68  Stroke in Children

Meredith R. Golomb, José Biller

CHAPTER OUTLINE rate of arterial ischemic stroke around 1 in 4000 neonates

(Lynch and Nelson, 2001). Laugesaar et al. (2007) looked at
all prospectively and retrospectively diagnosed perinatal
STROKE AND THE DEVELOPING CEREBROVASCULAR stroke in Estonia and found a rate of 1 in 1587 live births.
SYSTEM DeVeber and colleagues (2001) found a rate of 0.67 cases of
EPIDEMIOLOGY cerebral venous thrombosis (CVT) per 100,000 children per
Full-Term and Near-Term Neonates year, with neonates making up 43% of cases; rates were not
The General Population of Children described in relation to the number of term births.
Chapter 111 discusses cerebral vascular injury in the prema-
High-Risk Subgroups
ture neonate.
PRESENTATIONS
ETIOLOGY The General Population of Children
Cardiac
Estimates of the incidence of all pediatric stroke in the United
Hematological
States and France have ranged from 2.6 to 13 cases per 100,000
Trauma and Vascular Compression children per year (Giroud et al., 1995), with some variation
Infection among studies on the inclusion of neonates, traumatic strokes,
Vascular Malformations/Vasculopathy/Migraine and meningitis, and whether to use 16 or 18 as the cutoff age
Drugs/Toxins for pediatric stroke. A review of 13 years of data in New Jersey
Metabolic found a stroke incidence of 2.24 per 100,000 per year, with
Gender and Ethnicity roughly equal rates of ischemic and hemorrhagic stroke
Genetic (Gandhi et al., 2012),
DIFFERENTIAL DIAGNOSIS
EVALUATION High-Risk Subgroups
History and Physical Certain subgroups of children are at high risk for stroke, with
Imaging Studies rates approaching or surpassing those in older adults. Medical
Coagulation Workup conditions may place children at risk for intracranial hemor-
Cardiac Evaluation rhage, ischemic stroke, or both.
Some types of central nervous system (CNS) vascular mal-
Other Studies
formations (e.g., arteriovenous malformations, telangiecta-
TREATMENT sias) are part of well-known neurocutaneous syndromes such
The Acute Period and Initiating Chronic Therapy as Sturge Weber, Osler–Weber–Rendu, Louis–Bar syndrome,
Additional Issues in Chronic Therapy Wyburn–Mason syndrome, and Klippel–Trenaunay syndrome.
Other Issues Vascular malformations may present with intracranial hemor-
rhage. A review of 22 cases of spontaneous intracranial hemor-
SUMMARY rhage seen over 10 years at two Swiss hospitals found that 55%
had arteriovenous malformation (Fig. 68.1), 18% had aneu-
rysm, 14% had cavernous malformation, and 14% had unclear
etiology (de Ribaupierre et al., 2008). Cavernous malforma-
tions and aneurysms may be genetic and can present in child-
STROKE AND THE DEVELOPING hood. Risk varies depending on the mutation involved (Denier
CEREBROVASCULAR SYSTEM et al., 2006). Brain aneurysms are rare in children and are
often dysplastic. The carotid bifurcation is the most common
Unlike adults, in most children with stroke, conditions such
site for pediatric intracranial aneurysms, followed by the pos-
as diabetes and hypertension make little contribution to the
terior circulation. Intracranial hemorrhage may lead to vaso­
etiology of stroke. Developmental, genetic, and environmen-
spasm and resultant ischemic stroke, but this is less common
tal factors are the major contributors to cerebrovascular injury
in children than in adults (Menkes et al., 2000).
in children.
Children with bleeding disorders are at high risk for intra­
cerebral hemorrhage. A study of intracranial hemorrhage in
EPIDEMIOLOGY Italians with hemophilia found the highest rate during the first
year of life, 24.4 per 1000, with a drop to 14.9 per 1000 in the
Full-Term and Near-Term Neonates second year of life (Zanon et al., 2012).
Neonates appear to be at higher risk for stroke than older Children with sickle cell anemia are at risk for ischemic
children. Asymptomatic subdural hemorrhage affects almost stroke because sickling red blood cells may lead to thrombosis
half of term neonates and can occur in infants delivered by or endothelial injury and in some patients are associated with
both vaginal and cesarean delivery (Rooks et al., 2008). Symp- moyamoya syndrome (Pegelow, 2001; Pegelow et al., 2002)
tomatic intracranial hemorrhage affects 1 in 100 full-term (Fig. 68.2). The rate of stroke in children with sickle cell
neonates (Gradnitzer et al., 2002). Most estimates place the anemia has dropped since the institution of transfusion

996
 Stroke in Children 997

68

A B C D
Fig. 68.1  Axial and coronal T2W MRI and AP and lateral views of catheter cerebral angiography of a 17-year-old female with a left
thalamic arteriovenous malformation (Grade III Spetzler–Martin) fed from the PCA territories bilaterally.

A B C
Fig. 68.2  Magnetic resonance imaging (MRI) of a 10-year-old girl with sickle cell anemia. A–C, At age 5, she presented with a left hemi-
paresis. MRI then showed acute ischemia in the right middle cerebral artery (MCA) territory and chronic ischemic changes in the left cerebral
hemisphere. Magnetic resonance angiography (MRA) showed stenoses in both anterior circulations. These stenoses progressed over time, and
she was treated with pial synangiosis and burr holes. There was no clear progression of ischemic lesions. A, MRA demonstrates complete occlu-
sion of the left M1 segment of the MCA (solid arrow), and severe stenosis of the M1 segment of the right MCA (open arrow) and both A1 seg-
ments of the anterior cerebral arteries. There are multiple small vessels at the stenotic sites consistent with moyamoya. There appears to be an
anastomosis between the left superficial temporal branches and the distal left M1. B, C, Fast spin echo inversion recovery MRI demonstrates
multiple old infarcts in the bilateral frontal and parieto-occipital regions and centrum semiovale.

therapy (see the later section Treatment). In California, the
incidence of first stroke in children with sickle cell anemia
dropped from 0.88 per 100 person-years to 0.17 per 100
person-years (Fullerton et al., 2004); however, approximately
30% of children aged 5–15 years old have silent infarcts
(DeBaun et al., 2012). Children with sickle cell anemia may
also develop aneurysms and resultant intracranial hemor-
rhage, but this is more common in adults with sickle cell
anemia (Pegelow, 2001).
Children treated with mechanical circulatory support are
at increased risk for both intracranial hemorrhage and embolic
ischemic stroke. The rates of infarction after extracorporeal
membrane oxygenation (ECMO) vary dramatically among
series, ranging from 0% to 26%; one study examined the
brains of 44 patients who died while on ECMO and found
evidence of focal ischemic infarct in 50% and intracranial
hemorrhage in 52%. A recent large study of ECMO survivors
found cerebral infarction in 7% and intracranial hemorrhage
in 7% (Barrett et al., 2009). Stroke occurred in 7 of 17 treated
children (41%) at one center that started to use the Berlin
Heart EXCOR ventricular assist device (Rockett et al., 2008);
however, the incidence of strokes with the EXCOR dropped
with institutional experience (Byrnes et al., 2013).
Children with complex congenital heart disease are at
risk for cardioembolic stroke, thrombotic stroke, watershed
infarcts from drops in perfusion pressure, and cerebral venous
thrombosis (CVT) (Fig. 68.3). The rates of stroke in children
with complex congenital heart disease also vary among series,
with some of the variation due to the severity of the malforma-
tion, the number of corrective surgeries required, anesthetic
techniques during surgery, patient selection, and length of
follow-up. A large Canadian study looked at 5526 children
who underwent cardiac surgery and found a stroke rate of 5
per 1000 children (Domi et al., 2008). Mayer and associates
(2002) found evidence of cerebrovascular complications in 5
of 77 (6.5%) pediatric patients with heart transplants and an
average of 59.2 months of follow-up; 25 of the 77 patients
(32.5%) died. The greatest risk for children with congenital
heart disease occurs at the time of surgery or cardiac catheteri-
zation. One study found that 27% of children with stroke
associated with cardiac disease had recurrent stroke. Mechani-
cal heart valves, prothrombotic conditions, and infection at
the time of first stroke all raised the risk of stroke recurrence
(Rodan et al., 2012).
Children with cancer are at risk for both intracranial hem-
orrhage and ischemic infarction. Intracranial hemorrhage
occurs secondary to thrombocytopenia from bone marrow
suppression or bleeding within the tumors. Children with
cancer may develop ischemic infarction or CVT due to
leukostasis in the setting of leukemia; complications of
998 PART III  Neurological Diseases and Their Treatment

A B
Fig. 68.3  Magnetic resonance imaging (MRI) of a 3-year-old girl with a history of complex congenital heart disease. At age 10 months,
she had a procedure to repair a double inlet left ventricle and left transposition of the great arteries. She presented with seizures and dysconjugate
gaze 3 weeks later, and an acute right pontine infarct was diagnosed. Magnetic resonance angiography and catheter angiography demonstrated
narrowing of the distal basilar artery and the right superior cerebellar artery. At age 3, she presented with acute left hemiparesis and the following
imaging: diffusion-weighted MRI (A) and fast spin echo inversion recovery MRI (B) demonstrate multiple infarctions in the right temporal lobe,
inferior parietal region, and lentiform nucleus, consistent with cardioembolic stroke.

A B
Fig. 68.4  Magnetic resonance imaging (MRI) of an 8-year-old boy with leukemia who developed headaches and left hand numbness
during induction chemotherapy with L-asparaginase. A, Fast spin echo inversion recovery MRI demonstrates multifocal bilateral hemorrhagic
infarctions. B, Magnetic resonance venogram demonstrates irregularity of the superior sagittal sinus consistent with thrombosis (arrow).

chemotherapy such as L-asparaginase, which cause decreases
in antithrombin, fibrinogen, and plasminogen; fungal or bac-
terial meningitis leading to arteritis; vasculopathy secondary
to radiation; or complications of intracranial surgery (Fig.
68.4). Stroke affects approximately 1% of children with cancer,
most commonly children with leukemia or brain tumors
(Noje et al., 2013). One institutional study found that 4% of
children treated with cranial and/or cervical radiation had
stroke during the 10 years after radiation (Mueller et al., 2013).
Children with certain syndromes are predisposed to stroke,
sometimes for multiple reasons. Children with Down syn-
drome have higher-than-average rates of leukemia, which in
turn may lead to hemorrhagic stroke; moyamoya vasculopa-
thy, which may lead to ischemic or hemorrhagic stroke;
complex congenital heart disease, which may lead to cardio­
embolic stroke; and atlantoaxial instability and other
abnormalities of the cervical spine, which increase risk for
vertebral artery dissection. Children with neurofibromatosis
type 1 have higher-than-average rates of moyamoya and other
occlusive vasculopathies that are sometimes but not always
associated with radiation. Connective tissue disorders such as
Marfan and Ehlers–Danlos syndromes and pseudoxanthoma
elasticum may predispose to cervicocephalic arterial dissection
or aneurysmal dilatation. Metabolic syndromes that damage
the endothelium (e.g., homocystinuria, Fabry disease, familial
hyperlipidemia) may predispose to vascular damage and
thrombosis.
PRESENTATIONS
Seizures are the most common manifestation of intraventricu-
lar hemorrhages (IVH), arterial ischemic strokes, and CVT in

term neonates. Seizures are a presenting sign for 65% of term
neonates with IVH, at least 80% of term neonates with arterial
ischemic stroke (Volpe, 2001), and over 50% of neonates with
CVT (Fitzgerald et al., 2006). Other presenting signs include
apnea, irritability, jitteriness, lethargy, and bulging fontanel.
The immature central nervous system may not demonstrate
focal signs, and hemiparesis may not be apparent until a child
is older than 6 months of age.
Children older than 6 months of age may present with
seizures or focal signs similar to those seen in adult stroke,
with hemiparesis, ataxia, or aphasia. Children younger than 1
year of age are more likely to present with seizures and altered
mental status, whereas children older than 1 year of age are
more likely to present with focal motor signs (Zimmer et al.,
2007). Although severe headaches such as those in intracranial
hemorrhages often prompt parents to seek medical attention
immediately, most children arrive at the emergency room
more than 6 hours after the event (Gabis et al., 2002). Parents
may not detect focal motor weakness in a young child who
has not yet started to walk or aphasia in a young child who is
just starting to speak. Parents may interpret the sudden onset
of focal neurological signs as behavioral rather than neuro-
logical. It can be easier to detect focal neurological signs and
symptoms in older children, but these are also often missed
in the first minutes to hours, possibly because many parents
and children do not realize children can have strokes. Some
children may have no symptoms or only gradual onset of
developmental delay. While silent strokes are recognizable in
the sickle cell population, and several studies have screened
for them, the rates of silent infarction in other cerebrovascular
disorders are unclear because radiological investigations are
lacking in the absence of clinical manifestations.
ETIOLOGY
Cardiac
Complex congenital heart disease may lead to thrombosis
and ischemic stroke through several mechanisms. Abnormal
cardiac anatomy or associated cardiac arrhythmias lead to
abnormal flow and may predispose to the formation of int-
racardiac thrombi. Septal defects may lead to right-to-left
shunts that allow venous thrombi to cross to the arterial side
and cause cerebral infarction. Surgery and cardiac catheteriza-
tion can disrupt the endothelium and lead to thrombosis.
Cardiac surgery itself may lead to a temporary prothrombotic
state (Petaja et al., 1996). An abnormal heart valve can serve
as a nidus for bacterial or fungal vegetations that may cause
cardioembolic stroke. Chronic hypoxemia in severe cases of
congenital heart disease may lead to polycythemia, and the
increased blood viscosity may promote thrombosis. Aortic
coarctation may be complicated by infective endarteritis or
ischemic or hemorrhagic strokes, including brain aneurysms.
Based on autopsy findings, a patent foramen ovale (PFO) is
found incidentally in 20%–35% of the general population.
Although a PFO is more common in patients with cryptogenic
stroke than in the general population, the relationship between
a PFO and ischemic strokes without a clearly identifiable
source in both children and adults remains controversial.
Hematological
Any hematological disorder that disrupts coagulation can
place a child at risk for hemorrhagic stroke. Newborns have
lower levels of coagulation factors and have a drop in the
vitamin K-dependent factors in the first days of life. Bleeding
due to vitamin K deficiency was more common before
intramuscular or oral administration to neonates became
Stroke in Children 999
widespread; Cornelissen and colleagues (1996) found that
administering vitamin K lowered the incidence of vitamin K 68
deficiency bleeding from 7 to 1.1 per 100,000 births per year.
However, late-onset vitamin K deficiency bleeding can occur
in children with undiagnosed cholestatic jaundice who
received oral vitamin K and are exclusively breastfed, because
they cannot absorb the vitamin, and breast milk is low in
vitamin K (Ijland et al., 2008). Schulte and colleagues (2014)
reported a rise in late-presentation vitamin K deficiency bleed-
ing in Tennessee because parents were refusing vitamin K,
believing it was unnecessary or that the vitamin K injection
included “toxins.” Accidental ingestion or overdose of warfa-
rin has the same effect as a vitamin K deficiency and may occur
when a young child finds an older family member’s medica-
tions. The most common congenital coagulation factor defi-
ciencies are deficiencies of coagulation factor VIII (hemophilia
A), coagulation factor IX (hemophilia B), and von Willebrand
factor. Intracranial hemorrhage is the most common cause of
death from bleeding in patients with hemophilia; the site of
intracranial hemorrhage can be epidural, subdural, or intrapa-
renchymal. Spinal cord compression may result from spinal
hematomas.
A deficiency or imbalance of factors involved in regulating
coagulation may place the child at risk for thrombosis. Pedi-
atric ischemic stroke has been associated with iron-deficiency
anemia (Maguire et al., 2007), deficiencies of protein C,
protein S, and antithrombin; activated protein C resistance
due to the factor V Leiden mutation; the prothrombin gene
20210A mutation; the methylene tetrahydrofolate reductase
(MTHFR) gene variants; the ATG haplotype of the protein Z
gene (Nowak-Göttl et al., 2009); elevated lipoprotein (a);
elevated antiphospholipid antibodies (Kenet et al., 2010) and
lupus anticoagulant; elevated factor VIII levels; and low plas-
minogen or high fibrinogen. The importance of the plasmino-
gen activator inhibitor promoter polymorphism (PAI-1) in
childhood stroke is controversial. Temporary hematological
abnormalities and resultant thrombosis may result from inter-
current illness; for example, idiopathic nephrotic syndrome is
associated with decreased antithrombin levels and CVT and/
or arterial thromboembolic events (Fluss et al., 2006).
Abnormalities of blood cells or blood cell concentration
may place the child at risk for hemorrhagic or ischemic stroke.
Stroke occurs in children with β thalassemia intermedia (βTI)
and children with paroxysmal nocturnal hemoglobinuria.
Low platelet count due to autoimmune thrombocytopenia or
bone marrow suppression leads to hemorrhage. Anything that
increases blood viscosity (e.g., sickled cells, polycythemia,
chronic hypoxia) may predispose a child to arterial or venous
infarct. Dehydration is associated with arterial strokes and
CVT, possibly because it increases viscosity. Anemia has also
been associated with arterial ischemic infarction and CVT,
possibly due to alterations in hemodynamics or imbalances
in thrombotic pathways.
Several authors have noted the presence of multiple pro-
thrombotic abnormalities in some children with ischemic
stroke (Kenet et al., 2010). The combination of MTHFR and
endothelial nitric oxide synthase gene variants may raise
stroke risk more than MTHFR alone (Djordjevic et al., 2009).
Children with congenital heart disease or leukemia may be
at higher risk for developing thrombotic complications
during hospitalization if they also have a prothrombotic
abnormality.
Trauma and Vascular Compression
Trauma is a risk factor for both ischemic and hemorrhagic
stroke. Trauma can injure vessels directly, leading to hemor-
rhage from torn vessels, thrombosis in damaged intima, or
1000 PART III  Neurological Diseases and Their Treatment
traumatic pseudoaneurysm. Subdural hemorrhages, subarach-
noid hemorrhages, and ischemic infarctions occur in head
injury. Ascertaining the cause of the trauma is important; at
one pediatric trauma center, the mortality rate for nonacciden-
tal trauma was 9.7%, while the mortality rate for accidental
trauma was 2.2% (Roaten et al., 2006). Most subdural hemor-
rhages in infants are due to abuse (Matschke et al., 2009). In
older children and adults, low admission Glasgow Coma Scale
(GCS) score, low systolic blood pressure, brain herniation,
and requirement for decompressive craniotomy are all predic-
tors of post-traumatic cerebral infarction (Tian et al., 2008).
Bony abnormalities of the vertebrae or abnormalities of vessel
walls due to collagen-vascular disease or metabolic disease
may predispose to cervicocephalic arterial dissection after
mild trauma. Arterial dissection may be idiopathic in
otherwise apparently normal children (Rafay et al., 2006). A
prothrombotic state associated with trauma can promote
thrombosis and worsen outcome; trauma patients who go
into disseminated intravascular coagulation have worse out-
comes than those who do not. Trauma is the most common
precipitant of hemorrhages in children with hemophilia. In
neonates, compression of the sagittal sinus due to head posi-
tion has been associated with cerebral sinovenous thrombosis;
changing head position or minimizing compression with a
specialized pillow may improve venous flow (Tan et al., 2013).
Infection
The consequences of bacterial meningitis are disseminated
intravascular coagulopathy and vascular inflammation, and
subsequent arterial or venous thrombosis and infarction.
Other cerebrovascular complications of meningitis include
vasculitis, vasospasm, intracranial aneurysm formation, and
rarely subarachnoid hemorrhage. Group B streptococcal men-
ingitis is an important cause of stroke in neonates and trans-
mitted vertically from the mother or horizontally by nursery
staff. During the first 2 months of life, infants are susceptible
to bacteria found in maternal flora or in the local environ-
ment, including group B Streptococcus, Gram-negative enteric
bacilli, and Listeria monocytogenes. After 2 months of age, Strep-
tococcus pneumoniae and Neisseria meningitides are the most
common causes of bacterial meningitis. The institution of
Haemophilus influenzae type b vaccination at 2 months of age
has led to a dramatic drop in H. influenzae-b meningitis. In
immunosuppressed patients such as those with cancer or
acquired immune deficiency syndrome (AIDS), Aspergillus
species may lead to vasculitis and infarction. There are numer-
ous possible causes of ischemic and hemorrhagic stroke in
HIV/AIDS. Patients with AIDS may develop marantic endocar-
ditis, arteriopathy of medium and small vessels or aneurysms,
and although the presumed cause for most cases is direct or
secondary infection, the exact pathophysiology is not always
clear. Highly active antiretroviral therapy for AIDS may result
in dyslipidemia and may itself cause vascular injury and accel-
erated atherosclerosis (Mondal et al., 2004). Tuberculosis
leads to meningitis in 1% to 2% of cases, which may cause
vasculitis and infarction (Starke, 1999). Several cases of stroke
occurred in children with neurobrucellosis (Salih et al.,
2006b). Lyme disease is a rare cause of infectious vasculitis
and aneurysm formation. Varicella-zoster virus (VZV) may
cause vasculitis by direct infection of the arterial wall or by a
postinfectious inflammatory reaction that manifests weeks to
months after the primary infection. Even minor recent infec-
tion has been identified as a risk factor for stroke, and may act
by inducing an inflammatory prothrombotic state or by
causing vascular injury (Hills et al., 2012). In some cases,
arteriopathy is associated with recent upper respiratory infec-
tion (Amlie-Lefond et al., 2009a).
Vascular Malformations/Vasculopathy/Migraine
As discussed previously, vascular malformations may present
with intracerebral hemorrhage, and resulting vasospasm may
lead to ischemic infarction. Arterial abnormalities such as
large-artery stenosis are common in otherwise healthy chil-
dren with arterial ischemic stroke (Ganesan et al., 2003). At
least 10% of hemorrhagic strokes and most subarachnoid
hemorrhages in children are caused by ruptured aneurysms
(Jordan et al., 2009).
One potential cause for stroke in pediatric patients is
moyamoya disease. Moyamoya is a rare, chronic, progressive
steno-occlusive intracranial vasculopathy involving the distal
supraclinoid internal carotid artery and the proximal anterior
and middle cerebral arteries, and is associated with the forma-
tion of an abnormal vascular network at the base of the brain
resembling a “puff of smoke” on angiography. The mechanism
of the disease is still unknown. Moyamoya disease has a high
prevalence in Japan, Korea, and China but has been reported
worldwide (Han et al., 2012). There is a bimodal distribution,
presenting most often in children (girls more common
than boys) younger than 10–15 years and in adults in the
third to fifth decades of life. Children usually present with
recurrent transient ischemic attacks or strokes, headaches,
seizures, or movement disorders. Adults may present with
intracranial hemorrhage, including subarachnoid hemor-
rhage, subependymal hemorrhage, or intraventricular hemor-
rhage. Some patients with moyamoya develop brain aneurysms.
Many disorders have been associated with moyamoya disease
(Table 68.1).
Fibromuscular dysplasia (FMD), a segmental, non-
atherosclerotic, noninflammatory vascular disease of unknown
pathophysiology, may result in arterial stenosis, vessel occlu-
sion, aneurysm, and/or arterial dissection. FMD most com-
monly affects adult women and is rarely recognized in children
with cerebral ischemia (DiFazio et al., 2000; Kirton et al., 2013
Zurin et al., 1997).
Primary angiitis of the central nervous system (PACNS)
may occur in children and can be fatal if not treated with
aggressive immune suppression. There are more frequently
reported cases of less virulent vasculopathies in children, often
occurring after varicella infection, which respond to aspirin
alone and do not require immune suppression (Chabrier
et al., 1998; Lanthier et al., 2001). Stroke can result from vas-
culopathy outside the brain. Childhood stroke can be a first
manifestation of Takayasu arteritis, an inflammatory large-
vessel vasculitis that affects the aorta and its branches (Brunner
et al., 2008). A growing body of literature exists examining the
role of inflammatory factors in stroke in children and in
adults.
Although true migrainous infarctions are rare, migraine is
associated with a twofold increased risk of ischemic stroke.
The risk is more apparent for individuals who have migraine
with aura, smokers, and women who use oral contraceptives
(Shürks et al., 2009). While migraine has been associated
with childhood stroke in large studies (Gioia et al., 2012;
Pezzini et al., 2014), a prospective study of 1008 children with
migraine did not detect any clear infarcts (Mar et al., 2013).
Drugs/Toxins
Abuse of illicit drugs is an important cause of ischemic and
hemorrhagic strokes in young patients. Maternal use of cocaine
may lead to vasospasm and cerebral infarction in the fetus,
and use of cocaine by children may lead to intracranial hemor-
rhage or ischemic stroke. Other drugs such as amphetamines,
which lead to sudden increases in blood pressure or vaso­
spasm, also raise the risk of infarction. Ischemic stroke has
 Stroke in Children 1001

TABLE 68.1  Disorders Associated with Moyamoya Other metabolic diseases lead to cerebral infarction by con-
tributing to thrombosis from arterial damage. Homocystinuria 68
Neonatal anoxia Brain tumors
may lead to infarction, presumably through elevated homo-
Head trauma Parasellar tumors cysteine levels and subsequent vascular injury. The C677T
Basilar meningitis Wilms tumor MTHFR gene variant may be associated with childhood stroke,
but it is not clear how large a role it plays; at least 10% of
Leptospirosis Post-radiation vasculopathy healthy children are homozygous for the MTHFR C677T
Tuberculosis Atherosclerotic disease (Gunther et al., 2000; Koch et al., 1999; Nowak-Göttl et al.,
Neurofibromatosis 1 Hypertension
1999). Studies vary on the degree of associated risk, and car-
riers do not always have elevated homocysteine levels at the
Tuberous sclerosis complex Cerebral dissecting and time of infarction. Fabry disease is an X-linked lysosomal
saccular aneurysms storage disease that causes a deficiency of α-galactosidase and
Sturge–Weber syndrome Fibromuscular dysplasia resultant accumulation of glycolipids in the endothelial wall.
Phakomatosis pigmentovascularis Coarctation of the aorta
Male patients experience paresthesias of the hands and feet
type IIIB and cardiac abnormalities that can begin in childhood; hypo-
hidrosis and renal dysfunction tend to occur later in the course
Pseudoxanthoma elasticum Renal artery stenosis of the disease (Ries et al., 2005). Both male and female het-
Hypomelanosis of Ito Arteriovenous malformations erozygotes are susceptible to cerebral thrombosis, possibly
Marfan syndrome Cavernous malformations
because of an increase in vasoreactivity in damaged vessels or
endothelial and leukocyte activation. Males may be more
Turner syndrome Systemic lupus erythematosus severely affected but rarely show cerebrovascular involvement
Williams syndrome Sneddon syndrome before age 23 (Schiffmann, 2001). α1-Antitrypsin deficiency
may lead to decreased structural integrity of the arterial wall
Noonan syndrome Polyarteritis nodosa
by disrupting the balance of activity between proteases and
Prader–Willi syndrome Sjögren symdrome antiproteases. α1-Antitrypsin deficiency has been associated
Alagille syndrome Sarcoidosis with aneurysms and with vascular changes consistent with
fibromuscular dysplasia. The hyperlipidemias can cause
Apert syndrome Use of oral contraceptives atherosclerotic vascular changes in children similar to those
Down syndrome Drug abuse (cocaine) in older adults.
Sickle cell anemia Homocystinuria
β-Thalassemia Type I glycogenosis Gender and Ethnicity
Fanconi anemia Osteogenesis imperfecta The role of gender in pediatric stroke has been controversial.
Aplastic anemia Glycogen storage disease One study found that both arterial ischemic stroke and sino-
Hereditary spherocytosis Hyperlipoproteinemia
venous thrombosis are more common in boys, with male
predominance particularly in cases of stroke caused by trauma-
Protein C deficiency Primary oxalosis associated arterial dissection (Golomb et al., 2009). However,
Protein S deficiency Hirschprung disease a recent population-based study in England did not find male
gender to be a risk factor (Mallick et al., 2014). Higher testo-
Antiphospholipid antibody Giant cervico-facial
syndrome (APAS) hemangiomas
sterone levels have been associated with increased risk of
stroke in boys (Normann et al., 2009).
Thrombotic thrombocytopenic Hyperthyroidism Ethnicity is a risk factor for stroke. Black children appear
purpura to be at an increased risk for both ischemic and hemorrhagic
Factor XII deficiency Graves disease stroke which cannot be fully explained by sickle cell disease.
Asian ethnicity has been associated with stroke risk in the
Adapted from K. Houkin and T. Mikami, Moyamoya Disease and
Moyamoya Syndrome, in: J.E. Wanebo, N. Khan, J.M. Zabramski,
United Kingdom but not in the United States; differences in
R.F. Spetzler (Eds), Moyamoya Disease: Diagnosis and Treatment. the ethnic makeup of the Asian populations between coun-
Thieme, New York, 2011. tries may explain some of the difference (Fullerton et al.,
2003; Mallick et al., 2014).
Gender and ethnicity may influence recovery from stroke.
A study of mortality from childhood stroke in England and
Wales from 1921 to 2000 found that boys had a higher mortal-
ity rate (Mallick et al., 2009). Black children have had higher
been associated with both “natural” and “synthetic” (“Spice”) stroke mortality than white children in the United States. This
marijuana use. Proposed mechanisms include cannabinoid- has been in part due to sickle cell anemia, and the disparity
induced intracranial arteriopathy and/or cardiovascular effects has decreased since the Stroke Prevention Trial in Sickle Cell
such as arrhythmias (Barber et al., 2013; Freeman et al., 2013; Anemia (STOP trial) (Lehman et al., 2013).
Wolff et al., 2011). Accidental ingestion or overdose of medica-
tions used to treat thrombosis may lead to hemorrhage.
Genetic
Metabolic Genome-wide association studies and whole-exome sequenc-
The mitochondrial diseases may lead to metabolic strokes, ing have led to the identification of genetic risk factors, but
particularly during times of metabolic stress. MRI can demon- the function of the identified genes is not always clear. Muta-
strate infarction in nonvascular territories (Fig. 68.5). However, tions in the CECR1 (cat eye syndrome chromosome region,
in rare cases, mitochondrial mutations have been associated candidate 1) which encode adenosine deaminase 2 have
with moyamoya vasculopathy (Longo et al., 2008; Papavasil- been associated with early stroke and vasculopathy. Zebrafish
iou et al., 2007). and human studies suggest that adenosine deaminase 2 may
1002 PART III  Neurological Diseases and Their Treatment
A B
Fig. 68.5  Magnetic resonance imaging (MRI) of an 18-year-old girl who presented at age 12 with headaches and went on to develop
bilateral incoordination, decreased attention span, decline in school performance, and fatigability. A, Fluid spin echo inversion recovery
MRI demonstrates multiple bilateral lesions in nonvascular territories. B, A section of the involved area is selected for evaluation using MR spec-
troscopy (MRS). C, MRS demonstrates a lactate doublet peak consistent with mitochondrial disease in an area of signal abnormality (arrows).
function as a growth factor for endothelial cell development
(Zhou et al., 2014). The AB collagen type IV alpha (COL4A1)
gene codes for a collagen which plays a role in the basement
membranes of cerebral vasculature, and mutations can lead to
hemorrhagic strokes starting in childhood (Jeanne et al., 2012;
Shah et al., 2010). Genetic variants in the plasma glutathione
peroxidase gene (GPX3), which codes an enzyme which may
modify fibrinogen, has been associated with pediatric ischemic
stroke due to arteriopathy (Nowak-Göttl et al., 2011). A pre-
disposition to pediatric stroke has been associated with four
members of the ADAMTS gene family: ADAMTS13, ADAMTS17,
ADAMTS2, and ADAMTS12. The currently best-understood
of these genes, ADAMTS13, codes for von Willebrand factor
cleaving protease, and leads to increased von Willebrand
factor-induced endothelial platelet aggregation. Some muta-
tions in this gene are associated with familial thrombocyto-
penic purpura. However, the biological functions of the
ADAMTS genes with the greatest risk for stroke, ADAMTS2 and
ADAMTS12, are unknown (Arning et al., 2012).
DIFFERENTIAL DIAGNOSIS
Children with stroke often present with seizures, and in the first
few hours after a seizure, before cranial imaging, it can be dif-
ficult to determine whether a new hemiparesis is due to a
temporary postictal Todd paresis or to infarction. Todd paresis
usually does not last more than 24 hours, though in rare cases
it may persist several days. Migraine may lead to infarction and
permanent motor impairment, but hemiplegic migraine may
lead to temporary motor impairment. A strong family history
of hemiplegic migraine or documentation of a missense muta-
tion of the CACNA1A calcium channel gene on chromosome
19p13 may help differentiation (Terwindt et al., 2002), but
variation exists in mutations among families (see Chapter 103).
Alternating hemiplegia of childhood is a progressive neurode-
generative condition. The origin is generally unclear, although
cerebrovascular factors and mitochondrial disease may be con-
tributory. Neuroimaging studies usually do not demonstrate
pathology. Edema, bleeding, or shifting of brain tumor may
cause sudden onset of neurological signs. Encephalitis or
meningoencephalitis may lead to sudden onset of focal neuro-
logical symptoms. Several metabolic diseases including glutaric
aciduria and carbohydrate-deficient glycoprotein syndrome (see
Chapter 91) can present with stroke-like episodes, and serum
and urine testing together with MRI help make the diagnosis.
Acute disseminated encephalomyelitis (ADEM), multiple scle-
rosis, vasculitis, and the vasculitic form of Hashimoto
C
encephalopathy (Salpietro V. et al., 2014) are all causes of
sudden onset of focal or multifocal neurological symptoms,
and all may cause multiple T2 bright lesions on MRI.
EVALUATION
History and Physical
In the young patient, the history should include questions
about delivery and the perinatal period, attainment of hand
preference, and basic developmental milestones. Develop-
ment of a hand preference before 1 year of age may be a sign
of a mild hemiparesis in the nondominant hand, which could
be due to a perinatal infarction. Any early hemorrhagic or
ischemic infarction may lead to slowed development. Medical
history should include questions about previous hemor-
rhages, abnormal bruising, petechiae, thromboses, and other
medical conditions that may raise the risk of early stroke (e.g.,
complex congenital heart disease, renal failure, sickle cell
anemia). Children with moyamoya usually present with recur-
rent transient ischemic attacks or cerebral infarction. Symp-
toms may be triggered by crying, physical exertion, or
hyperventilation. Family history should include questions
about abnormal bleeding in other family members, strokes or
heart attacks before age 45, peripheral arteriopathy, or deep
venous thrombosis. A history of multiple miscarriages may be
suggestive of antiphospholipid antibody syndrome.
Physical examination should include examination of the
face for signs of dysmorphic features suggestive of a genetic
syndrome. Always assess head circumference. Early stroke may
lead to macrocephaly due to hydrocephalus or to microceph-
aly due to tissue loss and poor brain growth from infarction.
Examination of the skin should document signs of bruising
or petechiae, livedo reticularis suggestive of Sneddon syn-
drome, systemic lupus erythematosus or other autoimmune
disorders, café-au-lait spots suggestive of neurofibromatosis
type 1, hypopigmented macules suggestive of tuberous sclero-
sis complex, excess skin laxity suggestive of a collagen disorder
such as Ehlers–Danlos syndrome, cyanosis suggestive of heart
failure and anoxia, and pallor suggestive of anemia. The head
and neck should be auscultated for vascular bruits and the
heart for murmurs and arrhythmias; peripheral pulses should
be compared, and the abdomen should be auscultated for
renal bruits suggestive of a systemic vascular disorder. Neuro-
logical examination should look for signs of focal abnormal-
ity, with the caveat that signs may not localize well in the very
young child or may be difficult to assess in the frightened or
uncooperative child (Table 68.2).
 Stroke in Children 1003

TABLE 68.2  Physical Examination of the Child with Stroke

68
Finding Possible significance/suggestive of Finding Possible significance/suggestive of
HEAD CIRCUMFERENCE Telangiectasias Osler–Weber–Rendu disease (hereditary
hemorrhagic telangiectasia)
Macrocephaly Hydrocephalus caused by IVH, SDH,
SAH, or vascular malformation Oral/genital ulcers Behçet disease
Microcephaly Failure of brain growth resulting from Angiokeratomas Fabry disease
stroke or genetic disorder
Lentigines in non-sun- Predisposition to dissection or to atrial
EYES exposed areas myxoma, which may lead to
cardioembolic stroke
External/Iris
Discoloration of fingers with Raynaud phenomenon as sign of
Epicanthal folds, Brushfield Down syndrome
cold: white, blue, then collagen disease or systemic lupus
spots
red erythematosus
Horner syndrome Carotid dissection (postganglionic)/
Subcutaneous nodules on Rheumatic fever, systemic lupus
vertebral dissection (central)
elbows, forehead, erythematosus, rheumatoid arthritis
Pulsating exophthalmos Carotid-cavernous fistula tendons
Lens subluxation Marfan syndrome, homocystinuria Erythematous macules that Acute varicella (chicken pox); shingles if
evolve to clear, fluid-filled in a dermatomal distribution
Angioid streaks Pseudoxanthoma elasticum
vesicles
Xanthelasma on lids, Hyperlipidemia
Multiple round, white, Past varicella infection
corneal arcus
puckered scars
Corneal opacity Fabry disease
Needle tracks IV drug addiction with risk for
Retina endocarditis and HIV
Papilledema Increased ICP resulting from MOUTH
hydrocephalus, vascular malformation,
High, arched palate Marfan syndrome
or acute brain edema
Petechial hemorrhages Infective endocarditis
Hemorrhages Trauma (consider child abuse), bleeding
diathesis, ruptured aneurysm, collagen HEART AND PERIPHERAL PULSES
disease, emboli
Murmur Complex congenital heart disease, valve
Vasculopathy Systemic vasculitis abnormality
Angioid streaks Pseudoxanthoma elasticum, Paget Decreased pulses Takayasu arteritis
disease, sickle cell anemia
Increased pulses Hypertension
Angioma Familial cavernous angiomatosis, von
ABDOMEN
Hippel–Lindau disease
Hepatomegaly Infection, cancer, liver failure
SKIN
Bruit Renal artery stenosis
Bruising Bleeding diathesis (consider child abuse)
BACK
Petechiae Platelet count low or dysfunction; DIC
Scoliosis, vertebral Possible increased risk of dissection
Purpura Henoch–Schönlein purpura
anomalies
Pallor Anemia
HANDS
Erythema Polycythemia
Long, tapering fingers Marfan syndrome
Cyanosis Complex congenital heart disease, other
Other anomalies of bones May be seen in association with
cause of hypoxia
of hands congenital heart disease
Skin necrosis Meningococcemia
Clubbing of fingers Congenital heart disease
Café-au-lait spots Neurofibromatosis type 1
JOINTS
Hypopigmented macules, Tuberous sclerosis complex
Painful, restricted Arthritis due to autoimmune disease,
shagreen patches, facial
movement past bleeds (hemophilia)
angiofibromas
Warm Autoimmune disease, infection
Yellow papules Pseudoxanthoma elasticum
OVERALL SIZE
Premature aging Progeria
Tall Marfan syndrome, homocystinuria
Malar rash Systemic lupus erythematosus
Short Progeria, mitochondrial disease,
Skin laxity Ehlers–Danlos syndrome type IV
dwarfism (risk of vertebral anomalies)
DIC, Disseminated intravascular coagulation; HIV, human immunodeficiency virus; ICP, increased intracranial pressure; IV, intravenous; IVH,
intraventricular hemorrhage; SAH, subarachnoid hemorrhage; SDH, subdural hematoma.
Physical findings taken from Hurst, J.W., 1993. Cardiovascular Diagnosis: The Initial Examination. Mosby-Year Book, St. Louis. Information on
lentigines from Neau, J.P., Rosolacci, T., Pin, J.C., et al., 1993. Cerebral infarction, cardiac myxoma and lentiginosis. Rev Neurol (Paris) 149,
289–291; and Schievink, W.I., Michels, V.V., Mokri, B., et al., 1995. Brief report: a familial syndrome of arterial dissections with lentiginosis. N Engl
J Med. 332, 576–579.
1004 PART III  Neurological Diseases and Their Treatment
Imaging Studies
Ultrasound (see Chapter 40) is useful in assessing IVH or
periventricular leukomalacia in the premature infant or carotid
flow in any child, but its sensitivity for detecting arterial stroke
in the neonate is probably below 50% (Golomb et al., 2001).
Power Doppler ultrasound may be useful in detecting CVT in
the neonate. Transcranial Doppler ultrasound is used to screen
children with sickle cell anemia, and higher blood flow veloci-
ties are associated with higher stroke risk. Studies have sug-
gested that this screening should begin in infancy (Telfer et al.,
2007).
Cranial computed tomography (CT) (see Chapter 39) is
better at assessing hemorrhage in the older child and ischemic
stroke in the neonate and older child, but it may not detect
arterial stroke until 24 hours or more after the event. CT angi-
ography and venography (see Chapter 40) can image the cer-
ebral vasculature.
MRI is the imaging tool of choice for most types of child-
hood stroke, and diffusion-weighted imaging (DWI) can
detect brain ischemia within hours (see Chapter 39). DWI
stays bright for approximately 2 weeks in the older child
or adult but may “normalize” (pseudonormalization) within
days in the neonate (Mader et al., 2002). Stroke imaging at
any age should include DWI, T2, and fluid-attenuated inver-
sion recovery (FLAIR) to detect areas of early infarction.
Magnetic resonance angiography (MRA) may be helpful in
diagnosing vasculitis and dissection involving larger vessels.
In moyamoya, MRI typically demonstrates diminished flow
voids in the distal ICAs, and proximal MCAs and ACAs, in
addition to prominent collateral flow voids in the basal
ganglia region (Fig. 68.6). Magnetic resonance spectroscopy
(MRS) and single-photon emission CT (SPECT) demonstrate
changes in regional blood flow and may be helpful in assess-
ing patients with moyamoya disease and other sources of
vasculopathy. MRS provides the earliest detection of ischemic
lesions. Conventional angiography can clarify the structure of
vascular malformations and is the most accurate method for
detecting moyamoya, vasculitis, and dissection, but angiogra-
phy may not always be possible in the acutely ill child. In
patients suspected of moyamoya, six-vessel angiography
A B
C D
E F
Fig. 68.6  A 14-month-old girl with a history of complex partial seizures now develops a postictal right hemiparesis. A–F, DWMRI shows
acute transcortical infarcts involving the right MCA territory, small segment of the left ACA territory, small segmental left PCA territory, and punctate
left MCA territory. On MRA, the intracranial arterial circulation demonstrates left supraclinoid carotid occlusion and reconstitution of left M1 and
A1 segments via moyamoya-type collaterals. There was normal course and caliber of both cervical carotid and vertebral arteries.
remains the gold standard, and should include selective injec-
tions of both ICAs, external carotid arteries, and vertebral
arteries. Use all forms of neuroimaging in combination with
other laboratory and physical findings, because no one tech-
nique has perfect sensitivity or specificity for detecting vascu-
lopathy. Continuous arterial spin labeling MRI has been used
in research settings to study regional cerebral blood flow in
persons with sickle cell anemia (Van den Tweel et al., 2009).
Other newer forms of imaging such as functional MRI and
diffusion-weighted tensor imaging are used in research set-
tings and may provide insights into stroke evolution and
recovery but are not widely available.
Coagulation Workup
The basic evaluation for prothrombotic disorders may include
prothrombin time (PT) with international normalized ratio
(INR) and activated partial thromboplastin time (aPTT) and
a complete blood cell count, including platelets, protein C,
protein S and antithrombin levels, activated protein C resist-
ance, plasminogen, fibrinogen, homocysteine, antiphospholi-
pid antibody screen, lipoprotein (a), and a lipid panel. Testing
for protein Z may become part of the evaluation in the future
if other studies confirm its role in childhood stroke. Genetic
testing may include screening for the factor V Leiden muta-
tion, the prothrombin 20210A gene, and the MTHFR gene
variants. Some mutations are very common, and the ratio of
symptomatic to nonsymptomatic carriers may be very high in
some populations; more than 40% of healthy children in a
European study were either homozygous or heterozygous for
the C677T MTHFR variant (Koch et al., 1999). The frequency
of different prothrombotic risk factors varies among popula-
tions (Salih et al., 2006a). Unfortunately, identifying asymp-
tomatic carriers of prothrombotic genes might adversely affect
later health, life, and disability insurance status (Golomb
et al., 2005).
Cardiac Evaluation
The basic cardiac evaluation may include electrocardiogram
(ECG) with rhythm strip and a transthoracic echocardiogram

with injection of agitated saline to screen for a patent foramen
ovale. If any suspicion exists for cardioembolic events and
those two studies are unrevealing, perform transesophageal
echocardiography and a Holter monitor study.
Other Studies
Flexion and extension radiographs of the cervical spine may
identify bony abnormalities predisposing to dissection. Elec-
troencephalogram (EEG) may help localize the lesion in chil-
dren who present with seizures and is helpful for evaluating
cerebral function in the unresponsive and possibly locked-in
patient with a brainstem stroke (see Chapter 5). Visual evoked
potentials and brainstem auditory evoked potentials may be
particularly helpful in evaluating the very young or somnolent
patient (see Chapter 34).
Serum and plasma studies may help identify the cause of
the stroke. Thrombocytopenia, deficiencies of factors I, VII,
VIII, IX, and XIII, and deficiency of von Willebrand factor are
all risk factors for intracranial hemorrhage, whereas poly-
cythemia, thrombocythemia, and anemia are all risk factors
for ischemic stroke. Abnormalities in platelet count and fibrin-
ogen may be markers for disseminated intravascular coagula-
tion, which may lead to thrombosis and ischemic stroke.
Elevated serum lactate is a marker for mitochondrial disease,
but not all patients with mitochondrial disease have elevated
serum lactate; genetic tests may be required to confirm the
diagnosis. Muscle biopsy may help confirm mitochondrial
disease (see Chapter 93). Serum studies for plasma
α-galactosidase will identify Fabry disease. Serum ammonia,
amino acids, and organic acids may help identify metabolic
disease such as hyperhomocysteinemia and mitochondrial
diseases that can lead to stroke (Menkes, 2000).
TREATMENT
The Acute Period and Initiating Chronic Therapy
Children with intracranial hemorrhage or hemorrhagic stroke
require close observation in the first hours. Children with
hemophilia need immediate factor replacement and may
require blood transfusion. Children with large hematomas
with significant mass effect may need surgery (Johnson, 2000).
Any child presenting with unexplained or poorly explained
intracranial hemorrhage should also be evaluated for other
sites of injury and possible child abuse.
Between 2000 and 2003, fewer than 2% of children with
ischemic stroke received thrombolytic therapy (Janjua et al.,
2007). Some of these children were not treated in accordance
with guidelines used for adults (Amlie-Lefond, 2009b; Roach
et al., 2008). Few children present within the originally man-
dated 3 hours of infarct onset. The benefit of thrombolytic
therapy in children is not clear. No evidence-based guidelines
are currently available on using intravenous or intra-arterial
thrombolytics in children. Unfortunately, a recent NIH-funded
dose-finding study of tissue plasminogen activator for acute
pediatric stroke was closed because of difficulty enrolling
patients (Amlie-Lefond, 2014). Thrombolytic therapy may not
be helpful in neonates, who have lower levels of plasminogen
than older children (Andrew et al., 2000).
No clear guidelines are available on the use of heparin in
pediatric arterial stroke and CVT patients either. Pilot studies
and case series have described good results with heparin and
low-molecular-weight heparin (deVeber et al., 1998; Massi-
cotte et al., 1996). Large-scale studies with catheter-related
noncranial thrombosis have shown good results (Andrew
et al., 2000). Moharir et al. (2009) showed that neonates
and children with sinovenous thrombosis who are not
Stroke in Children 1005
anticoagulated are at increased risk for thrombus propagation,
which can be asymptomatic and lead to poor outcome. Other 68
low-molecular-weight heparinoids such as danaparoid may be
alternatives for patients with heparin-induced thrombocyto-
penia (Neuhaus et al., 2000; Ranze et al., 1999; Risch et al.,
2006).
In sickle cell anemia, exchange transfusion is the usual
treatment for acute stroke (Menkes et al., 2000). The Stroke
Prevention in Sickle Cell Trial (STOP) demonstrated that in
children with vasculopathy shown by transcranial Doppler
ultrasound screening, regular transfusions to keep the sickle
hemoglobin concentration at less than 30% reduced the risk
of recurrent stroke by 90% (Adams, 2000). This trial has
helped decrease the disparity in stroke mortality between
black children and white children in the United States
(Lehman et al., 2013). However, chronic transfusions carry the
risk of infection and cause increases in serum ferritin (Files
et al., 2002). Some children require treatment with deferox-
amine chelation to prevent iron overload (Wayne et al., 2000).
Stopping exchange transfusion therapy leads to increased vas-
cular disease and stroke risk (Adams and Brambilla, 2005).
Attempts at treating and preventing metabolic stroke and
cerebrovascular disease have been made by addressing the
pathological defects in metabolic pathways, using coenzyme
Q10 and other antioxidant vitamins. L-Arginine improves
endothelial dysfunction in children with MELAS (mitochon-
drial encephalopathy, lactic acidosis, and strokes) and may aid
in treating the stroke-like episodes (Koga et al., 2006). Folate,
vitamin B6, and vitamin B12 all play a role in homocysteine
metabolism, which is impaired in homocystinuria and in
carriers of the MTHFR C677T gene variant. Several different
enzyme abnormalities may lead to homocystinuria, and the
enzyme affected determines whether supplementation with
folate, vitamin B6, or vitamin B12 is helpful (Menkes, 2000).
Dietary supplementation with folate lowers serum homo-
cysteine levels in adults with the MTHFR C677T gene variant
(Thuillier et al., 1998) and may be helpful in children with it.
Enzyme replacement with α-galactosidase decreases the symp-
toms of Fabry disease and normalizes cerebrovascular reactiv-
ity but does not remove the risk of recurrent stroke (Schiffmann
et al., 2006).
Patients with protein C deficiency have been treated with
protein C concentrate (Ettingshausen et al., 1999). Good
results are reported when using antithrombin concentrate to
treat consumptive coagulopathy and antithrombin deficiency
at the time of acute stroke, but it does not appear to prevent
thrombosis in leukemia patients treated with L-asparaginase
(Hongo et al., 2002).
Additional Issues in Chronic Therapy
Patients with hemophilia and severe bleeding may require
prophylaxis with regular factor transfusions. Young or ataxic
children may need to wear protective helmets until their
balance improves.
Patients with genetic chronic thrombotic abnormalities
such as protein C or S deficiency, or with antiphospholipid
antibody syndrome, may require long-term care with low-
molecular-weight heparin or warfarin (Andrew et al., 2000).
For many patients, however, the best long-term therapy is not
clear. Low-molecular-weight heparin may be used for 3 to
6 months after cervicocephalic arterial dissection or CVT
(Andrew and deVeber, 1999), with an Insuflon patch to make
administration tolerable. Warfarin or aspirin are more often
used for long-term therapy (Andrew et al., 2000). Families of
children on warfarin need to be counseled about regulating
vitamin K levels in the diet, bony changes, possible tera-
togenicity, and the risks of under- or overtreatment. Families
1006 PART III  Neurological Diseases and Their Treatment
of children taking aspirin are generally concerned about Reye
syndrome, but there are no reports in children taking aspirin
for stroke prophylaxis (Roach, 2000). Strater and colleagues
(2001) did a prospective follow-up study of 135 children with
first onset of ischemic stroke. The children received prophy-
lactic treatment with either low-dose low-molecular-weight
heparin or aspirin and were followed for a median of 36
months. Low-dose low-molecular-weight heparin was not
superior to aspirin in preventing stroke recurrence. For chil-
dren with sickle cell anemia, chronic treatment with hydrox-
yurea can increase levels of fetal hemoglobin and decrease
complications of sickle cell anemia, but careful monitoring is
required for cytotoxicity and genotoxicity (Khayat et al.,
2006). Bone marrow transplantation with matched donors
may be an option for some children (Vermylen, 2003). Surgery
or interventional procedures play a role in treating some types
of cerebrovascular disease. Indirect surgical revascularization
procedures, such as encephaloduroarteriosynangiosis (EDAS),
encephalomyosynangiosis (EMS), encephalomyoarteriosy-
nangiosis (EMAS), pial synangiosis, multiple burr holes, crani-
otomy with inversion of the dura, omental transplantation,
omental pedicle graft, and cervical sympathectomy, may be
used to treat children with moyamoya disease. Direct revascu-
larization procedures such as superficial temporal artery (STA)
to middle cerebral artery (MCA) bypass are technically diffi-
cult to perform in children. Other surgical procedures such as
clipping, coiling, radioablation, or removal may be useful in
the treatment of aneurysms or malformations.
Socioeconomic status and social stressors may play a role
in family compliance with therapy and patient outcome. In a
Texas study of children with sickle cell anemia, families with
private insurance were more likely to be compliant with
Doppler ultrasound screenings than families on Medicaid
(Raphael et al., 2008).
Other Issues
The risks that accompany pregnancy in adolescence are greater
for young women with a history of hemorrhagic or ischemic
stroke (see Chapter 112).
Oral contraceptives carry a very small risk for the general
population but may carry more risk for women with pro-
thrombotic disorders (Slooter et al., 2005). Oral contraceptive
use raises the risk of both arterial thromboembolism and CVT.
These issues require explicit discussion with patients and their
families, preferably before adolescence, as some oral contra-
ceptives are used to treat acne or menstrual disorders in young
adolescent women.
SUMMARY
Children with stroke are at risk for future cognitive impair-
ment, motor impairment, and epilepsy. In full-term neonates,
it is difficult to predict outcome based on initial cranial
imaging, and it is unclear whether the side on which the inf-
arcts occur affects language development. Evidence of degen-
eration of corticospinal tracts and resulting asymmetry in the
midbrain on MRI performed during the second 6 months of
life does predict hemiplegia. About half of children with neo-
natal arterial ischemic stroke have feeding problems; when
severe, feeding dysfunction can lead to aspiration and failure
to thrive (Barkat-Masih et al., 2010). Children who present
with signs of perinatal stroke after the perinatal period appear
to have worse motor outcomes than children with perinatal
stroke who present in the neonatal period (Lee et al., 2005).
For these children, young age at presentation, fever at presen-
tation, and right middle cerebral artery infarction have been
associated with poor outcome (Cnossen et al., 2010). Bilateral
hemispheric lesions and low muscle tone of affected limbs at
presentation have also been associated with poor outcome
(Kim et al., 2009). Studies in both infants and older children
show that larger and multiple infarcts are more likely to cause
cognitive and motor impairment as well as epilepsy. Overall,
the intelligence of children with stroke falls within the normal
range, but some require extra help in school.
The prognosis for children with progressive cerebrovascular
diseases is particularly problematic. Those children with severe
forms of sickle cell or moyamoya disease who are not treated
or who do not respond to therapy may develop significant
cognitive and motor disabilities and epilepsy (Lagunju et al.,
2013; Weinberg et al., 2011). More than 20% of children who
survive childhood arterial ischemic stroke may have recurrent
transitory ischemic attacks or stroke (Ganesan et al., 2002).
Prothrombotic disorders and abnormalities on vascular
imaging raise the risk of recurrence (Strater et al., 2002).
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