin 20210A mutation
• Arterial dissection • Antithrombin III deficiency
• Vasculitis • Hyperhomocysteinaemia
• Sickle-cell arteriopathy
Acute systemic disorders
• Post-varicella arteriopathy
• Fever >48 h
• Other specified arteriopathy
• Sepsis (with positive blood, urine, or CSF cultures)
• Unspecified arteriopathy
• Shock
Cardiac disorders • Dehydration
• Congenital heart disease • Acidosis
• Acquired heart disease • Hypoxia
• Isolated patent foramen ovale • Viral gastroenteritis
• <72 h after cardiac surgery
Chronic head and neck disorders
• Previous cardiac surgery
• Migraine
• Cardiac catheterisation
• Brain tumour
• Extracorporeal membrane oxygenation
• Other cranial or neck tumour
• Left ventricular assist device
• Ventricular shunt
• Arrhythmia
• Cerebral aneurysm
• Other cardiac
• Intracranial arteriovenous malformation
Chronic systemic disorders • PHACES syndrome
• Sickle-cell disease
Acute head and neck disorders
• Indwelling catheter
• Head or neck trauma
• Trisomy 21
• Pharyngitis
• Other genetic disorders
• Meningitis
• Haematological malignancy
• Recent intracranial surgery
• Iron deficiency
• Otitis media
• Oral contraceptive pill
• Sinusitis
• Connective tissue disorder
• Mastoiditis
• Solid extracranial tumours
• L-asparaginase Risk factors for atherosclerosis in adulthood
• Hypertension
Prothrombotic states
• Hyperlipidaemia
• Methylenetetrahydrofolate reductase deficiency
• Type 1 diabetes mellitus
• Hyperlipoproteinaemia (alpha)
• Factor V Leiden Reproduced from Mackay and colleagues4 with permission from John Wiley and Sons.
PHACES=Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac
• Other genetic thrombophilia
defects, Eye abnormalities, Sternal cleft.
• Acquired thrombophilia

arterial ischaemic stroke was also assessed by case note incidence rates were also age adjusted to standard
review and by parental interview 12 months after the European20 and WHO populations.21
index stroke. We used capture–recapture techniques to estimate the
completeness of ascertainment22,23 using a three-source
Statistical analysis (paediatric neurology, paediatrics, and other sources)
We used data from the Office for National Statistics,10–15 the analysis.24 Goodness-of-fit-based CIs were calculated and
States of Jersey Statistics Unit,16,17 and the States of dependency between sources was investigated and
Guernsey Policy and Research Unit18 to estimate the accounted for by log-linear modelling.25 We used a
population denominator. We calculated crude, age- standardised approach with Akaike and Bayesian
specific, sex-specific, and racial-group-specific incidence information criteria to select the best fitting model.26 We
rates. 95% CIs were calculated using the Poisson calculated an adjusted incidence rate using the estimated
distribution.19 To compare incidence rates, we used the total number of cases from the best fitting model.
Poisson model to calculate incidence rate ratios We described the presenting features and risk factors
(expressed as relative risk [RR]), 95% CIs, and two-tailed of the whole cohort of children with arterial ischaemic
p values. To facilitate comparisons with other studies, stroke. We tested differences in the frequency of

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presenting features according to sex and age group, and study period. The total at-risk population was
differences in the frequency of risk factors according to 5 987 400 and therefore the crude incidence rate of
racial group, using Fisher’s exact test. Logistic regression, childhood arterial ischaemic stroke was 1·60 per
using a penalised maximum likelihood estimation 100 000 per year (95% CI 1·30–1·96). The age-
approach,27 was used to identify relations between risk standardised incidence rates were 1·53 per 100 000 per
factors and age at stroke and presenting features. Age at year (95% CI 1·22–1·83) using the European
stroke onset in decimal years was classed as a continuous 2013 standard population20 and 1·58 per 100 000 per year
variable in logistic regression analyses. (95% CI 1·26–1·89) using the WHO 2000–2025 standard
Statistical analyses were done with Stata IC 11.2 population.21
(Statacorp, College Station, TX, USA). Figure 2 shows the distribution of cases by age at onset
of arterial ischaemic stroke. The incidence of arterial
Role of the funding source ischaemic stroke was numerically highest in children
The sponsor of the study had no role in the study design, aged under 1 year (4·14 per 100 000 per year, 95% CI
data collection, data analysis, data interpretation, writing 2·36–6·72) compared with those aged 1–5 years (2·42 per
of the report, or decision to submit for publication. The 100 000 per year, 1·78–3·22), 6–10 years (0·56 per
corresponding author had full access to all the data in the 100 000 per year, 0·27–1·03), or 11–15 years (1·22 per
study and had final responsibility for the decision to 100 000 per year, 0·78–1·84).
submit for publication. 49 children were boys and 47 girls. The crude incidence
rate for boys was 1·60 per 100 000 per year (95% CI
Results 1·18–2·12) and for girls was 1·61 per 100 000 per year
905 (76%) of 1185 health professionals invited to respond (1·18–2·14). The age-standardised rate for boys was
did so at least once during the identification period. The 1·56 per 100 000 per year (95% CI 1·13–2·00) and for
mean response rate to the monthly electronic reminders girls was 1·59 per 100 000 per year (1·14–2·04) using the
was 48·3% (range 45·5–52·8). WHO 2000–2025 standard population. The RR of arterial
186 separate notifications met the case definition. ischaemic stroke for boys compared with girls was
After accounting for duplicates, we identified 96 unique 1·00 (95% CI 0·65–1·52; p=0·99). The mean age at
incident cases of childhood arterial ischaemic stroke. presentation for boys was 6·2 years (SD 0·8) and for girls
One case had had a previous arterial ischaemic stroke 5·0 years (SD 0·6). Age at presentation did not vary
2·8 years before the event within the study period. All significantly by sex (p=0·22, two-tailed t test).
other cases were first-ever strokes and no child had Incidence was significantly affected by race, with Asian
another or recurrent arterial ischaemic stroke within the (p=0·017) and black (p=0·034) children at higher risk of
arterial ischaemic stroke than white children (table 1).
16
The incidence rate for white boys was 1·49 per 100 000 per
year (95% CI 1·05–2·06) and for girls was 1·23 per
14
100 000 per year (0·82–1·76), resulting in a male:female
12 RR of 1·22 (0·73–2·05; p=0·43).
Number of cases

10
8

4
Paediatric Paediatrics
2
neurology 17
0 11
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age at stroke onset (completed years) 22

Figure 2: Age distribution of cases of arterial ischaemic stroke (n=96) 10


13
9
Number Incidence (per 100 000 Relative risk p value
of cases per year [95% CI]) (95% CI)
White 66 1·36 (1·06–1·74) ·· ·· 14
Asian 14 2·92 (1·60–4·90) 2·14 (1·11–3·85) 0·017
Black 9 3·11 (1·42–5·91) 2·28 (1·00–4·60) 0·034 Other sources

Other 7 1·83 (0·74–3·77) 1·34 (0·52–2·92) 0·451

Table 1: Incidence rates of arterial ischaemic stroke according to


racial group Figure 3: Number of cases of arterial ischaemic stroke identified according to
source of ascertainment

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58 (60%) cases were identified by the paediatric systemic disorders, acute head and neck disorders,
neurology group, 51 (53%) by the paediatrics group, and chronic head and neck disorders, or recent infection) was
46 (48%) by the other sources group (figure 3). 47 (49%) present in 27 (28%) cases.
cases were identified by one source, 39 (41%) by two Cerebrovascular imaging was done in 69 (72%) cases,
sources, and ten (10%) by all three sources. 13 (19%) of whom had more than one modality of
The best fitting model in the three-source capture– cerebrovascular imaging. MR angiography was done in
recapture analysis, which included the interaction 68 (71%) cases, conventional angiography in 11 (11%)
between the paediatric neurology and other sources, cases, and CT angiography in six (6%) cases.
estimated 108 (95% CI 99–124) cases of arterial ischaemic Echocardiography was done in 75 of 94 (80%) cases,
stroke, suggesting that case ascertainment was 89% 34 (36%) of whom had bubble contrast. Echocardiography
(95% CI 77–97) complete (table 2). Using the point was done transthoracically in 71 (76%) cases and via the
estimate of 108 cases, the adjusted incidence rate of transoesophageal route in seven (7%) cases. Testing for at
childhood arterial ischaemic stroke was 1·80 per least one prothrombotic risk factor was done in 52 (61%)
100 000 per year (95% CI 1·48–2·18). of 85 cases. Children with apparently idiopathic arterial
Focal features, in particular hemiparesis, were the ischaemic stroke (no identified risk factor; n=16) were
most common presenting features of arterial ischaemic investigated at least as extensively as the group as a
stroke (table 3). 31 (32%) children only had focal features whole: 14 (88%) had vascular imaging, 14 (88%) had
at presentation, but diffuse features and seizures seldom echocardiography, eight (50%) had bubble contrast
occurred in isolation (five [5%] children and one [1%] echocardiography, and 13 (81%) had testing for at least
child, respectively). 32 (33%) children had both focal and one prothrombotic risk factor.
diffuse presenting features, five (5%) had focal features Older children (adjusted for sex and race) were less
and seizures, eight (8%) had diffuse features and likely than younger children to have more than one risk
seizures, and 14 (15%) had focal features, diffuse features, factor (odds ratio [OR] 0·91, 95% CI 0·84–1·00; p=0·043),
and seizures. acute systemic disorders (0·89, 0·81–0·99; p=0·030), or
The frequency of presenting features (including infection (0·89, 0·80–0·99; p=0·036).
subcomponents of the main categories) did not vary Risk factors varied with race. Chronic systemic
significantly according to sex (data not shown), but there disorders were found at higher rates in Asian (OR 5·64,
were differences in the frequency of presenting features 95% CI 1·68–19·0; p=0·005) and black children (36·0,
according to age group (table 4). Seizures were most 5·32–243·8; p<0·0001) than in white children. Black
common in very young children (<1 year) whereas diffuse children also had higher rates of arteriopathy (OR 4·64,
features in general and headache in particular were more 95% CI 1·13–19·0; p=0·033) than white children. All
common in older children (≥6 years). Diagnosis was analyses were controlled for age and sex. Further
often delayed, with the median time to diagnosis from examination of these risk factor categories showed that
onset of symptoms being 24·3 h (IQR 6·5–76·0). Asian children had a significantly greater prevalence of
No risk factor was identified in 16 (17%) cases. One risk iron deficiency anaemia than white children (four [29%]
factor category was identified in 35 (36%) cases, two in of 14 cases vs three [5%] of 66 cases, p=0·016).
33 (34%) cases, and three in 12 (13%) cases. Figure 4 shows Haemoglobin concentrations at presentation for Asian
the frequency of risk factor categories. Infection as a risk children with iron deficiency anaemia ranged from 25 g/L
factor (infection risk factors categorised under acute to 96 g/L and mean corpuscular volumes ranged from

Degrees of Deviance p value Akaike Bayesian Estimated Estimated 95% CI


freedom (G2) information information number of un- total
criteria criteria ascertained cases population
Independent 3 3·99 0·26 –2·01 –4·19 19 115 104–132
Paediatric neurology—paediatrics 2 3·64 0·16 –0·36 –1·81 21 117 104–142
Paediatric neurology—other 2 0·44 0·80 –3·56 –5·01 12 108 99–124
Paediatrics—other 2 2·73 0·26 –1·27 –2·72 23 119 105–142
Paediatric neurology—paediatrics, 1 0·42 0·52 –1·58 –2·31 11 107 98–129
paediatric neurology—other
Paediatric neurology—paediatrics, 1 1·51 0·22 –0·49 –1·22 34 130 107–188
paediatrics—other
Paediatric neurology—other, 1 0·09 0·76 –1·91 –2·65 14 110 100–132
paediatrics—other
Saturated 0 0 1 0 0 17 113 98–171

Models adjusted for interactions between listed sources.

Table 2: Results of three-source capture–recapture analyses

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Number of cases
Discussion
(%; n=96) In this epidemiological study of arterial ischaemic stroke
in children, we found a crude incidence rate of 1·6 per
Focal features 82 (85%)
100 000 per year, higher than previously reported in the
Hemiparesis 69 (72%)
UK.28 We show a striking effect of age on incidence, with
Facial weakness 39 (41%)
children under age 1 year being particularly at risk
Speech disturbance 32 (33%)
(4·14 per 100 000 per year). The risk of arterial ischaemic
Visual disturbance 5 (5%)
stroke was not affected by sex, but both black and Asian
Other focal features 18 (19%)
children had significantly higher rates of stroke than did
Diffuse features 59 (61%)
white children. Children with arterial ischaemic stroke
Decreased consciousness level 40 (42%)
present similarly to adults, with focal neurological
Headache 23 (24%) deficits such as hemiparesis, but their diagnosis is often
Vomiting 10 (10%) delayed. However, the risk factor profile for children with
Papilloedema 1 (1%) arterial ischaemic stroke is very different to that for
Other diffuse features 8 (8%) adults, with few of them having conventional adult
Any seizure 28 (29%) atherosclerostic risk factors. A substantial proportion of
Focal seizures 19 (20%) children with stroke have an underlying arteriopathy and
Generalised seizures 11 (11%) evidence of coincident infection.
Both focal and generalised seizures 2 (2%) We believe that this incidence study has produced one
Table 3: Presenting features of arterial ischaemic stroke of the most accurate estimates in the published work so
far (panel 2). However, a small number of cases who
were resident in the study population but treated for
<1 year 1–5 years 6–10 years 11–15 years p value their stroke outside the study area will have been missed.
(n=16) (n=47) (n=10) (n=23)
Although this is the largest prospective population-based
Focal features 12 (75%) 42 (89%) 7 (70%) 21 (91%) 0·18 study of childhood stroke so far, the actual numbers of
Hemiparesis 11 (69%) 40 (85%) 6 (60%) 12 (52%) 0·02 stroke cases is still small in statistical terms. We
Facial weakness 4 (25%) 22 (47%) 4 (40%) 9 (39%) 0·50 acknowledge that when no difference in incidence was
Speech disturbance 2 (13%) 15 (32%) 4 (40%) 11 (48%) 0·12 found by sex, we might have missed a marginal real
Diffuse features 10 (63%) 22 (47%) 10 (100%) 17 (74%) 0·004 difference in the population because the numbers of
Decreased conscious level 9 (60%) 17 (36%) 5 (50%) 9 (39%) 0·39 cases were too small to detect one. Similarly, the
Headache 0 (0%) 6 (13%) 5 (50%) 12 (52%) <0·0001 differences reported in RR for racial groups might be
Seizures 12 (75%) 12 (26%) 2 (20%) 2 (9%) <0·0001 susceptible to a type 1 error in view of the small numbers
and the fact that the CIs for the incidence rates by racial
Table 4: Presenting features of arterial ischaemic stroke by age group
group overlap. The analysis of risk factors was limited by
the extent to which the individual clinicians pursued
35
31%
their investigations. This study was observational and we
30
29% did not provide clinicians with an investigation protocol,
25% although guidelines for investigation of childhood stroke
25 23%
19% exist.9 Therefore, there is probably under-reporting of
Cases (%)

20
specific risk factors. For example, only 72% of cases had
15
cerebrovascular imaging and therefore cases of
10
5% arteriopathy will have probably gone undetected.
4% 4%
5 2% In this study, we used several sources of ascertainment
0 and verified each incident case by case note and radiology
review. We also attempted to assess the extent of
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100 000 per year are higher than many previous estimates
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Risk factor category


and this is probably a result of more complete
ascertainment. Most previous epidemiological studies of
Figure 4: Arterial ischaemic stroke risk factor categories identified childhood arterial ischaemic stroke used retrospective
searches of databases, typically using International
59·6 fL to 69·0 fL. Unsurprisingly, black children had a Classification of Diseases (ICD) codes, to identify
significantly greater prevalence of sickle-cell disease than cases.5 This method probably led to substantial
white children (eight [89%] of nine vs none [0%] of inaccuracies in previous estimates because both the
66 children) and a greater prevalence of sickle-cell specificity and sensitivity of ICD codes for arterial
arteriopathy (six [67%] of nine vs none [0%] of 66 children). ischaemic stroke are low.29–31 Four studies31–34 have

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reported higher incidence rates (from 1·7 to 2·4 per


100 000 per year) than those in this study, but these all Panel 2: Research in context
included neonates, accounting for between 8% and 46% Systematic review
of their total cases. Neonates have a high incidence of We searched PubMed and Embase from 1955 until Nov 6,
stroke and the inclusion of neonates in these studies will 2013, for studies published in English for the following
have substantially inflated the overall incidence rate for terms: “stroke”, “cerebrovascular accident”, “infant”, “child”,
childhood arterial ischaemic stroke. “adolescent”, “paediatric”, “pediatric”, “incidence”, and
The high incidence rate of arterial ischaemic stroke in “epidemiological studies”. We searched the reference lists of
infancy reported in this study is consistent with those retrieved articles for any further studies that might have
from other studies.33,35,36 In this study, the nadir of the been missed in the initial search. We identified 17 studies
age-specific incidence rates was in mid-childhood that had calculated the incidence of childhood arterial
followed by a small rise in adolescence. A higher rate in ischaemic stroke.
adolescence has also been reported in other
studies.35,36 Why the incidence rate of childhood arterial Interpretation
ischaemic stroke changes with age is not clear, but is Most previous studies (15 of 17) were retrospective reviews
presumably a result of changes in the underlying risk of populations that have identified patients using
factors with age. International Classification of Diseases codes, which have
We did not find a significant sex difference in the risk limited sensitivity and specificity. We undertook a large,
of stroke. This contrasts with previous studies in prospective, population-based study of childhood arterial
California35 and the IPSS,37 which both found a small but ischaemic stroke in the published work. We accessed
significantly increased risk of stroke in boys. However, detailed clinical and radiological information about each
the California study relied on information extracted from case and verified case ascertainment by capture–recapture
a retrospective database search using ICD codes, and the techniques. The present study shows how stroke incidence
IPSS is not a population-based study. In the present varies by race (more common in black and Asian children
study, the incidence of stroke in boys was numerically, than white children) and by age (more common in children
but not significantly, higher than in girls for white <1 year than 1–15 years), but we did not detect any
children. Racial differences between cohorts might affect difference in sex. We showed that stroke presents differently
differences between sex-specific rates. according to age: seizures were present in most children
In this European study, we show racial differences in younger than 1 year whereas headache was more common
the risk of childhood arterial ischaemic stroke. Both in older children. However, focal neurological deficits (85%)
Asian and black children had higher rates of arterial and hemiparesis (72%) were the most common presenting
ischaemic stroke than white children. In their study of features in childhood arterial ischaemic stroke. Increased
childhood stroke in California, Fullerton and awareness of arterial ischaemic stroke in children is needed
colleagues35 also showed that black children had a higher to help reduce the substantial time delays in diagnosis that
risk of ischaemic stroke (arterial ischaemic stroke and prevent rapid initiation of neuroprotection and possible use
cerebral venous thrombosis) than white children, but of thrombolysis.
Asian children did not.35 The Asian populations in
England and California are very different. Asian children Focal neurological deficits (85% of cases), and
in England are predominantly from an Indian hemiparesis in particular (72% of cases), were the most
subcontinent background (India, Pakistan, Bangladesh, common presenting features of childhood arterial
Sri Lanka, Nepal, and Bhutan). In California, about 90% ischaemic stroke. However, diffuse presenting features
of the Asian population have an eastern Asian and seizures were also common, occurring in 61% and
background (China, Philippines, Vietnam, Japan, and 29% of cases, respectively. The presenting features of
Korea).38 In the present study, the increased risk of childhood arterial ischaemic stroke are not dissimilar to
arterial ischaemic stroke for black children was largely those in adult arterial ischaemic stroke, and stroke
explained by sickle-cell disease, which confers a high risk recognition instruments developed for use in adults have
of arterial ischaemic stroke.39 The higher risk of arterial reasonable sensitivity in childhood arterial ischaemic
ischaemic stroke in Asian children in our study could stroke.44 Nevertheless, there is still a need for increased
possibly be explained by the high prevalence of iron awareness of childhood arterial ischaemic stroke among
deficiency anaemia in this racial group. Severe iron health professionals if the diagnostic delays that are
deficiency anaemia without any other identifiable risk frequently reported are to improve.45,46
factors has been described as a cause of childhood arterial However, presenting features did vary with age. In
ischaemic stroke in other studies.40,41 Asian children in particular, seizures were more common in infants,
the general population of England have higher rates of occurring in 75% of those aged less than 1 year at stroke
iron deficiency anaemia than white children, which is onset. Children under the age of 1 year with arterial
related to factors such as socioeconomic deprivation, low ischaemic stroke in a North American cohort also had an
maternal iron stores, and feeding practices.42,43 increased risk of presenting with seizures.47 The

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immature brain might be more excitable because of age- 5 Mallick AA, O’Callaghan FJ. The epidemiology of childhood stroke.
related differences in brain receptor composition, Eur J Paediatr Neurol 2010; 14: 197–205.
6 Nelson KB, Lynch JK. Stroke in newborn infants. Lancet Neurol
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injury such as arterial ischaemic stroke.48 The prevalence surveillance in the UK and Republic of Ireland. Euro Surveill 2006;
11: E060720 4.
of some presenting features such as speech disturbance
8 Fullerton HJ, Elkind MS, Barkovich AJ, et al. The vascular effects of
and headache might vary with age because of age-related infection in Pediatric Stroke (VIPS) Study. J Child Neurol 2011;
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associated with increasing age. Headache is largely a self- 9 Paediatric Stroke Working Group. Stroke in childhood: clinical
guidelines for diagnosis, management and rehabilitation. London:
reported symptom so relies on the development of Royal College of Physicians, Clinical Effectiveness and Evaluation
sufficient communication to be able to be identified. The Unit, 2004.
youngest child with reported headache was 2·4 years old. 10 Office for National Statistics, Population Estimates Unit.
Mid-2008 population estimates: selected age groups for local
Much of the increase in headache with increasing age authorities in the United Kingdom; estimated resident
may be because of an age-related reporting bias. population. Fareham: Office for National Statistics Centre for
Reported risk factors for childhood arterial ischaemic Demography, 2010.
11 Office for National Statistics, Population Estimates Unit.
stroke are varied and different from those linked with Mid-2008 population estimates: estimated resident population by
adult stroke. At present, there is a scarcity of robust quinary age groups for local authorities. Fareham: Office for
evidence to support the use of the term risk factors in National Statistics Centre for Demography, 2010.
12 Office for National Statistics, Population Estimates Unit.
childhood arterial ischaemic stroke and many of the risk Mid-2009 population estimates: selected age groups for local
factors reported must be regarded as putative.49 Nevertheless, authorities in the United Kingdom; estimated resident population.
we have used the term risk factor to ensure consistency Fareham: Office for National Statistics (Population Demography
Division), 2011.
with the existing paediatric arterial ischaemic stroke
13 Office for National Statistics, Population Estimates Unit.
published work.4 Nearly half of children in the present Mid-2009 population estimates: estimated resident population by
study had multiple risk factors. However, 17% of cases quinary age groups for local authorities. Fareham: Office for
National Statistics (Population Demography Division), 2011.
remained idiopathic (although, as described, the battery of
14 Office for National Statistics, Population Estimates Unit.
investigations was not prescribed and was, therefore, not Mid-2008 population estimates: single year of age and sex for local
uniform). Almost a third of cases had an arteriopathy and authorities in the United Kingdom; estimated resident population.
Fareham: Office for National Statistics (Population Statistics
there is increasing belief that focal cerebral arteriopathies, Division), 2010.
perhaps related to infection, underlie many cases of 15 Office for National Statistics, Population Estimates Unit.
childhood stroke.50,51 The discovery of an arteriopathy Mid-2009 population estimates: single year of age and sex for local
authorities in the United Kingdom; estimated resident population.
might have substantial implications both for treatment Fareham: Office for National Statistics (Population Statistics
and prognosis,34,52 and we echo recent guidelines that Division), 2010.
suggest vascular imaging should be done in all cases of 16 States of Jersey Statistics Unit. Report on the 2001 Census.
suspected childhood stroke.1 St Helier: States of Jersey Statistics Unit (Policy and Resources
Department), 2002.
Contributors 17 States of Jersey Statistics Unit. Jersey Census 2011: bulletin 1—
The study was conceived by FJO’C, VG, and FJK and designed by FJO’C, total population. St Helier: States of Jersey Statistics Unit, 2012.
VG, FJK, and AAM. AAM, SA, and HBE collected the data. AAM and 18 States of Guernsey Policy and Research Unit. Guernsey annual
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Articles

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