Strokes in Children

Michael J. Rivkin and Joseph J. Volpe

Pediatrics in Review 1996;17;265
DOI: 10.1542/pir.17-8-265

The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://pedsinreview.aappublications.org/content/17/8/265

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and
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ARTICLE

Strokes
Michael

in Children
J. Rivkin,

IMPORTANT
1.
2.

3.
4.

5.

6.

MD* and Joseph

Stroke occurs at an annual frequency

of 2.5 cases per 100,000 children.
Stroke in children is caused by heart disease, infection,
metabolic
disorders, hematologic
disorders,
and vasculitic
disorders
often due to autoimmune processes.
The three processes
that can cause stroke in children are embolism,
thrombosis,
and hemorrhage.
Although
lateralized
findings may be found on neurologic
examination
in a
neonate who has suffered
a stroke, focal seizure
may serve as the sole
initial
manifestation
of this disorder in a newborn.
Magnetic
resonance
imaging provides not only better image resolution
than computed
tomography
but also is much more sensitive
to subtle
parenchymal
changes that accompany
stroke soon after its occurrence.
Acute lateralized
weakness
in a child does not always indicate the occurrence of stroke. Conditions
that produce
symptoms
and signs similar to
stroke indude Todd postictal paralysis, hemiparetic
seizures, sub- and
epidural hemorrhage,
hypoglycemia,
and alternating
hemiplegia
of childhood.

Epidemiology
Childhood
stroke
occurs
with an
annual
incidence
of 2.5 cases per
100,000
population
and has been
reported
in all racial and ethnic
groups.
The sequelae
are not trivial.
In addition
to lasting
lateralized
weakness,
cognitive
deficits,
disturbances
of language,
visual deficits,
and seizures
may persist
long after
the acute event has concluded.
The causes
of stroke
in children
differ from those in adults.
Stroke
in
adults
is associated
largely
with

*Assistant

Harvard

Pediatrics

MDt

POINTS

Stroke
denotes
the sudden
onset of a
focal neurologic
deficit
and most
often includes
the abrupt
appearance
of weakness.
Interruption
of blood
flow to a part of the central
nervous
system
(CNS)
usually
underlies
the
resultant
weakness.
Because
most
strokes
in children
are related
to focal
cerebral
involvement,
the most common clinical
manifestation
is the
abrupt
appearance
of hemiparesis.
Less frequently,
the cause of stroke
involves
the brain stem, cerebellum,
or spinal
cord. The functional
consequences
always
reflect
the neuroanatomic
features
of the affected
CNS region.

tBronson

J. Volpe,

Professor
Crothers
Medical

iv i Review

of Neurology.
Professor
School,

of Neurology,
Boston,

MA.

Vol. /7

No.

August

hypertension
or atherosclerosis
and
their respective
hemorrhagic
and
ischemic
consequences.
Stroke
in
children
more commonly
is caused
by
or related
to congenital
heart disease,
infection,
metabolic
disorders,
hematologic
diatheses,
and vasculitic
disorders,
frequently
due to autoimmune
processes
(Table
1). Nonetheless,
despite
the most thorough
of evaluations, etiology
escapes
detection
in
approximately
30% of the pediatric
patients
in whom stroke
occurs.

Pathogenesis
Ischemic
injury of the brain occurs
as
a result of one of three different
mechanisms:
embolism,
thrombosis,
or diminished
systemic
perfusion.
Embolic
damage
to the brain occurs
when material
formed
at a site in the
vascular
system
proximal
to the brain
lodges
in a blood vessel,
thus blocking cerebral
perfusion.
Emboli
originate most commonly
from the heart,
arising
from a clot on cardiac
chamber walls or from vegetations
on
valve leaflets.
Artery-to-artery
emboli
are composed
of a clot or platelet
aggregates
that originate
in vessels
proximal
to the brain but ultimately
come to rest and to occlude
flow in
vessels
critical
for cerebral
perfusion.
Thrombosis
denotes
vascular
occlusion due to a localized
process
within
a blood vessel
or vessels.
Although

atherosclerosis
underlies
most thrombotic processes
affecting
adults,
it is
not a common
cause of thrombosis
in
children.
Localized
lumenal
clot formation
occurs
in polycythemia
or in a
hypercoagulable
state. Alternatively,
anatomic
abnormalities
may lead to
clot formation
or mechanical
obstruction, as in fibromuscular
dysplasia,
arteritis,
or arterial
dissection.
If systemic
pressure
declines
sufficiently
to compromise
cerebral
perfusion, the CNS may suffer injury due
to diminished
systemic
perfusion.
Cardiac
pump failure
(related
to congenital
heart disease
and its surgical
repair)
as well as systemic
hypotension due to hypovolemia
are common
causes
of hypotensive
cerebral
ischemic
injury.
Often brain injury
is
much more diffuse
in the context
of
diminished
cerebral
perfusion
compared with the more focal injuries
characteristic
of thrombotic
and
embolic
cerebral
events.
Cerebral
ischemia
serves
as the final common
pathway
leading
to brain injury
irrespective
of whether
an embolic,
thrombotic,
or hypoperfusive
mechanism has caused
the stroke.
Both thrombotic
and embolic
strokes
may be heralded
by the occurrence of transient
ischemic
attacks
(TIAs).
TIAs are brief episodes
of
focal,
nonconvulsive
neurologic
deficit
attributable
to interruption
of
cerebral
perfusion.
As with stroke,
the onset is abrupt,
but a TIA episode
lasts less than 24 hours,
and recovery
is complete.
A TIA frequently
portends the subsequent
occurrence
of a
stroke
and its resultant
fixed deficits.
Hemorrhage
occurs
when blood
is
released
into the extravascular
intracranial
or intraspinal
space.
In
this circumstance,
focal injury of
brain or spinal tissue occurs
as a
result of both pressure
exerted
by the
space-occupying
mass of blood and
hemorrhage-related
ischemia.
Such
injury
may be exacerbated
by the
damaging
effects
on neural
tissue of
substances
released
in the blood.
Epidural
and subdural
hemorrhage
are intracranial
collections
of blood
separated
from brain parenchyma
by
dural or arachnoid
membranes.
Subarachnoid
hemorrhage
occurs

1996

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265

NEUROLOGY

Strokos
TABLE!.

Etiologies

Thrombosis
#{149}
Vascular
Dysplasias
-Moyamoya
disease
-Neurofibromatosis
type
-Fibromuscular
dysplasia
-Dissecting
aneurysm
-Vascular
malformations
#{149}
Vasculopathy
-Sickle
cell
-Radiation
-Trauma
Intraoral
Neck

disease

#{149}
Vasculitis
-Infection-mediated
meningitis
-Viral
and postviral
causes
-Autoimmune-mediated
Systemic
lupus erythematosus
Polyarteritis
nodosum
Takayasu
arteritis
Henoch-SchOnlein
Kawasaki
disease
#{149}
Vasospasm
-Migraine
I
-Cocaine
use
-Glue
sniffing
-Wasp/Scorpion

purpura

sting

#{149}
Hematologic
-Hemoglobinopathies
Sickle cell disease
Sickle C disease
-Polycythemia
-Thrombocytosis
-Leukemia/Lymphoma
-Coagulopathy
Protein
S deficiency
Protein
C deficiency
Antithrombin
III deficiency
Lupus anticoagulant
Oral contraceptive
use

of Stroke

nant importance
of ischemia
as the
final common
pathway
to brain
injury.
Evidence
of hypoxic-ischemic
injury
to the neonatal
nervous
system
as a result of asphyxia
is reflected
by
a constellation
of signs that appear
early in the postpartum
period.
This
constellation
constitutes
the clinical
entity of HIE. Although
diffuse
hypotonia is the most frequently
observed
motor deficit
found early in the
course
of neonatal
HIE, patterns
of
weakness
may emerge
by the end of
the first day of life that reflect
the
distribution
of cerebral
injury from a
generalized
hypoxic-ischemic
insult.
Term infants
may demonstrate
a pattern of parasagittal
cerebral
injury
manifested
as quadriparesis
with predominant
proximal
limb weakness.
This pattern
derives
from ischemia
in
the watershed
or parasagittal
regions
of brain, which correspond
to the border zones of circulation
between
the
anterior
and middle
cerebral
arteries
and the middle
and posterior
cerebral
arteries.
Preterm
infants
may manifest deficits
reflecting
periventricular
leukomalacia.
The resulting
weakness
occurs
primarily
in the lower extremities due to perinatal
ischemic
injury
of motor fibers subserving
the legs.
These
fibers lie dorsal
and lateral
to
the external
angles
of the lateral
yentricles.
In each of these cases, clinical
features
and cerebral
neuropathologic
findings
sharing
a bilateral
distribution are found.
However,
focal cerebral infarction-that
s, stroke-does
occur in the newborn.

in Children

Pregnancy
and the
postpartum
state
L-Asparaginase
Disseminated
intravascular
coagulation
#{149}
Metabolic
-Homocystinuria
-Fabry
disease
-Sulfite
oxidase
-Pseudoxanthoma
-Mitochondrial

deficiency
elasticum
disorders

Embolus
#{149}
Cardiac
Disease
-Congenital
disease
Aortic
stenosis
Mitral
stenosis
Ventricular
septal defects
Patent ductus arteriosus
Cyanotic
congenital
heart
disease
with right-to-left
shunt
-Acquired
disease
Endocarditis
Cardiomyopathy
Atrial myxoma
Arrhythmia
-Air embolus
-Fat embolus

Hemorrhage
#{149}
Head Trauma
-Subdural
hemorrhage
-Epidural
hemorrhage
#{149}
Spontaneous
Occurrence
-Arteriovenous
malformation
-Ruptured
aneurysm
Mycotic
aneurysm
Saccular
aneurysm
-Thrombocytopenia
-Hemophilia
-Other
bleeding
diatheses

FOCAL CEREBRAL
INFARCTION
THE TERM NEONATE
Etiologies

when blood flows out of the intracranial vascular

bed and onto the surface
of the brain to admix
with cerebrospinal
fluid in the subarachnoid
space.
Intracerebral
hemorrhage
denotes
bleeding
into the parenchyma
of the brain.

Stroke

in the Newborn

HYPOXIC-ISCHEMIC
ENCEPHALOPATHY
Brain
266

injury

(HIE)

consequent

to asphyxia,

IN

hypoxia,
or ischemia
is an important
cause of neonatal
neurologic
morbidity. Tissue
oxygen
deficiency
is presumed
to underlie
the neurologic
injury caused
by hypoxic-ischemic
insults.
Asphyxia
denotes
an impairment in gas exchange
that results
not
only in a deficit
of oxygen
in blood
but also in an excess
of carbon
dioxide and, thereby,
acidosis.
Further,
sustained
asphyxia
almost
always
results
in hypotension
and ischemia,
consistent
with the likely predomi-

The cause of cerebral

infarction
frequently
escapes
detection
among
infants
who have not been subjected
to overt perinatal
asphyxia.
Indeed,
in
37 of 5 1 reported
cases of neonatal
stroke
(73%),
a cause could not be
identified.
Interestingly,
a left hemispheric
location
has been noted to be
most common;
the reason
for this
neuroanatomic
predilection
has not
been discovered.
Embolic
or thrombotic etiologies
have been recognized.
Emboli
from the placenta
may
lodge in cerebral
vessels
and cause
stroke.
Further,
it is possible
that features of the normal
newborns
heart,

Pediatrics

iii

Review

Vol. 17

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No.

August

1996

NEUROLOGY
Strok.s
such as a patent
foramen
ovale,
permit the transmission
of emboli
into
the systemic
arterial
circulation
through
right-to-left
shunts.
Once in
the systemic
arterial
tree, the emboli
ultimately
may ramify
in the cerebrovascular
bed and cause focal
infarction.
In addition,
congenital
heart defects
involving
right-to-left
shunts
through
septal defects
or a
patent
ductus
arteriosus
serve as settings for embolic
stroke
in neonates.
Another
etiology
of neonatal
stroke
is thrombosis.
Thrombotic
infarction
probably
is most common
in the newborn as a consequence
of bacterial
meningitis.
Polycythemia
and its
resultant
hyperviscosity
can cause
abnormalities
of blood flow and even
thrombosis.
Approximately
I .5% of
neonates
are polycythemic,
with newborns who are small for gestational
age being affected
most frequently.
Most cases of polycythemia
are idiopathic
or due to acquired
abnormalities of oxygen
delivery
(such as
maternal
smoking).
Nonetheless,
polycythemias
bearing
autosomal
dominant
or recessive
inheritance
patterns
have been described.
Cerebral
venous
thrombosis
may
cause focal infarction
in the newborn.
Cerebral
veins conduct
deoxygenated
blood from the parenchyma
to the
dural sinus system.
These
sinusesthe sagittal,
straight,
transverse,
cayernous,
and petrous-convey
the
blood to the jugular
veins for return
to cardiopulmonary
circulation.
Thrombotic
occlusion
of flow anywhere
in these venous
conduits
leads
to ischemia
and sometimes
infarction,
usually
hemorrhagic.
Infection,
dehydration,
polycythemia,
congenital
heart disease,
and protein
C deficiency all have been implicated
as causes
of cerebral
venous
thrombosis
in
neonates;
however,
no definitive
cause need be found.
Intracranial
hemorrhage
occurs
in
neonates
in one of four neuroanatomic distributions:
subdural
(SDH),
subarachnoid
(SAH),
intraparenchymal
(IPH),
or intraventricular
(IVH).
SDH
occurs
more commonly
in the term
infant;
the other three types of hemorrhage are more common
in preterm
infants.
SDH in neonates
appears
to
result primarily
from mechanical
trauma.
Cephalopelvic
disproportion,
rigidity
of the bony pelvis,
prolonged
duration
of labor, unusual
presentaPediatrics

in Review

Vol. 17

No.

August

tions, or the need for prolonged

manipulation
or forceps
application
may generate
increased
forces on the
fetal head and predispose
the infant to
SDH. Shearing
forces may create
tears in the vein of Galen or superficial cerebral
veins.
If forces
are
extreme,
tears at the junction
of falx
and tentorium
can generate
large subdural blood collections
in the relatively small posterior
fossa, culminating in brain stem compression
and
cerebellar
tonsillar
herniation.

the embolic
material
occluding
the
cerebral
vessel
eventually
fragments,
partial
or total perfusion
through
the
previously
occluded
vessel
is reestablished.
Hemorrhage
ensues
as blood
escapes
through
the vascular
walls,
which
have been weakened
by the
embolus-induced
ischemia.
Clinical

Features

Focal seizures
have been identified
as
the most common
clinical
feature
indicating
the presence
of stroke
in

Once stroke is suspected,

diagnostic
efforts
should
concentrate
on
discovering
the underlying
cause.
CCTand
MRI provide
rapid evidence
of infarction
hemorrhage.
...

Smaller
tentorial
tears are relatively
common.
With improved
obstetric
practice,
the incidence
of SDH has
declined
steadily.
Blood can occupy
the subarachnoid
space in two ways. First, it may reach
the space after hemorrhage
has
occurred
in the cerebral
parenchyma
or in the periventricular
region.
Second,
SAH may result from disruption of the superficial
leptomeningeal
arteries
or of the fragile
vessels
that
bridge
the subarachnoid
space;
disruption
of either vascular
structure
leads to direct bleeding
into the
space,
so-called
primary
SAH. Primary SAH commonly
occurs
after
hypoxic-ischemic
brain insults
and
after fetal head trauma.
Often the
pathogenesis
is unclear.
IPH in the absence
of IVH occurs
most commonly
in term infants.
Hemorrhage
into the parenchyma
of
the cerebral
hemispheres
can be due
to head trauma,
vascular
malformation, coagulopathy,
tumor,
or infarction. Even though
vitamin
K, a carboxylating
and activating
agent for
clotting
factors
II, VII, IX, and XI, is
administered
routinely
to newborns,
its deficiency
should
be considered
in
breastfeeding
full-term
neonates
who
present
with intracranial
hemorrhage.
In the absence
of recognized
coagulation or anatomic
abnormalities,
cerebral hemispheric
IPH usually
is a
manifestation
of hemorrhagic
infarction. In this circumstance,
embolic
stroke
precedes
hemorrhage.
When

or

the full-term
nonasphyxiated
infant.
Although
lateralized
findings
may be
found on neurologic
examination,
they need not be present
as hallmarks
of cerebral
infarction.
Further,
diminished movement
of extremities
on the
side of the focal seizure
may represent a Todd postictal
paralysis
rather
than paresis
from upper
motor neuron
injury
due to cerebral
infarction.
Recognizing
focal seizure
as a manifestation
of cerebral
infarction
is
important
because
this may be the
only sign of the cerebrovascular
event;
initially,
other neurologic
signs
may be absent.
Clinical
features
of SDH depend
on the location
and size of the hemorrhage.
Tentorial
laceration
can cause
stupor
or even coma.
Pupillary
and
extraocular
movement
abnormalities
are common.
Retrocollis
or opisthotonus is seen. Finally,
abnormalities
of respiratory
pattern,
such as
apneustic
or ataxic
respirations,
are
evident
and signify
imminent
respiratory arrest.
Less severe
SDH in the
posterior
fossa evolves
more slowly
and causes
less severe
brainstem
dysfunction.
Subdural
collections
of
blood over the cerebral
surfaces
due
to tears of superficial
cerebral
veins
may be asymptomatic
or accompanied only by irritability.
If the collection is sufficiently
large or accompanied by cerebral
contusion,
seizures
can occur. Greater
pressure,
with
transtentorial
herniation,
may dilate
pupils
unilaterally
and ablate
pupil-

/996

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267

NEUROLOGY

Strokes
lary light responses.
However,
SDH
may escape
diagnosis
in the first few
weeks
of life and appear
later as a
chronic
subdural
effusion.
Such an
occurrence
is marked
by a rapidly
enlarging
head circumference
and
increased
transillumination
of the
skull. Clinically,
mild SAH occurs
as
an occult
phenomenon
with few, if
any, manifestations.
Greater
amounts
of blood collecting
over the convexities may result in seizures.

include
hematocrit
and hemoglobin
electrophoresis
if polycythemia
is
suspected.
Screening
for infectious
and metabolic
disorders
as well as
coagulopathies
that could reflect
thrombotic
or embolic
stroke
should
be performed.
Echocardiographic
examination
of the heart, especially
employing
bubble
contrast,
will help
identify
a structural
defect
that may
have contributed
to a newly
identified
embolic
cerebral
infarct.

Diagnosis

Treatment

Once stroke
is suspected,
electroencephalography
(EEG)
and neuroimaging
are the most useful
methods
of documenting
its occurrence.
If
focal seizures
herald
focal cerebral
infarction,
the EEG often is the first
diagnostic
test ordered.
Evidence
of
localized
brain dysfunction
on EEG
consists
of focal, persistent
voltage

Treatment
is supportive
and symptomatic. Anticonvulsants
are given if
seizures
have occurred.
Phenobarbital
is the preferred
drug and is administered as a loading
dose of 20 mg/kg.
Doses
of 3 to 4 mg/kg
daily are sufficient for maintenance
therapy.
Attention
should
be given to hydration state, acid-base
balance,
and

In neonates,
focal
neurologic
findings
feature
of a stroke.

seizures
rather
are the most

reduction
or marked
focal slowing
and sharp wave activity.
Periodic
lateralized
epileptiform
discharges
may
be present.
In some instances,
there
may be electrographic
evidence
of
clinically
observed
seizures.
Each of
these findings
may exist while the
EEG remains
relatively
less affected
over other regions
of the brain.
The areas of electrical
abnormality
should
correspond
to the affected
areas of brain revealed
by neuroimaging. Cranial
computed
tomography
(CCT) demonstrates
a low-density
region
that eventually
evolves
to atrophy. However,
early in the period
following
infarction,
the affected
cerebral territory
may not be well visualized with CCT. Magnetic
resonance
imaging
(MRI)
permits
identification
of cerebral
infarction
early after its
occurrence.
MRI will demonstrate
low or isointense
signal intensity
on
Tl-weighted
images
and high signal
intensity
on T2-weighted
images
because
of increased
water content
in
the infarcted
region.
Diffusionweighted
MRI is most sensitive
in the
first hours after the event.
Finally,
intracranial
bleeding
can be identified
easily
with either
CCT or MRI.
Other laboratory
tests should
268

rhage rarely have normal

development during
follow-up.
Long-term
follow-up
of infants
who had cerebral
injury
identified
by MRI shortly
after
birth is still needed.
In the case of
idiopathic
cerebral
venous
thrombosis,
although
follow-up
has been limited,
neurologic
prognosis
appears
good.

Stroke in Children
Than I Year

Older

Despite
the infrequency
of stroke
among
children,
a great variety
of etiologies
exists.
These
may be grouped
according
to whether
an embolic,
thrombotic,
or hemorrhagic
event has
occurred
(Table
1).
THROMBOSIS
Vascular

Dysplasia

Moyamoya
syndrome
is observed
most commonly
in children
younger
than 15 years who typically
present
with TIAs or fixed motor deficits
of
sudden
onset.
Progressive
narrowing
and occlusion
of the intracranial
supraclinoid
internal
carotid
arteries
are
characteristic.
Endothelial
proliferation, fibrosis,
and intimal
thickening
constitute
the vascular
pathology.
Resultant
proliferation
of collateral
vessels,
principally
from the external
carotid
circulation,
creates
an intricate latticework
of compensatory
blood flow. The characteristic
appearance on angiography
is a fine vascular
network
in the region
of the basal
ganglia
(Fig. 1). It is from this
appearance
that Japanese
physicians
coined
the term moyamoya,
meaning something
hazy like a puff of
cigarette
smoke
drifting
in the air.
Children
usually
present
with acute
hemiplegia
due to uncompensated
occlusion
of the internal
carotid
artery.
Because
the anatomic
abnormality
is often bilateral,
bilateral
motor deficits
may be found.
In addition, fine motor
function
may be
observed.
Chorea
has been reported
in association
with moyamoya
syndrome.
Although
the vascular
abnormality
may be congenital,
moyamoya
syndrome
can occur as a sequel
to a
primary
disorder
causing
internal
carotid
artery occlusion.
It has been
found in children
who have sickle
cell disease,
neurofibromatosis,
tuberculous
meningitis,
and fibromuscular
dysplasia.
Evidence
suggesting
a hereditary
etiology
in some

than lateralized
common
clinical

hematocrit
and any deficits
corrected.
Underlying
infectious
or metabolic
conditions
or coagulopathy
must be
treated.
Idiopathic
cerebral
venous
thrombosis
does not appear
to require
anticoagulation.
Infants
who have
suffered
intracranial
hemorrhage
should
be evaluated
neurosurgically
to determine
the need for clot evacuation or vascular
repair.
Prognosis
It is difficult
to estimate
the developmental
outcome
following
cerebral
infarction.
The periods
of follow-up
reported
in series of neonatal
stroke
have been highly
variable.
Although
seizures
frequently
abate over time,
chronic
motor deficits
often become
apparent.
MRI evidence
of cerebral
infarction
may be helpful
in determining
the prognosis.
Most infants
who have evidence
of marked
white
matter
damage
or cystic/multicystic
encephalomalacia
have proven
to
have neurodevelopmental
abnormalities on short-term
follow-up.
Infants
whose
CCT studies
are normal
demonstrate
little or no neurologic
deficit
when studied
in follow-up.
Those
infants
demonstrating
marked
parenchymal
hypodensity
or hemorPediatrics

in Review

Vol.

17

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No.

August

1996

I
I

NEUROLOGY

Strok.s

families
has been reported
in Japan.
Fibromuscular
dysplasia
may
involve
multiple
sites throughout
the
systemic
arterial
tree. First described
in renal arteries,
the pathologic
features of fibromuscular
dysplasia
have
been found in carotid,
vertebral,
and
intracranial
arteries.
It involves
irregularly spaced
focal zones of fibrous
and muscular
hyperplasia
of the
media,
disruption
of the elastic
lamina, and even eventration
of the
media.
The constricted
regions
of

vascular
fibrosis
alternate
with
regions
of lumenal
dilation
to create
the characteristic
beaded
appearance
on angiography.
Fibromuscular
dysplasia is more common
in young
females
and has been found in adolescents.
If renal arteries
are affected,
hypertension
may be present.
The
most common
neurologic
symptoms
signifying
cerebrovascular
involvement are TIAs and mild strokes.
A
thrombotic
mechanism
is presumed
by many but has never been proven.
There is no effective
treatment
for
symptomatic
patients.
Congenital
structural
abnormalities
of cervical
or cerebral
vasculature
may be associated
with thrombotic
stroke
in children.
Occasionally,
thrombotic
stroke
may occur in association
with vascular
malformations,
such as arteriovenous
malformations
and cavernous
angiomas.
Abnormal
vascular
wall structure
and a tortuous
vascular
bed combine
to alter laminar
blood flow and promote
the formation of thrombus.
As a result,
both
local vascular
occlusion
and distal
embolic
occlusion
of cerebral
vessels
may occur.
Finally,
a vascular
steal
phenomenon
may contribute
to the
pathogenesis.
Intracranial
arterial
occlusive
disease
may complicate
neurofibromatosis.
Additionally,
cervical and cerebrovascular
dysplasia,
including
dissecting
and nondissecting aneruysm,
may be found in neurofibromatosis,
Ehiers-Danlos
syndrome,
and Marfan
syndrome.
Vasculopathy

FIGURE

1. Six-year-old

den

onset

of right

angiogram

shows

artery

(arrow)

arborized,
(arm

boy who
A.

left internal

carotid

leading

network

typical

The

typical

middle

tree

is absent.

Cerebral

to a highly

telangiectatic

wheads)

has sud-

hemiparesis.

of vessels

of Moyamova

vascular

coronal

magnetic

resonance

imaging

(MR1)

shows

a region

low

intensity

in the

middle

cerebral

signal

artery

B. Cranial

disease.

artery

cerebral

territory

(curved

arrows).

ganglia

(small

manifestations
culation

Pediatrics

typical

that

denotes

Flow

infarction

voids

in the

armws)

are

radiographic

of the

basilar

collateral

of this

in Review

of

vascular

Vol. 17

basal

cir-

anomaly.

No.

August

Acute hemiplegia
may occur in children who have sickle cell disease.
Cerebral
infarction
occurs
in approximately
6% of patients
afflicted
by
this hemoglobinopathy,
often in the
setting
of sickle crisis.
Neurologic
signs commonly
include
hemiparesis,
aphasia,
and visual
disturbances.
Neuroimaging
studies,
particularly
recent
MRI investigations,
reveal
that
stroke
often occurs
in watershed
distributions
between
two cerebrovascular territories
and affects
both cortex
and white matter.
The proposed
pathophysiologic
mechanisms
encompass
both large vessel
injury
caused
by sickling
in vasa vasorum,
thereby
leading
to thrombotic
hypoperfusion,
and small cerebral
vessel
obstruction
due to the decreased
compliance
of sickled
erythrocytes.

Cerebral
vessels
reveal
endothelial
proliferation,
disruption
of the elastic
lamina,
and stenosis.
Recently,
increased
velocity
of blood flow, as
determined
by transcranial
Doppler
ultrasonography,
has been found to
identify
children
at greatest
risk for
stroke.
Exchange
transfusion
may
reduce
the occurrence
of stroke
in
these patients.
Children
who have
suffered
large strokes
demonstrate
correspondingly
multifaceted
deficits
of cognitive
function.
Those
in whom
focal strokes
have occurred
show
more subtle neuropsychologic
deficits.
Cervical
vessel
injury
caused
by
head, neck, or intraoral
trauma
may
cause stroke.
Neurologic
symptoms
may be delayed
more than 24 hours
after the inciting
trauma.
Stroke
due
to carotid
artery
injury
has been well
documented.
A typical
presentation
is
intraoral
trauma
to the internal
carotid
artery
in a toddler
who falls
with a pencil
or other object
in the
mouth.
Most often these cerebrovascular events
occur after head/neck
trauma
sustained
in motor
vehicle
accidents,
bicycle
accidents,
fights,
or
falls. Hemiparesis
is a common
symptom
at presentation
if the injury
affects
the carotid
artery.
Carotid
angiography
reveals
internal
carotid
artery occlusion.
The site of occlusion most often is at the level of the
carotid
bifurcation.
Pathologic
findings vary from an intimal
tear with
attendant
thrombus
blocking
the arterial lumen
to lumenal
obstruction
from arterial
dissection.
Vertebral
artery
injury due to trauma also may cause stroke
in children.
Traction
injuries
of the neck appear
especially
to cause vertebral
artery
injury.
The vertebral
artery is most
vulnerable
to traumatic
injury at its
atlanto-axial
portion.
The resultant
strokes
occur in the vertebrobasilar
portion
of the cerebral
circulation.
Therefore,
symptoms
are referable
to
the CNS structures
receiving
blood
from this vascular
system:
brain stem,
cerebellum,
thalamus,
and the occipital and temporal
lobes.
Clinical
symptoms
of vertebrobasilar
stroke
include
difficulty
swallowing,
ataxia,
facial weakness,
tinnitus,
vertigo,
anisocoria,
extraocular
movement
palsies,
dysmetria,
dysesthesia,
cortical blindness,
and changes
in mental
status.
Because
both the sensory
and

1996

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269

NEUROLOGY

Strokes

motor
long tracts course
through
the
brain stem, symptoms
of general
sensorimotor
impairment
may be found
as well. Vertebral
artery
injury in
children
has been reported
in the setting of athletics
(eg, judo),
automobile accidents,
or chiropractic
cervical spine manipulation.
The resultant
vertebrobasilar
strokes
are due to
thrombosis
or to vertebral
artery dissection.
Anticoagulation
with
antiplatelet
agents
has been proposed
as therapy.
Finally,
cranial
radiation
therapy
received
as part of cancer
therapy
may induce
an occlusive
vasculopathy
leading
to focal cerebral
ischemia.
Basal ganglia
frequently
are affected
by this vasculopathy,
resulting
in extrapyramidal
movement dysfunction,
such as choreoathetosis.
Vasculitis
Infection
is an important
and treatable cause of stroke
in children.
Cerebral
vessels
may become
inflamed
in the course
of bacterial
meningitis.
The subarachnoid
arteries
become
immersed
in purulent
exudate, and smaller
vessels
are affected
as exudate
moves
down VirchowRobin
spaces.
The vessel
walls of
arteries
and veins are affected
by the
inflammatory
process,
and occlusion
of either can result in stroke.
Antibiotics
combined
with steroids
early
in the course
of treatment
are the cornerstone
of therapy.
Viral infection
also may promote
vascular
inflammation that may involve
the cerebral
vessels
and culminate
in stroke.
Cerebral
vasculitis
and stroke
has
been described
in association
with
human
immunodeficiency
virus
(HIV) infection
in children.
Aneurysms
have been observed
in
association
with the HI V-associated
vasculitis.
In addition,
herpes
zoster
and varicella
viruses
have been associated
with angiitis
of the CNS,
resulting
in acute hemiplegia.
Vasculitis
leading
to arterial
occlusion also has been observed
in rubella
and coxsackievirus
A9 infections,
probably
as a postviral
immunologic
phenomenon.
However,
vasculitis
and infarction
have been observed
in
the postviral
syndrome
of acute
necrotizing
hemorrhagic
leukoencephalopathy.
Autoimmune
disorders
often
include
vasculitis
that may involve
270

the CNS (Table

2). Symptoms
of
abrupt
onset with accompanying
deficits
referable
to the CNS long
have been associated
with systemic
lupus erythematosus
(SLE).
A CNS
vasculitis
had been presumed
to
underlie
the CNS manifestations
of
SLE, but autopsy
study of patients
suffering
from SLE revealed
a virtual
absence
of cerebrovascular
inflammation. Rather,
small areas of infarction
relate to proliferative
changes
in cerebral arterioles,
leading
to lumenal
occlusion.
Large areas of infarction
more likely are related
to lupus anticoagulant-derived
thromboembolism
or to embolism
from the sterile
cardiac valve leaflet
vegetations
associated with SLE.
Stroke
may occur in the course
of
polyarteritis
nodosa;
involvement
of
the CNS is found in 20% to 40% of
patients.
Mixed
connective
tissue disease (MCTD),
which
overlaps
clinically with polymyositis,
lupus,
and
progressive
systemic
sclerosis,
can
involve
the CNS. Cranial
neuropathy,
most commonly
trigeminal
nerve
dysfunction,
has been the deficit
cited
most frequently.
Recently,
however,
stroke
manifesting
as sudden
onset
hemiparesis
and aphasia
has been
reported
in children
afflicted
with
MCTD.
Takayasu
arteritis,
involving
the aorta and its principal
branches,
has been associated
with thrombotic
stroke.
Inflammation-induced
lumenal constriction
leading
to thrombosis
is thought
to cause cerebral
ischemia

TABLE

2. Autoimmune
Central

Nervous

in these children.
Angiographic
improvement
of vessels
in the carotid
tree is observed
with immunosuppressive
treatment.
Necrotizing
arteritis with inflammatory
infiltrate
has
been found in both meningeal
and
cerebral
vessels
of children
suffering
from Henoch-Sch#{246}nlein
purpura.
Both fixed and transient
deficits
(TIAs)
may occur in this disorder.
Treatment
with steroids
or other
immunosuppressive
agents
prove
most helpful.
Long-term
anticoagulation has not been studied.
Neurologic
complications
accompany
Kawasaki
disease
in I % of cases.
Hemiplegia
and seizures
have been reported.
Changes
indicative
of focal cerebral
infarction
have been observed
on cranial CT studies.
Finally,
the CNS may
be involved
in children
who have
hemolytic-uremic
syndrome
(HUS);
encephalopathy
is found in 20%.
Stroke
accompanied
by radiographic
evidence
of focal CNS injury has
been observed
in 5% of children
who
have HUS. Focal infarction
is found
primarily
in the cerebral
hemisphere
and basal ganglia.
Endothelial
cell
damage
due to the Shiga toxin produced
by the causative
Eschericia
coli 0157:H7
organism
is thought
to
activate
platelets
and coagulation
cascades,
culminating
in thromboembolic stroke.
Vasospasm
Stroke
may occur
migraine
headache.

Disorders
Associated
System Involvement

lupus

Migraine
headache,
seizures,
stroke, cerebellar
dysfunction,
transverse
myelopathy,
aseptic
meningitis

erythematosus

Mixed

connective

Polyarteritis

Wegener

Takayasu

With

CNS MANIFESTATIONS

DISORDER
Systemic

in the setting
of
The occurrence

tissue

disease

nodosum

granulomatosis

stroke, cerebellar
dystrigeminal
neuropathy

Migraine
arachnoid

headache,
stroke, subhemorrhage,
seizures

Migraine
headache,
hemorrhage,
stroke
Seizure,

arteritis

Henoch-Sch#{246}nlein

Seizures,
function,

purpura

stroke

Headache,

Pediatrics

subarachnoid

in Review

stroke,

seizures,

Vol. 17

Downloaded from http://pedsinreview.aappublications.org/ at Pakistan:AAP Sponsored on November 20, 2013

No.

chorea

August

1996

NEUROLOGY
Strokes
of focal motor deficits
during
a
migraine
headache
denotes
complicated migraine
Acute hemiparesis
has been well-documented
during
these episodes
and is believed
to
reflect
the involvement
of the cerebral circulation
derived
from the
carotid
artery.
Symptoms
such as
ataxia,
cortical
blindness,
and cranial
nerve dysfunction
correlate
with
involvement
of the vertebrobasilar
circulation.
Focal symptoms
may be
fixed or may occur as TIAs.
Initially,
an association
between
migrainous
stroke
and discharged
emboli
from
mitral
valve prolapse
was hypothesized, but recent
studies
have not supported
this theory.
Although
oral contraceptives
are associated
with hyper.

constriction
result.
The probability
of
SAH is higher
among
cocaine
users
who have occult
intracranial
aneurysms or arteriovenous
malformations
than among
those who have normal
cerebral
vasculature.
The resultant
sudden
rise in systemic
blood pressure is thought
to precipitate
SAH.
Ischemic
lesions
also have been
found in patients
who have used
cocaine.
Yet, the association
of these
ischemic
strokes
with cocaine
use is
less clear. The application
of cocaine
directly
to the vasculature
of animals
has caused
marked
vasoconstriction,
which
favors
vasoconstriction
as the
underlying
etiology
of ischemic
stroke
after cocaine
use. Nonetheless,
intracranial
hemorrhage
appears
to

Acute hemiplegia
may follow
a generalized
seizure
(Todd paralysis).
These are short-lived.
Preservation
consciousness
is not a feature
of generalized
seizures.

coagulability,
which
is thought
to predispose
to stroke,
the postulated
additive risk for stroke
in migraine
headache
among
those taking
oral
contraceptives
has been challenged.
Angiographic
studies
in patients
suffering
focal deficits
consistent
with
stroke
in the setting
of migraine
headache
have documented
vasoconstriction
of vessels
in either the vertebrobasilar
or carotid
circulations.
In
these cases,
the neuroanatomic
position of the constricted
vessels
correlated with the location
of the
observed
deficits.
As a result,
ischemia
provoked
by vasoconstriction during
prolonged
migraine
has
been hypothesized
as the mechanism
of stroke
in these patients.
Calcium
channel
blockers
have been used for
treatment,
but definitive
studies
of
their efficacy
are needed.
Drug abuse may promote
thrombotic stroke.
Cerebral
infarction
and
peripheral
neuropathy
have been
associated
with glue sniffing
in children, and cerebral
infarction
and
SAH have been observed
after
cocaine
use. Cocaine
blocks
the reuptake of catecholamines
at the synaptic
cleft. The resulting
elevated
synaptic
concentrations
of epinephrine
and
norepinephrine
markedly
enhance
the
neural
activity
of adrenergic
systems.
Tachycardia,
hypertension,
and vasoPediatrics

in Review

Vol.

17

No.

August

occur more commonly

infarction
among
those
Treatment
is supportive.
Hematologic

of

than ischemic
using cocaine.

Etiologies

Several
disorders
of coagulation
can
lead to embolic
or thrombotic
stroke.
Adverse
consequences
of antiphospholipid
antibodies
have been identifled in all age groups.
However,
children, adolescents,
and young
adults
manifest
the cerebrovascular
consequences
of these antibodies
most
often. Antiphospholipid
antibodies
are polyclonal
antibodies
found in
serum
that can bind to both neutral
and negatively
charged
phospholipids. The best studied
are the lupus
anticoagulant
(LAC)
and anticardiolipin antibodies
(aCL).
These
antibodies
first were associated
with
thrombotic
or embolic
cerebrovascular events
among
patients
who have
SLE. Subsequently,
patients
suffering
stroke
who had no evidence
of underlying immune-mediated
illness
other
than the LAC or aCL antibody
were
found.
The antibody
prolongs
the partial thromboplastin
time (PTT)
in
vitro, but acts as a procoagulant
in
vivo. The mechanism
by which
thrombosis
or embolism
occurs
is
still unclear,
but the presence
of these
antibodies
in a patient
who also
smokes
cigarettes
has a positive
anti-

nuclear
antibody
test, or suffers
from
hyperlipidemia
may impart
a higher
risk for stroke
than if the patient
carries the antibody
alone. The antibodys
presence
is indicated
by a prolonged
PTT and a false-positive
serum VDRL;
it can be demonstrated
conclusively
both functionally
and
immunologically.
The most common
location
for arterial
thrombosis
among
children
who have antiphospholipid
antibody
is the cerebral
circulation.
Cerebral
infarction
and
TIAs are neurologic
manifestations
observed
most frequently.
Therapy
for patients
who have antiphospholipid antibodies
and have suffered
stroke
has not been substantiated
fully by randomized
prospective
study, but low-dose
anticoagulation
has been advocated.
An absence
of specific
serum
proteins that act as inhibitors
of coagulation may lead to stroke
in children.
Deficiencies
of two of these proteins,
protein
S and protein
C, have been
associated
with thrombotic
or embolic cerebrovascular
disease
in the
young.
Protein
C and its cofactor
protein S act as anticoagulants
and synergistically
attenuate
coagulation
by
deactivating
the activated
forms of
factors
V and VIII. Absence
of either
of these proteins
will tip the scale of
balanced
coagulation
toward
increased
spontaneous
clotting,
which
can result in stroke.
Antithrombin-III
opposes
the action
of the activated
forms of factors
II, IX, X, XI, and XII
through
the irreversible
formation
of
inactivating
complexes
with these
factors.
Deficiencies
of proteins
S or
C or of antithrombin
III may cause
arterial
thrombotic
or embolic
stroke
or venous
infarction.
Although
these
deficiencies
often are congenital,
they
may be acquired
through
liver disease
or the nephrotic
syndrome.
Screening
tests, including
PT, PiT,
and specific
immunologic
and functional
testing
for the proteins
suspected
of being
deficient,
is essential
for diagnosis.
Malignancies
and their treatment
may predispose
children
to cerebrovascular
ischemic
events.
Promyelocytic leukemia
and its treatment
can
provoke
disseminated
intravascular
coagulation,
leading
to stroke.
Lymphoreticular
cancers
more than
solid tumors
have been linked
to
thrombotic
and embolic
strokes.
TIAs
following
induction
chemotherapy
for

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271

NEUROtY

acute lymphoblastic
leukemia
have
been reported.
In addition,
dural sinus
and cerebral
venous
thrombosis
have
been found after therapy
with Lasparaginase
(Fig. 2).
Oral contraceptives
have been
associated
with stroke
in young
women.
In some series,
the combination of migraine
headache
and concurrent
oral contraceptive
use has
been cited as a risk factor for stroke
(see earlier
discussion).
Pregnancy
and the postpartum
state have been
considered
periods
of hypercoagulability.
In addition,
venous
stasis
increases.
These
two factors
are
believed
to promote
the occurrence
of
cerebral
venous
thrombosis
and resultant cerebral
venous
infarction
in
pregnant
and immediately
postpartum
females.
Frequently,
the initial manifestation
is headache.
Seizures,
either
focal or generalized,
are common.
Acute hemiparesis
is the most common focal feature
on neurologic
examination.
Papilledema
can appear
as intracranial
pressure
rises due to
resultant
obstruction
of cerebral
venous
outflow.
The appearance
of
these signs or symptoms
in a gravid
or postpartum
adolescent
should
raise
suspicion
about the existence
of
underlying
cerebral
venous
thrombosis. If seizures
occur,
anticonvulsant
treatment
should
be initiated.
Once
the diagnosis
is confirmed,
anticoagulants should
be administered.
Finally,
insect stings have caused
focal
cerebral
infarction
in children.
Wasp
and scorpion
venom
activate
platelets,
promoting
thrombogenesis,
which can
culminate
in focal infarction.
Metabolic

Etiologies

Homocystinuria,
a disorder
of homocysteine
metabolism,
can cause
thrombotic
stroke
in children
(Table
3). Abnormal
homocysteine
metabolism
results
from one of three
heritable
enzymatic
defects.
The most
striking
phenotype
results
from deficiency
of cystathionine
synthetase,
the enzyme
that catalyzes
the catabolism of homocysteine
to cystathionme. Accumulation
of both homocysteine and methionine
results.
Children
affected
by this autosomal
recessive
disorder
manifest
marfanoid
habitus,
global
developmental
delay, lens dislocation,
and thromboembolism.
Serum
hyperhomocys272

a 9-year-old
boy treated
with L-asparaginase for acute lymphocytic
leukemia
who
experienced
new headache,
seizures,
and
lethargy.

Bright

sagittal
the

sinus

straight

denotes
venous

signal
(large

sinus

in the

superior

arrowheads)
(small

L-asparaginase-induced

and

in

arrowheads)
cerebral

thrombosis.

teinemia
injures
the vascular
endothehum, with the denuded
vessel
wall
becoming
a site for thrombosis.
The
resulting
thrombus
may remain
at its
site of origin or it may embolize
to a
distal locus. Therefore,
stroke
may
have thrombotic
or embolic
characteristics,
and both arterial
and venous
infarcts
may result.
Treatment
is
dietary
and aimed
at reducing
levels
of homocysteine
in serum.
Pyridoxine
administration
and methionine
restriction
are effective
as prophylactic therapy
for the deleterious
sequelae in 30% to 40% of treated
patients
who harbor
a defect
of cystathionine
synthase.
Sulfite
oxidase
deficiency,
another
autosomal
recessive
disorder
of sulfur
amino
acid metabolism,
results
in the
accumulation
of serum sulfites.
The
associated
phenotype
may be due to
deficiency
of either the enzyme
or its
associated
and essential
pterin-contaming
molybdenum
cofactor.
Mental
retardation,
seizures,
lens displacement, and acute hemiplegia
result.
The mechanism
of the stroke-like
episodes
has not been elucidated
fully. It is possible
that ischemic
mechanisms
are not involved
and that
direct metabolic
neurotoxicity
accounts
for the sudden
onset of
deficits
resembling
those of stroke.
Sulfites
and 5-sulfocysteine
accumulate in urine. Dietary
attempts
to
reduce
sulfite
accumulation
have
been unsuccessful.
Fabry disease,
a lipid storage
disease, is attributable
to ceramide
triPediatrics

hexosidase
deficiency.
It results
in
accumulation
of the sphingolipid,
tnhexoside,
in the kidney,
vascular
endothelium,
and cornea.
Symptoms
become
apparent
in childhood
or adolescence.
Angiokeratomas
and painful
paresthesias
often are the first symptoms, followed
by renal failure.
However,
the endothelial
accumulation of sphingolipid
in vessel
walls
may cause cenebnovascular
occlusion
and subsequent
stroke.
Recurrent
stroke
is not uncommon
in this rare
X-linked
disorder.
Supportive
care
and treatment
designed
to improve
renal function
and minimize
pain are
important.
Mitochondrial
disorders
may be
manifested
by recurrent
and sometimes catastrophic
stroke.
The syndrome
of MELAS
(mitochondrial
encephalomyopathy,
lactic acidosis,
and stroke)
presents
in childhood
and
is due to a mutation
of mitochondrial
DNA. The most common
biochemical
finding
is a deficiency
of complex
I
of the electron
transport
chain. An
elevated
level of lactate
in the serum,
or more consistently,
in the CSF, sup-

TABLE

3. Common

Genetic

Causes

of Stroke

Thrombotic/Embolic

Stroke

Homocystinuria
Fabry

disease

Sickle

cell disease

Fibromuscular

dysplasia

Hemorrhage
Factor

Vifi

Factor

LX deficiency

Factor

XI deficiency

Familial
Sickle

intracranial

cavernous

Organic

acidemia

Mitochondrial
from

RT. Mendelian

Neurol.

in Review

angioma

Mechanism

Unknown

Ann

aneurysms

cell disease

Familial

Adapted

deficiency

disorders
Natowicz
M, Kelley
etiologies of stroke.
22:1 98 7;1 73.

Vol. 17

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No.

August

1996

:
ports the diagnosis.
The diagnosis
can
be confirmed
from molecular
blood
analysis.
Although
some features
of
MELAS
are shared
by other mitochondrial
syndromes,
hemiparesis
of
abrupt
onset,
particularly
with hemianopia,
is characteristic
of this syndrome.
A maternal
family
history
of
migraine
is common.
Excruciating
headache
that resembles
migraine
usually
precedes
or accompanies
the
stroke-like
episodes.
Seizures,
sensorineural
hearing
loss, dementia,
and
short stature
usually
are present
at
some point in the course
of illness.
Because
the strokes
involve
the postenor
cerebrum,
hemianopia
or more
complex
visual defects
are characteristic. Neuropathologic
study of brain
from patients
who have MELAS
has
shown
cystic cavities
and necrosis
of
the cortex,
especially
the posterior
cerebrum,
with relative
sparing
of
white matter.
Other metabolic
disorders
have
been associated
with stroke
in childhood. Urea cycle defects,
especially
ornithine
transcarbamylase
deficiency
that presents
in hemizygous
girls, can
cause stroke.
Metabolic
disorders
such as these reflect
some of the heritable disorders
that are associated
with stroke
(Table
3).
EMBOLUS
Congenital
heart disease
remains
a
very common
cause of stroke
in
childhood.
Both the structural
cardiac
defects
and the complications
related
to corrective
surgery
contribute
significantly
to the occurrence
of stroke.
Children
who have cyanotic
congenital heart disease
face the greatest
risk.
The most common
cerebrovascular
event is embolic
stroke.
Cardiac
defects
involving
right-to-left
shunts
allow emboli
originating
in the
peripheral
circulation
to bypass
the
standard
filtration
and removal
by the
pulmonary
vascular
bed. Thus,
emboli
entering
the heart via venous
return
may be shunted
to the peripheral arterial
circulation,
only to lodge
in the cerebrovascular
tree (Fig. 3).
Patent
foramen
ovale (PFO)
contributes
significantly
to the occurrence of stroke in children
and young
adults.
Echocardiographic
evaluation
of young
patients
who have suffered
stroke
reveal
PFO or evidence
of
right-to-left
shunting
in more than

Pediatrics

in Review

Vol. 17

No.

August

three times as many patients

suffering
stroke
than control
patients.
Transesophageal
echocardiography
conducted
with Valsalva
bubble
studies
for evidence
of direct right-to-left
conduction
is the most useful
diagnostic test.
Congenital
valvular
defects
such as
aortic stenosis
and mitral
stenosis
can
result in stroke.
Rheumatic
valvular
disease,
once a common
cause of
embolic
stroke,
has become
infrequent,
but infected
valves
found in
subacute
bacterial
endocarditis
(SBE)
still pose considerable
risk. Infective
mitral
and aortic valvular
vegetations
may dislodge,
travel distally,
and ultimately
occlude
cerebral
arteries.
The
most common
organisms
found are
streptococci
and staphylococci.
Vegetation
still may embolize
and
cause stroke,
even after having
been
sterilized.
Finally,
emboli
from
infected
valvular
vegetations
may
lead to other vascular
lesions.
For
example,
emboli
may travel to the
cerebral
vasculature
and seed the
adventitia
of the cerebral
vessel.
The
resultant
infection
and inflammation
weakens
the vessel,
causing
development of a mycotic
aneurysm.
These
aneurysms
typically
occur in the distal cerebral
vasculature.
They may lie
dormant
for some time before
their
rupture
leads to SAH or IPH and
resultant
neurologic
signs (Fig. 4).
Recently,
focal cerebral
injury
related
to corrective
surgery
for con-

FIGURE

3. Axial

ing a hypodense
cerebral
sphere

focal

artery
from

tetralogy
seizures.

CTdemonstrat-

in the middle

territory

(arrowheads).

obtained
has

cranial

region

of the
This

a 4-month-old
of Fallot

and

left

study
infant
presented

hemi-

was
who
with

:NEUROLOGY

Strokes

genital
cardiac
defects
has been identified,
such as cerebral
vascular
accidents during
the Fontan
correction.
A
paradoxic
dissociation
of intravascular and mitochondrial
oxygenation
occurs
during
intraoperative
deep
hypothermic
cardiopulmonary
bypass
and circulatory
arrest,
which
may
provide
a clue to the cause of such
cerebral
injury.
Poor cellular
oxygenation,
particularly
at the mitochondrial
level, can be associated
with cerebral
injury.
Fat or air emboli
can ramify
in the
cerebral
vessels.
These
emboli
most
commonly
are formed
following
trauma involving
long bone fractures.
However,
both of these types of
emboli
have been associated
with
nontraumatic
conditions.
Fat emboli
have been observed
in association
with pancreatitis,
sickle cell disease,
connective
tissue diseases,
and intravenous
lipid administration.
Both fat
and air emboli
have been observed
after cardiopulmonary
bypass
surgery.
Because
fat or air emboli
occur as showers,
multiple
sites within the CNS may be involved.
As a
result,
impaired
consciousness,
sometimes accompanied
by delirium,
may
be observed.
Focal or lateralizing
neurologic
signs are apparent
in only
one third of patients.
HEMORRHAGE
Although
some coagulation
disturbances
may predispose
a patient
to
ischemic
stroke,
others
may promote
intracranial
bleeding.
Both A and B
hemophilias
are X-linked
disorders
that may result in intracranial
bleeding (Table
3). Bleeding
may occur in
either
intraparenchymal
or subarachnoid locations.
Hemophilia
A arises
from factor VIII deficiency.
Affected
males may experience
intracranial
bleeding
in association
with head
trauma.
Unfortunately,
spontaneous
intracranial
bleeding
unassociated
with head trauma
also occurs.
The
risk of spontaneous
bleeding
rises as
the severity
of factor VIII deficiency
increases.
Hemophilia
B derives
from
a deficiency
of factor
IX. Intracranial
bleeding
is less frequent
in these
patients
than in those who have
hemophilia
A. The less frequent
occurrence
of hemophilia
B compared with hemophilia
A may account

1996

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273

NEUROLOGY
Strokes

FIGURE
seining

4. Mycotic

cerebral

intraparenchyinal

cerebral

artery

tree

cerebral

artery

(straight

neuroradiologic
coven

of low-grade

aneurysm

hetnorrimage.

C. Anterior-posterior

(arrows).

studies
fever

hemorrhage.
B. Cerebral

arrow),
were
and

which
performed
a cardiac

angiographic

is located

lateral

on a boy

who

to the
presented

CT reveals
in lateral

view
more

hvperdense
view

shows

confirms

medially

with acute

region

the location
located

onset

in left temporal

oft/ic

anterior

of aphasia

lobe (arrowheads),
repreabnormality
in the timiddle

vascular

lobulated

vascular

cerebral
and

rig/it

in the middle

abnor,nalitv

artery
hemipare.sis

(curved

arrow).
2 weeks

These
after

the dis-

murmur

for the less frequent

observation
of
intracranial
bleeding.
Clinical
symptoms depend
on the intracranial
location of the hemorrhage.
If the bleeding occurs
in the subarachnoid
space,
severe
headache,
nuchal
rigidity,
and
meningismus
occur.
Mental
status
frequently
is altered.
If bleeding
occurs
within
brain parenchyma,
focal clinical
features,
including
hemiparesis,
may be observed.
Severe
thrombocytopenia
leads to
cerebral
hemorrhage
in very few
patients.
Significant
risk of IPH
appears
to occur only at platelet
counts
of 20,000/mm3
or less. Small
petechial
hemorrhages
into white
matter
are more common
than large
parenchymal
hemorrhages.
Causes
of
thrombocytopenia
include
idiopathic
thrombocytopenic
purpura,
infection,
and malignancy.
The features
of these
underlying
causes
dominate
the clinical picture.
SAH occurs
among
children
who
have sickle cell disease,
although
the
frequency
is less than that of infarction, occurring
in fewer
than 2% of
patients.
The ruptured
cerebral
aneurysm
that frequently
is found
in
adult sickle cell patients
who have
SAH is absent
in children.
Clinical
findings
include
severe
headache,
vomiting,
and altered
mental
state.
Meningeal
signs and focal neurologic
deficits
may be found on examination. Angiography
usually
should
be
performed
to detect
any surgically

274

A. Cranial
angiography

correctable
vascular
lesion
underlying the hemorrhage.
Medical
therapy
consisting
of transfusion
therapy
has
been suggested.
Arteriovenous
malformation
(AVM)
of the brain is the most common cause of intracranial
hemorrhage
in preadolescent
children
and is more
common
in males than females.
This
developmental
anomaly
presents
with
hemorrhage
more frequently
in children than in adults.
The AVM consists of dilated
vascular
channels,
some of which exhibit
the highly
muscularized
walls of arterioles.
Gliotic
neural
tissue resides
in and
among
the vascular
branches
of the
malformation.
The most frequently
observed
events
associated
with AVM
in children
are seizures
and hemorrhage. The vast majority
of AVMs are
located
in the cerebral
hemispheres,
with 10% arising
in the posterior
fossa. The clinical
feature
of hemorrhage due to AVM may be acute onset
of focal neurologic
deficit,
according
to the area of brain in which the hemorrhage
has occurred.
Children
who
have AVM complicated
by hemorrhage have a higher
mortality
rate
than adults.
The risk of hemorrhage
from an unruptured
AVM approximates 3% per year.
Intracranial
aneurysms
are a common cause of intracranial
bleeding
in
patients
younger
than 20 years of age.
Saccular
aneurysms
are more frequent among
males than females.
Unlike
aneurysms
in adults,
the most
Pediatrics

common
site of bleeding
in children
is along the intracranial
portion
of the
internal
carotid
artery;
the vertebral
and basilar
arteries
are other common
sites. Intracranial
aneurysms
in children tend to be larger than those
found in adults.
Most aneurysms
are
due to vascular
developmental
anomalies, but there are other causes.
Disorders
of connective
tissue,
such
as Ehler-Danlos
syndrome
and
Marfan
syndrome,
are associated
with
the formation
of saccular
cerebral
aneurysms.
Intracranial
aneurysms
are more common
among
patients
suffering
from polycystic
renal disease and those who have aortic coarctation.
Patients
should
be observed
closely
for complications
associated
with subarachnoid
bleeding
from
aneurysm
rupture.
Hydrocephalus
causing
increased
intracranial
pressure may occur subsequently.
Aneurysmal
bleeding
that results
in
significant
SAH can precipitate
cerebral vasospasm,
which
in turn can
cause secondary
cerebral
infarction.
Vasospasm
occurs
most commonly
7
to 10 days after the hemorrhage.
DIAGNOSIS
Once stroke
is suspected,
diagnostic
efforts
concentrate
on documenting
the occurrence
and discovering
the
underlying
cause.
Neuroradiologic
and laboratory
evaluation
are conducted
simultaneously.
A suggested
format
for diagnostic
evaluation
is

iii

Review

Vol. /7

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No.

August

1996

NEUROLOGY
Strokes
-

Radiologic

Evaluation
I. MRI
2. CCT

$4

Laboratory

Evaluation

CNS

Infarction

$4

Subarachnoid
blood

1. CBC

Cardiac

& differential

2. Platelet

count

murmur

found

definition

cerebral

3. PTfPT
4. Electrolytes
6. CSF

examination:

total protein, glucose,

lactate, pyruvate
7. Blood

Li

cell count, cultures,

cultures

of
vasculature

needed

screen

found

Additional

suspected

or PFO

5. Toxicology

or

intraparenchymal

Echocardiography

I. MRA
2. Percutaneous
angoigram

$4
I. ANA/RF
2. Coagulation
including

panel
protein

S. C,

& antithrombin

III

assays
3. Antiphospholipid
body

anti-

& lupus anti-

coagulant
4. Serum

assays
amino

5. Lysosomal

acids
storage

enzymes

FIGURE

5. Diagnostic

CBC

complete

clear

antibody;

evaluation

blood
RF

count;
rheumatoid

of stroke

PT

factor;

provided
in Figure
5. CCI
and MRI
provide
rapid, topographic
evidence
of infarction
or intracranial
hemorrhage.
CCT images
are acquired
more
rapidly
than MRI and provide
clear
evidence
of acute intracranial
hemorrhage.
MRI, which provides
greater
resolution
and structural
detail than
does CCI,
demonstrates
smaller
infarctions.
The emerging
capability
of diffusion-weighted
MRI permits
visualization
of CNS infarction
very
early in its course.
This technique
focuses
on the molecular
motion
of
water rather than on 11W, 12W, or
contrast-enhanced
images.
An
increase
in intracellular
water associated with a reduction
in intracellular
Pediatrics

in Review

Vol. /7

No. 8

in children:

prothrombin

August

time:

MRI4

MRI

PiT

magtzetic

=
magnetic
resonance
partial
thromboplastin

resonance

imagitig;
time: CSF

CCT
=

cranial

cerebrospinal

computed
fluid;

tomography;
ANA

antinu-

angiographi

transport
functions
occurs
soon after
hypoxic-ischemic
cerebral
injury has
occurred,
and diffusion-weighted
MRI can visualize
the differences
in
water flux between
normal
and damaged cerebral
tissue before
changes
can be detected
by conventional
MRI.
Magnetic
resonance
angiography
(MRA)
yields
reliable
information
about blood flow in and structure
of
large cervical
and intracranial
vessels; small intracranial
vessels
are
visualized
poorly.
Invasive
angiography remains
the neuroradiologic
procedure
of choice
when detailed
knowledge
of the cerebral
vasculature
is required.
Initial
laboratory
tests should

screen
for hematologic
conditions
that predispose
a child to stroke.
In
addition,
laboratory
evidence
of
inflammatory
processes
should
be
sought.
Serum
electrolytes
will provide initial evidence
of a metabolic
acidosis
that may accompany
a mitochondrial
disorder
or an organic
acid
disturbance.
A toxicology
screen
should
be performed
if drug-induced
stroke
is suspected.
A lumbar
puncture should
be performed
for cerebrospinal
fluid examination
if CNS
infection,
inflammation,
or neoplastic
involvement
is suspected.
The lumbar
puncture
should
not be performed
if
the physical
examination
findings
or
neuroimaging
indicate
the presence

1996

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275

NEUROLOGY
kes
of a space-occupying
abnormality
causing
increased
intracranial
pressure. Performing
this procedure
in a
patient
who has such a unilateral
supratentorial
or cerebellar
lesion
could precipitate
transtentorial
or
transmagnal
herniation,
respectively.
If a stroke has been documented
clinically
and radiologically,
but the
initial panel of laboratory
tests has
yielded
normal
results,
additional
testing is warranted
(Fig. 5). Evidence
of
coagulopathy,
systemic
inflammation,
and lupus anticoagulant
should
be
sought.
CSF lactate and pyruvate
1evels should
be obtained,
even if serum
levels are normal,
if a mitochondrial
disorder
is suspected.
If the clinical
data suggest
a lysosomal
storage
disease or sulfite oxidase
deficiency,
the
appropriate
urine or blood tests should
be performed.
Echocardiography
should
be performed
if the child who
has sustained
a stroke also has a cardiac murmur.
Indeed,
if there is strong
clinical
suspicion
of a PFO, echocardiography
with bubble
contrast
should
be performed.
Currently,
approximately 30% of all cases of stroke in children appear
to be idiopathic.
TREATMENT
Resolution
of the disorder
underlying
a stroke
in children
is the most effective long-term
therapy.
Correcting
cardiac
defects
that contribute
to
embolus
formation
is crucial.
Treatment
with anticoagulants
may
be necessary
for children
who have
chronic
valvular
abnormalities
or in
those exposed
to right-to-left
shunts
for long periods.
The efficacy
of warfarm as an anticoagulant
is well
established;
the drug commonly
is
employed
for this purpose
in adults.
However,
it must be used judiciously
in children
because
there is a greater
probability
of trauma
and drug-related bleeding.
Prophylactic
therapy
remains
the
cornerstone
of therapy
for thrombotic
stroke.
Exchange
transfusion
designed
to diminish
the fraction
of
blood composed
of hemoglobin
5containing
red blood cells (RBCs)
reduces
the risk of recurrent
strokes
among
children
who have sickle cell
anemia.
Recent
clinical
trials have
shown
that hydroxyurea
can increase
the level of fetal hemoglobin-contain-

276

ing RBCs in those who have sickle

cell disease.
Although
this use of
hydroxyurea
remains
investigational,
it may reduce
the occurrence
of
stroke
among
those who have sickle
cell disease.
Stroke
due to coagulation factors,
such as protein
5, protein
C, or antithrombin
III, are treated
best with anticoagulation.
It has not
yet been determined
whether
warfarin
or steroid
therapy
is more effective
prophylactic
therapy
for stroke
among
patients
who have symptoms
of the lupus anticoagulant
(or
antiphospholipid
antibody);
recent
data favor the use of warfarin.
Cerebral
infarction
due to air or fat
emboli
is treated
best with systemic
steroids.
In general,
there is no effective
therapy for the metabolic
diseases
that
may lead to recurrent
stroke,
and they
have a poor prognosis.
However,
there
is palliative
treatment
for homocystinuria that involves
the reduction
of systemic homocysteine.
Some patients
respond
to 100 to 500 mg/day
oral vitamin B6 (pyridoxine)
therapy.
Those
who do not respond
should
be placed
on a low methionine
diet. Strict metabolic control
correlates
with reduction
of stroke occurrence.
Initially,
treatment
of vascular
malformations
consisted
of anticonvulsant therapy
for secondary
seizures.
Surgery
was reserved
for those AVMs
that bled at presentation.
MRI has
allowed
better
localization
of these
malformations,
and percutaneous
selective
embolization
of part or of
the entire AVM has permitted
resection in situations
considered
previously to be inoperable.
AVMs in critical regions
of the CNS that are not
amenable
to surgery
have been treated with stereotactic
radiosurgery
with
promising
results.
Radiation
damage
to the CNS has complicated
the
recovery
of approximately
3% of
patients.
Medical
treatment
of ruptured aneurysms
focuses
on maintaining blood pressure
through
intravascular volume
expansion;
such treatment can reduce the incidence
of posthemorrhagic
vasospasm.
Early enthusiasm for treatment
with calcium
channel
blockers
has been dampened
by failures
in prospective,
randomized clinical
studies.
The optimal
treatment
of moyamoya
disease
has

not been determined.

Calcium
channd blockers
have been reported
to
increase
collateral
vessel diameter,
improve
perfusion,
and ameliorate
neurologic
symptoms.
Several
surgical procedures
designed
to re-establish effective
perfusion
of endangered
brain have been performed
with
encouraging
results
in small numbers
of patients,
but additional
study and
experience
are required.

Conditions
That
Mimic Stroke

May

Acute hemiplegia
most frequently
indicates
stroke,
but a history
and
physical
examination
consistent
with
the occurrence
of stroke are critical
to
the diagnosis.
Because
stroke
occurs
most often in children
as a consequence
of an underlying
process,
circumspect
evaluation
of the childs
condition
for such a predisposing
condition
will increase
the accuracy
of the diagnosis.
Not all instances
of acute onset of
hemiplegia
or other focal deficits
represent acute cerebrovascular
events
(Table 4). Hemiparetic
seizures
that
are characterized
by acute lateralized
weakness
and preserved
mental
state
may be a form of partial
epilepsy.
In
addition,
seizures
can be followed
by
a postictal
(Todd)
paralysis
that may
mimic
the motor deficit
of stroke.
Seeking
a history
of previous
seizures
is essential.
A postictal
paralysis
is
short-lived
and not associated
with
neuroradiologic
characteristics
of
recent
stroke.
Preservation
of consciousness,
a feature
not shared
by

TABLE

4. Other

Conditions
That May
Postictal

in Childhood
Mimic
Stroke

Todd

Hemiparetic

paralysis
seizures

Subdural/Epidural

hemorrhage

Hypoglycemia
Anemia
Alternating

hemiplegia

of

childhood
Multiple

Pediatrics

in Review

sclerosis

Vol. 17

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No.

August

1996

generalized
seizures,
may help differentiate
between
epilepsy
and cerebrovascular
events.
The diagnosis
of
seizure
remains
clinical,
but EEG
may help to establish
its occurrence.
Subdural
and epidural
intracranial
hemorrhages
may mimic
stroke.
Because
they are located
adjacent
to
the relatively
nondistensible
skull, if
they are sufficiently
large, they will
exert pressure
on the brain, causing
motor or sensory
deficits
that conespond to the affected
cerebral
area.
Neuroimaging
permits
definitive
diagnosis.
If no parenchymal
injury
accompanies
the hemorrhage,
prompt
neurosurgical
evacuation
is effective.
Metabolic
disturbances,
such as
hypoglycemia,
may cause focal
motor
deficits
resembling
stroke.
Similarly,
transient
hemiparesis
unassociated
with radiologic
changes
typical of stroke
have been observed
in
children
who have juvenile
diabetes
mellitus.
Therefore,
surveying
for
conditions
that include
these metabolic disturbances
is important
via
serum electrolyte
and glucose
levels.
Similarly,
severe
anemia
causing
reduced
oxygen
delivery
to the brain
may result in evanescent
focal motor
deficits;
thus, evaluation
of an hematocrit is essential
for any patient
suspected
of having
suffered
stroke.
Alternating
hemiplegia
of childhood (AHC)
may simulate
stroke
in
children.
This disorder
usually
occurs
sporadically,
but familial
cases have
been described.
The first symptoms
of AHC appear
before
the age of 18
months.
Repeated
episodes
of lateralized hemiplegia
are most common,
but bilateral
hemiplegia
may occur.
Hemiplegic
attacks
may last for a few
minutes
to a few days. Extrapyramidal
symptoms,
oculomotor
dysfunction,
and dysautonomic
features also may be present.
Symptoms
disappear
during
sleep. Finally,
developmental
delay or mental
retardation
is present
in virtually
all cases.
Flunarizine,
a calcium
channel
blocker, has shown
some promise
in its
apparent
ability
to reduce
the frequency
and duration
of hemiplegic
attacks,
but experience
is limited.
Further
study of potential
therapies
is
necessary.

Conclusion
Focal cerebral
infarction
occurs
among
children
of all ages. Thus, it is
important
to recognize
the signs of
stroke
in neonates
as well as in older
children.
The causes
of stroke
may be
thrombotic,
embolic,
or hemorrhagic.
Most commonly,
pediatric
stroke
is
caused
by structural
abnormalities
of
cerebral
vasculature,
inflammatory
conditions
that involve
cerebral
yessels, or congenital
heart disease.
Diagnosis
still relies heavily
on clinical recognition
of the cardinal
signs
of focal cerebral
injury.
Topographic
determination
of the injured
cerebral
area has been enhanced
appreciably
by the advent
of neuroradiologic
methods
such as MRI. Nonetheless,
several
disorders
may mimic
presentation of focal cerebral
infarction;
differentiating
them from stroke
depends
heavily
on an accurate
history
and physical
examination.

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Causes
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R, McKie
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Pm

278

(AAP)

is accredited

A.

Anisocoria.

B.

Bulging
fontanalle.
Decerebrate
posturing.
Focal seizures.
Hemiparesis.

2.

3.

D.
E.
4.

Which
one of the following
disorders of amino acid metabolism
carries the greatest risk of cerebrovascular
occlusion?
A. Hartnup
disorder.
B. Homocystinuria.

Which
one of the following
therapies is most useful
in the management of cerebrovascular
occlusion
in a child who has sickle cell disease?
A.
B.

Coticosteroids.
Exchange
transfusion.

c.

Heparinization.

D.
E.

Streptotinase
infusion.
Surgical
thrombectomy.

Which

ications
pose
sis

5.

Maple

D.
E.

Phenylketonuria.
Tyrosinosis.

C.

thrombo-

C.

syrup urine disease.

Deficiency
of which of the following is associated
with an increased
risk of thrombotic/embolic
cerebrovascular
disease?
A. Factor
V.
B. Fibrinogen.

one of the following

medis most likely to predis-

to cerebrovascular

Albuterol.
Aspirin.
Nifedipine.
Oral contraceptives.
Theophylline.

C.

most common clinical manifestation

of stroke
in a full-term
newborn
is:

D.
E.

A.
B.

The

C.

Plasminogen.

D.

Platelet

activating

E.

Proteins

C and S.

factor.

Credit

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for acute lymphoblastic

J Pediatr
1993;l23:7l8-724

Ravelli
A, Martini
A, Burgio
0. Antiphospholipid antibodies
in paediatrics.
EurJ
Pediatr
1994; 153:472-479
Rivkin
M, Anderson
M, Kaye E. Neonatal
idiopathic cerebral
venous
thrombosis:
an unrecognized
cause of transient
seizures
or lethargy. Amimi Neural.
1992:32:51-57
Scott M, Barnes
P. Kupsky
W, Adelman
L.
Cavernous
angiomas
of the central
nervous
system
in children.
J Neurosurg.
1992:76:38-46
Sigal L. The neurologic
presentation
of vasculitic
and rheumatologic
syndromes.
Medicine.
l987;66:
157-180
Siegler
R. Spectrum
of extrarenal
involvement
in postdiarrheal
hemolytic-uremic
syndrome.
J Pediatr
l994;125:Sll-5l8
Simioni
P. Battistella
P. Drigo P. et al.
Childhood
stroke associated
with familial
protein
S deficiency.
Brain Devel.
1994:16:241-245
Warach
5, Chien D, Li W, et al. Fast magnetic
resonance
diffusion-weighted
imaging
of
acute human
stroke.
Neurolog
1992:42:1717-1723

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No. 8

August

1996

Strokes in Children
Michael J. Rivkin and Joseph J. Volpe
Pediatrics in Review 1996;17;265
DOI: 10.1542/pir.17-8-265

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