Chickenpox and Stroke in Childhood: A Study of Frequency and Causation

Rand Askalan, Suzanne Laughlin, Supriya Mayank, Anthony Chan, Daune MacGregor,
Maureen Andrew, Rosalind Curtis, Brandon Meaney and Gabrielle deVeber
Stroke. 2001;32:1257-1262
doi: 10.1161/01.STR.32.6.1257
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

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Chickenpox and Stroke in Childhood

A Study of Frequency and Causation
Rand Askalan, PhD; Suzanne Laughlin, MD; Supriya Mayank, MD; Anthony Chan, MD;
Daune MacGregor, MD; Maureen Andrew, MD; Rosalind Curtis, MD;
Brandon Meaney, MD; Gabrielle deVeber, MD
Background and PurposeThe purpose of this study was to determine whether infection with varicella is causal for
arterial ischemic stroke (AIS) in children.
MethodsFirst, a prospective cohort study was conducted in young children (aged 6 months to 10 years) with AIS at 2
institutions (cohort study). The presence of varicella infection 12 months before AIS was determined and compared
with the published frequency of varicella infection in the healthy pediatric population. The clinical and radiographic
features of AIS were compared between the varicella and nonvaricella study cohorts. Second, a literature search of
varicella-associated AIS was conducted, and the clinical and radiographic features were compared with the study
nonvaricella cohort.
ResultsIn the cohort study, 22 (31%) of 70 consecutive children with AIS had a varicella infection in the preceding year
compared with 9% in the healthy population. Children in the varicella cohort were more likely to have basal ganglia
infarcts (P0.001), abnormal cerebral vascular imaging (P0.05), and recurrent AIS or transient ischemic attacks
(P0.05) than those in the nonvaricella cohort. The pooled literature analysis of 51 cases of varicella-associated AIS
showed similar findings to the varicella cohort.
ConclusionIn young children with AIS, there is a 3-fold increase in preceding varicella infection compared with
published population rates, and varicella-associated AIS accounts for nearly one third of childhood AIS. Varicellaassociated AIS has characteristic features, including a 2-fold increase in recurrent AIS and transient ischemic attacks.
Varicella is an important risk factor for childhood AIS. (Stroke. 2001;32:1257-1262.)
Key Words: chickenpox child etiology stroke

rterial ischemic stroke (AIS) during childhood, although

relatively rare, occurs and frequently causes significant
long-term morbidity.1,2 The etiologies of AIS during childhood are multifactorial and differ from those during adulthood, in which atherosclerotic disease is the most common
etiology. Varicella has been identified as one potential risk
factor for AIS during childhood. However, the evidence
consists of case reports and small retrospective case series.320 The presence of a preceding varicella infection has
not been systematically surveyed in series of children with
AIS, nor have the clinical and radiographic features been
compared between varicella-associated AIS and other forms
of childhood AIS. The objective of the current study was to
establish whether varicella is likely causal for childhood AIS.
Two approaches were used, a prospective cohort study and a
pooled analysis of the literature.

See Editorial Comment, page 1262

Subjects and Methods

Study Design
The study design was a prospective, cohort study with statistical
comparisons between the subgroups.

Cohort Study
Patient Population
The study cohort comprised consecutive patients who were between
6 months and 10 years of age and had confirmed AIS during the
study interval, January 1, 1992, to January 1, 1999. All children were
identified by institutional Stroke Services at the Hospital for Sick
Children, Toronto and the Childrens Hospital at Chedoke McMaster, Hamilton, Canada. Children with varicella infection during the
preceding 12 months composed the varicella cohort and the
remainder the nonvaricella cohort. All parents (and patients, if

Received August 28, 2000; final revision received February 22, 2001; accepted March 16, 2001.
Presented in part at the American Academy of Neurology meeting; April 1999; Toronto, Ontario, Canada.
From the Hospital for Sick Children and the University of Toronto, Toronto, Canada (R.A., S.L., S.M., A.C., D.M., M.A., R.C., G.deV.), and the
Childrens Hospital at HHSC, Hamilton, Canada (B.M., G.deV.).
Correspondence to Gabrielle deVeber, MD, Division of Neurology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G
1X8. E-mail deveber@sickkids.on.ca
2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

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appropriate) gave written consent for the study. The Institutional

Review Boards of both participating centers approved the study
protocol.

Definition of Arterial Ischemic Stroke

The definition of AIS was a focal neurological deficit of acute onset,
and a CT scan or MRI of the brain showing a lesion characteristic of
focal arterial infarct in a vascular territory consistent with the
neurological presentation.

Clinical Features
Clinical information was obtained by the study neurologists (D.M.,
R.C., B.M., G.deV.) during the acute hospitalization or in subsequent
clinics 3 to 6 months after AIS. A previously reported Pediatric
Stroke Outcome Measure (PSOM) was used that consisted of a
standardized structured questionnaire, radiographic AIS classification, and neurological examination.1 Data were supplemented by
comprehensive standardized health-record reviews of all cases.
Information obtained included age at event, sex, neurological signs
and symptoms at presentation with AIS, risk factors, and antithrombotic therapy. The presence and timing of the varicella infection
were established by asking the parents the following questions: Has
your child had chickenpox? and if the response was yes, When?
The number of days, months, and years that varicella infection
preceded the AIS was documented. The rate of varicella infection in
the children with AIS was compared with published rates of varicella
in healthy children obtained by community survey and parental
reporting.21
Laboratory investigations for metabolic disorders, prothrombotic
conditions, and vasculitis were performed.22 Cardiac echocardiography was performed in all patients.

Radiographic Features
All patients underwent CT, MRI, MR angiography (MRA), or
conventional angiography. The study neuroradiologist (S.L.), who
was unaware of the clinical history, reviewed all original radiographic films for children in the varicella cohort and a randomly selected
20% for the nonvaricella cohort. For the remaining nonvaricella
patients, clinical reports alone were used.
Radiographic findings regarding infarct and vascular features
were recorded on standardized reporting sheets. The infarct features
were classified as (1) number of concurrent infarcts at presentation
(single, multiple), (2) infarct type (large-vessel and small-vessel),
and (3) infarct location (basal ganglia, nonbasal ganglia, and anterior
circulation, posterior circulation). The term basal ganglia included
the caudate, putamen, globus pallidus, and adjacent internal capsule,
and excluded the thalamus. The term anterior circulation included
the territory of the internal carotid artery or its branches. The
vascular features included (1) location of blood vessel abnormalities
(internal carotid artery, middle cerebral artery, anterior cerebral
artery, or posterior cerebral artery) and (2) extent of luminal
narrowing (none, stenosis, or occlusion).

Outcome Data
Outcomes included neurological outcome (normal or neurological
deficit) and recurrent cerebral ischemic events. Neurological outcomes were classified by the study neurologists, according to the
PSOM grading, as none, mild (function normal), moderate (function
slowed), or severe (function missing).1 Transient ischemic attacks
(TIAs) and cerebral infarcts that occurred before or after the index
AIS were included as recurrent AIS. Data regarding recurrent AIS
were obtained from parent interviews in clinic, review of radiographic films, and standardized health-record review of all patients.

Pooled Literature Analyses

A MEDLINE search was conducted from January 1980 to January
2000, using a combination of subject words. Cross-referencing of
each article was performed. Data on each patients age, sex, clinical
presentation, infarct location, vascular abnormality, neurological
outcome, and recurrence were tabulated. Patients had to be aged 18
years and to have had varicella 12 months before the AIS for

inclusion. These patients formed the literature-varicella stroke

group.

Statistical Analysis
Two-group comparisons were conducted between the nonvaricella
cohort and both the varicella cohort and literature-varicella group
with the Fisher exact test and t tests. The following variables were
tested: age, sex, hemiparesis, seizures, site of infarct, vessel involvement, neurological outcome (normal or neurological deficit), and
recurrence. Results were calculated as odds ratios and 95% confidence intervals with probability value (2-tailed).

Results
Cohort Study
During the study interval, 70 children with AIS between the
ages of 6 months and 10 years were identified. Twenty-two
patients (31%) with varicella in the 12 months preceding their
initial AIS formed the varicella cohort, and the remaining 48
children composed the nonvaricella cohort. The clinical and
radiographic features are summarized for both the varicella
and nonvaricella cohorts in Table 1.
Clinical Features
The mean interval from varicella infection to AIS in the
varicella cohort was 5.2 months (range 1 to 11 months;
Figure). There was no seasonal pattern to the frequency of
AIS in the varicella or nonvaricella cohort. There were no
significant differences between the varicella and nonvaricella
cohorts for age, sex, and presentation with seizures. Presentation with hemiparesis was significantly more likely
(P0.001), and seizures tended to be less likely (P0.05) in
the varicella cohort compared with the nonvaricella cohort
(Table 1). Children in the varicella cohort were less likely
than children in the nonvaricella cohort to have additional
risk factors (12% versus 27%, respectively). The additional
risk factors included: congenital heart disease (5% versus
23%), migraines (10% versus 10%), other vasculopathies
(0% versus 21%), presence of anticardiolipin antibody (33%
versus 36%), and other (1% versus 14%). Children in the
varicella cohort were more likely than children in the nonvaricella cohort to receive antithrombotic therapy (82% versus 65%,
respectively), which included aspirin (58% versus 48%), heparin
(18% versus 16%), and coumadin (6% versus 1%).
Radiographic Features
All patients had CT or MRI to confirm the diagnosis of AIS.
All children in the varicella cohort and 28 children in the
nonvaricella cohort underwent vascular imaging. In the varicella cohort, 20 children had MRA, 19 conventional angiography, and 17 had both. Review of 20% of the institutional
films for the nonvaricella cohort by the study neuroradiologist showed 100% agreement with the institutional radiology
reports for the presence or absence of basal ganglia infarction,
anterior circulation infarction, and cerebral artery abnormalities. Therefore, information from the institutional radiology
reports was used for the remaining nonvaricella cohort
patients.
Children in the varicella cohort were significantly more
likely than children in the nonvaricella cohort to have an
infarct located in the basal ganglia (P0.001), infarct(s)
limited to the anterior circulation (P0.05), and a large-

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Askalan et al

Chickenpox and Stroke in Childhood

1259

sis on the MRA or angiogram in 9 children and were multiple

(up to 7 episodes) in 8 of the 10 children. Four children were
receiving aspirin therapy at the time of recurrence.

Pooled Literature Analyses

Graph showing interval from varicella infection to AIS. Values on

the y axis indicate number of cases.

vessel stenosis (P0.05). The vascular abnormalities in the

varicella cohort consisted nearly exclusively of areas of
stenosis (20 of 22) in the proximal portion of the major
cerebral arteries.
Neurological Outcome
The final neurological outcome assessments for the study
cohorts were performed 3 months to 5.8 years (mean 2.1
years) after the AIS. Neurological outcomes in the varicella
cohort were normal in 7 (32%), with the remaining 15 (68%)
having neurological deficits graded as mild (10), moderate
(2), and severe (3). All 3 children with severe deficits
developed progressive hemidystonia beginning several
months after the AIS. Neurological outcomes in the 48
children in the nonvaricella cohort were normal in 16 (33%),
while the remaining 32 had neurological deficits graded as
mild (9), moderate (12), and severe (11). The neurological
outcomes did not differ significantly in the 2 groups.
Recurrence
Recurrent AIS occurred in 10 (45%) children in the varicella
cohort compared with 8 (20%) children in the nonvaricella
cohort (P0.05). All 5 children with recurrent infarcts also
had recurrent TIAs. Recurrences were associated with stenoTABLE 1.

Since 1980, 18 case series with a total of 57 cases of children

with varicella-associated AIS have been published.320 Of the
57 cases, there were 51 cases (designated literature-varicella
group) in which the varicella occurred 12 months before the
AIS, and adequate information on age, interval from varicella
to infarct, and infarct location were provided. The clinical and
radiographic features are summarized for the literaturevaricella group in Table 2.
Clinical Features
The mean interval from varicella infection to AIS in the
literature-varicella group was 2.6 months, with a range from
0.2 to 12 months. Similar to the varicella cohort, there were
no significant differences between the literature-varicella
group and nonvaricella cohort for age and sex, but a clinical
presentation with hemiparesis was significantly more likely
in the literature-varicella group compared with the nonvaricella cohort (Table 2) (P0.001).
Radiographic Features
Radiographic studies included CT scanning that was performed in all but 2 cases, conventional angiography in 33,
MRI in 17, and MRA in 1. Similar to the varicella cohort,
children in the literature-varicella group were significantly
more likely than children in the nonvaricella cohort to have
infarcts located in the basal ganglia (Table 2; 50 of 51 cases,
P0.001). Of the 33 children in the literature-varicella group
that underwent vascular imaging, 5 were normal and the
remainder had large-vessel stenosis (P0.05).
Neurological Outcome
Information on neurological outcome was available in 40
children, of whom 13 (32%) were described as normal and

Comparison of Varicella Stroke and Nonvaricella Stroke Cohorts

Patient Characteristics
No.
Age, mean (SD), y

Varicella
Cohort

Nonvaricella
Cohort

P
(2-sided)

OR
(95% CI)

22

48

4 (2.4)

5 (3.1)

0.49

15

31

0.44

17

Sex
Male
Female

1.6 (0.54.6)

Clinical
Hemiparesis

22

38

0.02*

17/44

0.05

22

18

0.001*

17

1.00

0.9 (0.22.5)

Anterior circulation

20

32

0.04*

5.0 (1.024.1)

Large-vessel stenosis

20

19/31

0.03*

6.3 (1.232.1)

16

1.0

0.9 (0.32.7)

10

0.01*

4.1 (1.312.9)

Seizures

12.2 (0.68219.7)
0.2 (0.10.9)

Radiographic
Basal ganglia infarct
Multiple infarcts

74 (4.21298.1)

Outcome
Normal
Recurrence

*Statistically significant at P0.05.

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TABLE 2. Comparison of Literature Varicella Stroke Group and Nonvaricella
Stroke Cohort
Patient Characteristics
No.

Literature-Varicella
Cohort

Nonvaricella
Cohort

P
(2-sided)

OR
(95% CI)

51

48

5 (2.9)

5 (3.1)

0.49

Male

29

31

0.64

Female

22

17

Age, mean (SD), y

Sex

1.3 (0.63.1)

Clinical
0.001*

28 (1.5494.6)

18

0.001*

83 (10.5656.7)

50

17

1.00

32

0.04*

25 (3.1197.0)

28/33

19/31

0.04*

3.5 (1.111.7)

13/40

16

9/20

Hemiparesis

51

38

Seizures

17/44

Basal ganglia infarct

50

Multiple infarcts

Radiographic

Anterior circulation
Large-vessel stenosis
Outcome
Normal
Recurrence

1.0

0.9 (0.61.5)

0.01*

4.0 (1.313.0)

*Statistically significant at P0.05.

the remainder as having hemiparesis that was graded as mild

in 8 or of unspecified severity in 5. These outcomes did not
differ from outcomes in the nonvaricella cohort (Table 2;
P1.0).
Recurrence
Information on recurrent TIA or AIS was available in 20
children, of whom 9 (45%) had a recurrence, which represents an increased recurrence rate compared with the nonvaricella cohort (P0.05).

Discussion
This is the first prospective cohort study to systematically
search for varicella as a preceding cause of AIS in children
and to differentiate the clinical and radiographic features of
varicella-associated AIS from other forms of AIS. Our results
show that 31% of consecutive children with AIS have a
history of varicella in the preceding year. Children with
varicella-associated AIS have an increased frequency of
hemiparesis, basal ganglia infarcts, anterior circulation infarcts, and stenosis of proximal portions of major cerebral
arteries compared with AIS in children without varicella.
Although the association of AIS with varicella does not
appear to influence the neurological outcome, the risk of
recurrent AIS or TIA is significantly increased.
The age range of children in our study was selected
because varicella is difficult to diagnose in children aged 6
months and rare in children aged 10 years.23 The 31%
incidence of varicella within the preceding year in our AIS
cohort represents a 3-fold increase over the 9% annual
incidence of varicella in Canadian children. Among idiopathic AIS, the incidence of varicella-related strokes increases 6-fold (to 50%) compared with population rates.6
Although varicella is an important risk factor for AIS, the
absolute risk of varicella-associated AIS is estimated at only

1 in 15 000 children.4,6,24,25 The reasons that such a small

percentage of children with varicella experience AIS are not
known. Variations in immune susceptibility or in the strain of
the varicella-zoster virus may account for differing susceptibilities to varicella-related AIS.
Parental reporting was selected in our study for identification of a recent varicella infection because of previously
proven accuracy.21 Other methods that were considered
included measuring varicella titers and examination of cerebrospinal fluid. However, the problematic issues with these
methods included the inability to provide information on the
timing of the infection and poor sensitivity in the case of
molecular testing for varicella zoster (VZ) in the cerebrospinal fluid.26 28 Definitive histopathological evidence for the
presence of VZ virus in the affected vasculature through
postmortem examination was not available, as all children
survived.
The clinical and radiographic features of varicellaassociated AIS that differed significantly from nonvaricella
AIS included hemiparesis, infarction in the basal ganglia and
anterior cerebral circulation, and stenosis of proximal portions of major cerebral arteries. The increased frequency of
hemiparesis and anterior circulation territory infarcts in
varicella-associated AIS reflected the location of all infarcts
in the basal ganglia. Case series of childhood basal ganglia
strokes have reported frequencies of varicella ranging from
5% to 56%.10,29 In our entire study cohort, 55% of all children
with basal ganglia infarcts had varicella. The underreporting
of varicella as a risk factor for AIS in children in the literature
likely reflects the delay of several months from infection to
AIS and failure to specifically obtain a history of varicella.
Obtaining a history of varicella is particularly important in
children with basal ganglia AIS, even when there are other
identified risk factors.

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Askalan et al
The underlying mechanism for varicella causing AIS is not
known. Multiple mechanisms for varicella-associated AIS
have been suggested.4,5,11,16,19,20,30 The most plausible mechanism involves intraneuronal migration of the VZ virus from
the trigeminal ganglion along the trigeminal nerve to the
cerebral arteries.31 In adults with herpes zoster ophthalmicus
(HZO) and delayed cerebral infarction, VZ virus is present
within the media of the affected large cerebral arteries.28,3234
The distribution of vascular lesions in varicella-associated
AIS in large cerebral arteries is similar and matches the
anatomic location and density of trigeminal innervation at the
circle of Willis.
The neurological outcome in the varicella cohort was
similar to that in the nonvaricella cohort at the time of
analyses. However, the emergence of longer-term complications of basal ganglia infarction, especially dystonia, needs to
be monitored. The significant increase in recurrent TIAs and
AIS in the varicella cohort was unexpected and may influence
long-term neurological outcome. The risk of recurrence
indicates that more effective antithrombotic strategies need to
be developed.
Initial treatment options for varicella-associated AIS include supportive care, antiviral therapy, and anticoagulant
therapy. Antiviral therapy has not been reported in children
with varicella-associated AIS, and the results of treatment
with acyclovir and steroids in adults with HZO are
mixed.27,35,36 However, antiviral and anti-inflammatory therapies may not be indicated in children with varicellaassociated AIS, as the survival rate is excellent compared
with a mortality of 25% in adults with HZO. Anticoagulant
therapy in the initial phases of varicella-associated AIS may
be helpful in preventing local extension of the thrombus and
embolization.
Primary prevention of varicella-associated AIS by the
varicella vaccine is an important consideration, but the impact
would likely be modest. A recommendation for varicella
immunization for the prevention of childhood AIS cannot be
made because the risk/benefit ratio and cost-effectiveness of
immunizing 15 000 children to prevent 1 AIS have not been
assessed. In contrast, secondary prevention with anticoagulants in children with varicella-associated AIS should be
seriously considered. The options include antiplatelet agents,
warfarin, and low-molecular-weight heparin (LMWH). At
this time, long-term therapy with aspirin can be suggested for
all children with varicella-associated AIS for secondary
prevention. More effective but potentially less safe treatment
with warfarin or LMWH should, in general, be reserved for
children in whom stroke recurs while on aspirin, until these
treatments have been studied in clinical trials.
In summary, our study has shown that there is a strong
association between varicella infection and childhood AIS
and that there are distinctive clinical and radiographic features of varicella-associated AIS, which include an increased
risk of recurrent AIS and TIA. The long-term clinical and
radiographic outcomes, as well as the role of antiviral
therapy, more effective antithrombotic therapy, and the impact of immunization for varicella on childhood AIS require
further study.

Chickenpox and Stroke in Childhood

1261

Acknowledgments
This work was supported by the Bloorview Childrens Hospital
Foundation. Dr deVeber is a Stroke Investigator of the Heart and
Stroke Foundation of Ontario, Dr Chan is a Research Scholar of the
Heart and Stroke Foundation of Canada, and Dr Andrew is a Career
Scientist of the Heart and Stroke Foundation of Canada. The authors
would like to gratefully acknowledge Trish Domi, MA, and Anita
Allen, RN, for their assistance with data management and patient
coordination for this study.

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Editorial Comment
Pediatric Stroke
In the article by Askalan et al, the authors report a strong
association between varicella infection and a particular form
of childhood arterial ischemic stroke (AIS). They describe a
triad of basal ganglionic infarction in association with an
anterior circulation stenotic vasculopathy accompanied in
two thirds of patients by recurrent stroke or transient ischemic
attacks. Although mortality is low, the morbidity can be high,
with the more neurologically devastated cases proceeding to
hemidystonia (3 of 31).
The authors are to be congratulated on their study design,
which might not have been possible without the development
of the Canadian pediatric stroke database (deVeber et al). It is
a 3-pronged approach that consists of a prospective cohort
study of children with AIS, a review of the reported demographics of varicella in the community, and a metanalysis of
the literature.
This article should raise awareness of pediatric stroke in
the medical community. The incidence is currently underreported and underrecognized. The occurrence of childhood
stroke is likely to increase in the future, with technical
advances such as fetal surgery and extracorporeal membrane
oxygenation allowing children who might otherwise not have
survived to enter the community. To use the old aphorism,
children are not little adults, and this is nowhere more true
than in pediatric stroke, where the etiology of cerebrovascular
accident is predominantly hematologic or cardiovascular and
not atherosclerotic, as in the adult population. This point
leads on to the need for clinical trials of anticoagulant and
antithrombotic therapies in children. There are few enough
controlled trials in adults, and they cannot be assumed to
extrapolate to the pediatric population.
At our institution, we have developed a multidisciplinary
approach to the diagnosis and management of pediatric AIS.
At the time of admission, an unenhanced CT scan is performed to rule out the presence of blood and, following a

thorough neurological examination, a complete blood

work-up is performed to include protein S activity, antithrombin III activity, protein C activity, and factor V Leiden and
prothrombin gene mutations, in addition to CBC, platelet
count, ESR, ANA, APLA, lactate, pyruvate and homocysteine levels, PT, and PTT. MRI and MR angiography are
carried out in addition to diffusion-weighted imaging (DWI).
The sensitivity of DWI is such that we have detected
changes of ischemic damage within 20 minutes of a cerebrovascular event in a child. Transthoracic and, where indicated,
transesophageal echocardiography form part of the routine
workup to establish an etiology. Conventional angiography is
reserved for those cases in which no cause has been found or
to better demonstrate a suspicious area noted, for example,
on MRA.
In the case of varicella-associated AIS in children, it is
interesting to speculate whether antiviral agents might offer
some protection in addition to anticoagulant therapy. The
future impact of vaccination programs may further reduce the
incidence of varicella vasculopathy, although only time will
help us further elucidate the mechanism of stroke in these
patients.
Finally, while only 1 in 15 000 cases of varicella may
result in AIS, this article raises a bigger question as to how to
elevate awareness of the phenomenon of pediatric stroke both
within the medical community and among the lay public, for
although with chickenpox the mortality may be low, the
morbidity is high, and society will continue to pay the cost of
a damaged child for many years to come.
Jill V. Hunter, MB, BS, MRCP(UK), FRCR
Guest Editor
Department of Radiology
Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania

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