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522 Archives of Disease in Childhood 1997;76:522525

Mechanisms of ischaemic stroke after chickenpox

V Ganesan, F J Kirkham

Abstract CASE 2
Ischaemic stroke is a recognised compli- A 5 year old boy presented with a right
cation of chickenpox. Seven cases of hemiparesis six weeks after chickenpox. MRI
ischaemic stroke in children after recent showed infarction in the left MCA territory,
varicella infection are discussed in detail with evidence of left MCA stenosis on MRA. A
to emphasise that there are several prothrombotic screen (levels of protein C,S
mechanisms by which this may arise. antithrombin III, heparin cofactor II, plasmin-
(Arch Dis Child 1997;76:522525) goen, activated protein C resistance ratio, and
investigations to detect the factor V Leiden
Keywords: chickenpox; stroke; protein S mutation or an antiphospholipid antibody) at
the time of the ictus was normal. He has been
treated with low dose aspirin; however, al-
Chickenpox is a common childhood illness, though he has only been followed up for three
predominantly aVecting children under the age months, he has had a transient ischaemic event
of 10 years. Central nervous system complica- during this time, without any evidence of pro-
tions are well recognised and include several gression of his vascular lesion, and has
reports of ischaemic stroke aVecting both significant dystonia aVecting his hemiparetic
adults and children.14 hand.
As part of a questionnaire given to parents of
children with ischaemic stroke (the main aim of CASE 3
which was to explore functional outcome), we A 6 year old girl developed a left hemiparesis
undertook a survey to investigate how fre- four months after having chickenpox. MRI of
quently ischaemic stroke in children occurred the brain showed an infarct in the territory of
within six months of chickenpox. The results of the right MCA; the right MCA was occluded
this survey are discussed and seven cases are on contrast cerebral angiography. A full
described in detail. prothrombotic screen (as in case 2) was
normal. She has a dense residual hemiparesis
but has had no recurrent events. She is on long
Case reports term low dose aspirin treatment. Repeat MRA
The patient details are summarised in table 1. six months after the ictus showed MCA steno-
sis with some distal flow.
CASE 1
A girl aged 18 months developed an acute left CASE 4
hemiparesis two months after otherwise un- A 3.5 year old Iranian boy developed an acute
Neurosciences Unit, complicated chickenpox. Magnetic resonance left hemiparesis one week after the onset of
Institute of Child imaging (MRI) of the brain showed infarction chickenpox. He was seen by us six months later.
Health (UCL), London in the territory of the right middle cerebral MRI of the brain revealed a mature infarct in the
V Ganesan artery (MCA) and magnetic resonance angiog- right parietal lobe with multiple small foci of
F J Kirkham raphy (MRA) showed loss of signal in the infarction in the right frontal white matter. MRA
Correspondence to: proximal right MCA, suggestive of stenosis. demonstrated reduced flow in both carotid
Dr V Ganesan, Newcomen She had no prothrombotic abnormalities. The siphons with prominent collateral vessels. A
Centre, Guys Hospital, St MCA lesion was unchanged on MRA 18 contrast cerebral angiogram confirmed the
Thomas Street, London SE1 diagnosis of bilateral moyamoya (large vessel
9RT.
months after the stroke. She is on long term
aspirin treatment and has made a good occlusion with collateral) aVecting both ante-
Accepted 10 February 1997 functional recovery, with no recurrent events. rior and posterior circulations. All investiga-
tions for additional risk factors for stroke,
Table 1 Patient details including a full prothrombotic screen six
months after the acute presentation, were nor-
Interval between
Patient chickenpox and mal. He has had several transient ischaemic
No stroke Cerebrovascular abnormality Prothrombotic abnormality events in the 16 months after the initial stroke
1 2 Months MCA stenosis; persistent at 18 None and has some persistent diYculties with
months coordination and language. He is being treated
2 6 Weeks MCA stenosis None with long term low dose aspirin treatment.
3 4 Months MCA occlusion acutely; MCA None
stenosis 6 months later
4 1 Week Moyamoya None CASE 5
5 2 Months MCA stenosis; persistent at 1 Low total protein S A 5 year old boy developed an acute right
year
6 1 Week Not known Low free protein S hemiparesis two months after otherwise un-
7 1 Month PCA occlusion Low free and total protein S, complicated chickenpox. The neurological
protein C, and deficit resolved within 16 hours; however he
antithrombin III
had evidence of left striatocapsular infarction
MCA = middle cerebral artery; PCA = posterior cerebral artery. on MRI. His total protein S concentration was
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Mechanisms of ischaemic stroke after chickenpox 523

low at the time of the stroke but normalised to necrosis. The levels of the anticoagulant
within three months. He had no other risk fac- proteins only normalised after 14 days.
tors for stroke. MRA a year later showed On the sixth day she had persistent bradycar-
persistent MCA stenosis. He has no residual dia and hypertension. Paralysing drugs were
neurological deficits and is being treated with withdrawn and neurological examination re-
warfarin. vealed a left hemiparesis. MRI of the brain
showed evidence of infarction in the territory
of the right posterior cerebral artery (PCA).
CASE 6
The was no signal from the right PCA on
A 6 year old boy complained of sudden visual
MRA, suggesting it was occluded. Echocardi-
impairment a week after developing chicken-
ography and electrocardiography were normal.
pox. He then developed tonic-clonic move-
ECMO was discontinued on day 7 and the
ments involving the right hand and foot, lasting
vessels which had been cannulated for vascular
two minutes. There was no loss of conscious-
access were reconstructed. She recovered well
ness. He was drowsy for an hour after this epi-
and despite a dense left hemiparesis was devel-
sode and went on to have three further events
opmentally age appropriate at the time of
within the next six hours. In hospital he was
discharge on day 21.
noted to have a left homonymous hemianopia
and a healing vesicular rash. Computed
Results of questionnaire survey
tomography with contrast showed a right
In a retrospective questionnaire survey of
occipital infarct and an electroencephalogram
parents of 58 children with stroke, 10 children
showed widespread slow activity over the right
(17%) were reported to have had chickenpox
hemisphere. No cerebrovascular imaging was
within the six month period preceding the
performed.
stroke, including three of the cases discussed in
Routine haematology and biochemistry were
detail above. Five of these children had a
unremarkable. The cerebrospinal fluid was
prothrombotic screen at the time of the event
acellular with normal chemical composition.
and none had any abnormalities. In addition to
Antivaricella zoster virus IgM was detected in
three patients discussed in detail above, one
his blood. Cardiac evaluation was unremark-
child had evidence of occlusion of the anterior
able. Although his basic coagulation profile
inferior cerebellar artery on contrast cerebral
(prothrombin time, activated partial thrombo-
angiography. Of the remaining six, one had
plastin time, thrombin time, and fibrinogen)
structural cardiac disease, one had meningitis,
was normal, measurement of the anticoagulant
and final diagnoses were hemiplegic migraine
proteins on the day of admission showed a low
in one case and acute disseminated encephalo-
concentration of free protein S at 57% (normal
myelitis in another. The remaining two chil-
range 75125%). The total protein S concen-
dren, one of whom did not have any cerebrov-
tration was normal at 94% (normal range
ascular imaging, had cerebral infarction on
75125%) as were those of protein C, anti-
MRI with no risk factors identified.
thrombin III, heparin cofactor II, and plas-
minogen; platelet aggregation studies were also
Discussion
normal. His complement profile at the time
Although cerebral infarction after herpes zoster
was normal, in particular the level of C4 was
ophthalmicus is well recognised,5 6 the litera-
not raised. The free protein S normalised after
ture on ischaemic stroke after chickenpox in
10 days. He made a good functional recovery
childhood is confined to a number of case
and was discharged on low dose aspirin. He has
reports13 and this complication has been said
had no recurrent events.
to be rare. However, a Japanese study in 1990
suggested that stroke complicates 1:6500 cases
CASE 7 of childhood varicella infection.7 The data from
A 8 month old girl became acutely encephalo- our questionnaire survey suggest that the
pathic one month after developing chickenpox. association is common and should be actively
She rapidly deteriorated after presentation to sought in order to direct investigation towards
hospital, becoming shocked with marked cardi- identification of possible vascular or throm-
orespiratory compromise. Venoarterial extra- botic abnormalities. It cannot, however, be
corporeal membrane oxygenation (ECMO) inferred that the preceding chickenpox was sig-
was started. Chest radiography showed a left nificant in all cases and in the seven cases iden-
pneumothorax and right empyema, from which tified from this survey, but not discussed in
Staphylococcus aureus was isolated. Shortly after detail, there appeared to be no clear link
being stabilised on ECMO she developed a between the two events. The literature suggests
florid purpuric rash aVecting the whole body that stroke is a delayed complication of
but particularly marked in the extremities. chickenpox; although this was true in five of
Haematological investigation showed evidence our seven cases, in the other two patients (cases
of a consumptive coagulopathy with thrombo- 4 and 6) cerebral infarction occurred within
cytopenia and extremely low concentrations of the first week of the illness.
protein C, protein S, and antithrombin III. She Previous reports have focused on cerebro-
was treated with repeated infusions of fresh vascular disease as the primary mechanism of
frozen plasma, protein C, and antithrombin III stroke in these cases. Where cerebral angiogra-
concentrates and a single dose of intravenous phy is performed, there is typically occlusion or
immunoglobulin. The cutaneous lesions began stenosis of proximal large vessels,1 well illus-
to improve, but she went on to have amputa- trated by our patients. Vasculitic changes,
tion of the tips of the digits on the left hand due irregular stenosis, and beading involving multi-
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524 Ganesan, Kirkham

ple vessels have also been described,2 3 reminis- Levin et al recently demonstrated that in
cent of granulomatous angiitis. It has been children with purpura fulminans complicating
suggested that such lesions represent the effects chickenpox, deficiencies of both free and total
of a vasculitic reaction to viral invasion along protein S were due to circulating autoantibod-
the ophthalmic division of the trigeminal ies directed against protein S, with immune
nerve.26 The arteries innervated by this nerve complex formation and increased clearance of
correspond to the typical distribution of vascu- protein S from the circulation.10 Their series
lar involvement in this condition. Pathological included a child with an acute encephalopathy,
studies in cases of herpes zoster ophthalmicus associated with a low density lesion on
have demonstrated virus particles in the media computed tomography, similar to case 6 in our
but not the endothelium of vessels, lending group. There is evidence to suggest that
further support to this hypothesis.8 However, it transient deficiencies of both protein S and
is not always possible to demonstrate either protein C may complicate varicella with a less
viral particles or viral antigens in aVected florid clinical picture. Nguyen et al described a
vessels6 and patients without facial or corneal patient with uncomplicated varicella who had
lesions, or indeed any cutaneous lesions,4 may low concentrations of free and total protein S
have typical vascular disease. Alternative but no thrombotic manifestations and another,
mechanisms that have been put forward similar to case 5, with MCA territory infarc-
include spread via the bloodstream or cerebro- tion, low concentrations of free protein S, and
spinal fluid or an immune mediated vascular no other manifestations of thrombosis.11 Al-
reaction secondary to distant infection.8 though it could be argued that free protein S
Moyamoya, as observed in case 4, has not deficiency in this context is the result of
previously been described after varicella infec- increased concentrations of C4b (the protein to
tion. Moyamoya is an angiographic description which protein S is normally bound), this may
still be of functional significance as it is the free
of large vessel occlusion with collateral forma-
fraction of protein S which exerts its anticoagu-
tion and thus can be the result of various
lant eVect. One patient (case 6) was shown to
pathological processes. Patients are prone to
have normal concentrations of C4 suggesting
recurrent ischaemic events. Children who
that in his case the free protein S deficiency was
initially have isolated large vessel stenosis may
due to increased consumption rather than
progress to develop moyamoya but the factors increased binding to C4b; it is unclear whether
which determine progression or resolution of this was the cause or eVect of severe thrombo-
vascular disease in individual cases remain sis.
unclear. Bodensteiner et al suggested that the The optimal treatment of cerebrovascular
cerebrovascular lesions in chickenpox could be lesions associated with varicella remains un-
mediated by sympathetic stimulation due to clear. Reports include the use of steroids and
the local irritant eVect of the varicella lesions in antiplatelet agents and improvement of vascu-
the region of the superior cervical ganglion.1 litic changes has been documented.1 2 It is
Such a mechanism has also been put forward uncertain whether such an improvement was
for the aetiology of idiopathic moyamoya.9 the eVect of treatment as up to 50% of
It has been stated that the risk of recurrent cerebrovascular lesions in childhood stroke will
events in stroke after varicella is low and that improve or resolve within a year without
vascular lesions seen after varicella improve specific treatment.12 Although the use of
over time.1 2 However, two of our patients steroids and immunosuppressants may be of
(cases 2 and 4) had recurrent transient ischae- benefit in cases of isolated cerebral angiitis,13
mic attacks within 18 months of the original there is no evidence to support the use of such
stroke. In the four children with cerebrovascu- therapy in cases of focal cerebrovascular
lar lesions whom we have followed up over at disease. The risk of inducing resurgent herpes
least six months, all have had persistent vascu- zoster infection would also make such therapy
lar abnormalities and some improvement was unattractive in these cases. The role of antiviral
seen in only one patient (case 3). Long term agents in this situation remains unresolved6 but
follow up should therefore include assessment the variable temporal relationship between
for evidence of persistent or progressive vascu- infection and onset of neurological symptoms
lar disease; this may be done non-invasively suggests that such treatment may have a
with serial MRA studies. limited role. Given the persistence of vascular
Although systemic thrombotic complica- abnormalities in some cases, we have elected to
tions, such as purpura fulminans, complicating oVer these children anticoagulant or antiplate-
chickenpox are well recognised, the role of let therapy in an eVort to reduce the risks of
thrombosis in stroke after chickenpox has pre- recurrence.
viously received little attention. Eidelberg et al Acute treatment with heparin and fresh fro-
demonstrated histological evidence of throm- zen plasma should be considered for patients
botic vascular occlusion, without evidence of a with prothrombotic abnormalities. Such treat-
vasculitic reaction, in three patients with herpes ment appears to be eVective in cases where
zoster opthalmicus and contralateral hemipare- there is peripheral thrombosis; it is more diY-
sis, involving proximal large branches of the cult to assess its eYcacy in cases of cerebral
circle of Willis.5 He suggested that virus medi- arterial thrombosis where permanent damage
ated endothelial injury promotes local throm- may have occurred before clinical presentation.
bosis and vascular occlusion, as viral antigen The association between ischaemic stroke in
was demonstrated in the vessel wall in these childhood and infection with varicella zoster
patients. virus appears to be significant; both cerebrov-
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Mechanisms of ischaemic stroke after chickenpox 525

ascular disease and thrombotic mechanisms 3 Kamholz J, Tremblay G. Chickenpox with delayed contral-
ateral hemiparesis caused by cerebral angiitis. Ann Neurol
appear to be implicated. Although prothrom- 1985;18:358-60.
botic abnormalities are usually transient, vas- 4 Vichez-Padilla JJ, Redon J, Ruiz A, Lopez-Aldeguer. CNS
varicella-zoster vasculitis. Arch Neurol 1982;39:785.
cular abnormalities may be persistent. This 5 Eidelberg D, Sotrel A, Horoupian DS, Neumann PE,
may account for the fact that some patients go Pumarola-Sune T, Price RW. Thrombotic cerebral vascu-
on to have recurrent events. A history of recent lopathy associated with herpes zoster. Ann Neurol 1986;19:
7-14.
chickenpox should be sought in children 6 Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS.
presenting with stroke and investigation should Herpes zoster ophthalmicus and delayed contralateral
hemiparesis caused by cerebral angiitis: diagnosis and
be directed towards identification of prothrom- management approaches. Ann Neurol 1983;14:543-53.
botic and vascular abnormalities as these have 7 Ichiyama T, Houdou S, Kisa T, Ohno K, Takeshita K. Vari-
implications for both acute and long term cella with delayed hemiplegia. Pediatr Neurol 1990;6:279-
81.
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RS. Postinfectious purpura fulminans caused by an
zoster. antibody directed against protein S. J Pediatr 1995;127:
355-63.
11 Nguyen P, Reynaud J, Pouzol P, Munzer M, Richard O,
VG and FJK were supported by the Wellcome Trust. Francois P. Varicella and thrombotic complications associ-
ated with transient protein C and protein S deficiencies in
1 Bodensteiner JB, Hille MR, Riggs JE. Clinical features of children. Eur J Pediatr 1994;154:646-9.
vascular thrombosis following varicella. Am J Dis Child 12 Shirane R, Sato S, Yoshimato T. Angiographic findings of
1992;146:100-3. ischaemic stroke in children. Childs Nerv Syst 1992;8:432-
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Mechanisms of ischaemic stroke after


chickenpox
V Ganesan and F J Kirkham

Arch Dis Child 1997 76: 522-525


doi: 10.1136/adc.76.6.522

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