Stroke in Neonates and Children

Miya E. Bernson-Leung, MD
Michael J. Rivkin, MD

Boston Children’s Hospital

Stroke and Cerebrovascular Center
 Incidence and Types of Stroke
• Stroke affects 2.3 to 13 per 100,000 older children per year
– About half ischemic and half hemorrhagic
• Ischemic stroke: focal damage to an area of brain tissue within
a vascular territory due to loss of blood flow or oxygenation
– Arterial ischemic stroke (AIS): due to loss of arterial flow
• Localized (“in situ”) thrombus formation: due to hypercoagulable states or in
response to localized endothelial damage and luminal narrowing OR
• Thromboembolism: a clot formed elsewhere in the body travels and becomes
lodged in a cerebral artery
– Venous infarction: due to loss of flow in a draining cerebral vein or
venous sinus
– Transient Ischemic Attack (TIA): defined in adults as symptoms of
stroke that resolve within 24 hours without imaging evidence of injury;
known to occur in children as well
 Incidence and Types of Stroke
• Hemorrhagic stroke: focal brain damage due to bleeding
through localized mass effect and ischemia of adjacent tissues
– Intraparenchymal hemorrhage: spontaneous (nontraumatic)
hemorrhage within the brain parenchyma
– Subarachnoid hemorrhage: immediately adjacent to the surface of the
brain
• Cerebral sinovenous thrombosis (CSVT): obstruction by clot of
one of the major venous sinuses draining the brain
parenchyma
– May or may not lead to venous infarction and/or hemorrhage
 Signs and Symptoms of Stroke
• Sudden-onset, focal neurologic deficits in 85% of
non-neonates
• Generalized signs and symptoms in 60%
– Headache in 40%-50% of strokes
– Altered mental status in about 50% of arterial strokes
• Seizures at onset in 31% of arterial strokes
– Up to 42% of younger children; only 5% of adults
– Postictal (Todd) paralysis is a diagnosis of exclusion: stroke
should always be considered for children with prolonged
postictal paralysis and/or first-time focal seizure
Selected symptoms of stroke in children. Symptoms of stroke vary by the vascular territory affected. This figure
depicts major manifestations of stroke in the anterior, middle, and posterior cerebral arteries as well as the
vertebrobasilar system that supplies the cerebellum and brainstem. Venous stroke and cerebral sinovenous
thrombosis may cause focal and/or diffuse deficits. Stroke may also produce other symptoms, and a stroke in a
given vascular territory may not produce all of the listed symptoms.
 Causes of Stroke
• 90% of children with ischemic or hemorrhagic stroke will have at least 1
risk factor identified after complete evaluation
• Many conditions can predispose to more than 1 type of stroke
– Example: infection and prothrombotic conditions are associated with both
arterial and venous ischemic stroke; sickle cell disease is associated with both
ischemic and hemorrhagic stroke
• Identification of risk factors may inform prognosis and management
– Example: arteriopathy/vasculopathy, a genetic or acquired abnormality of the
cerebral arteries, is the most common risk factor for pediatric AIS, occurring in
53%
• The presence of arteriopathy predicts a 66% recurrence rate
• Some arteriopathies may be treated with aspirin, anticoagulation, or immunomodulation
• All children with stroke should therefore receive vascular imaging (eg, MRA or CT)
– Additional evaluation for non-neonates generally includes echocardiography
with bubble study and thrombophilia evaluation
 Medical Conditions Associated with Childhood Arterial
Ischemic Stroke and Cerebral Sinovenous Thrombosis
Vasculopathy
• Sickle cell disease
• Moyamoya syndrome
• Alagille syndrome
• Radiation vasculopathy
• Arterial dissection
• Collagen vascular disorders
– Ehlers-Danlos type IV
– Marfan syndrome
– COL4A1 mutations
– Fibromuscular dysplasia
• Focal cerebral arteriopathy
• Primary angiitis of the central nervous
system
• Systemic vasculitides and autoimmune
disorders:
– Wegener granulomatosis
– Microscopic polyangiitis
– Polyarteritis nodosa
– Takayasu arteritis
– Systemic lupus erythematosus
– Mixed connective tissue disease
– Henoch-Schönlein purpura
– Hemophagocytic lymphohistiocytosis
– Kawasaki disease
– Inflammatory bowel disease
– Human immunodeficiency virus
• Vasospasm
– Reversible cerebral vasoconstriction
syndrome
– Subarachnoid hemorrhage
– Cocaine use
Prothrombotic conditions
• Polycythemia
• Deficiency of protein C, protein S,
antithrombin III
• Factor V Leiden mutation/activated
protein C resistance
• Prothrombin 20210 gene mutation
• Elevated Factor VIII
• Elevated von Willebrand factor antigen
• Hyperhomocysteinemia; if present,
assess for the methyltetrahydrofolate
reductase gene polymorphism
• Elevated lipoprotein(a)
• Antiphospholipid antibodies
• Migraine with aura
• Estrogen-containing oral contraceptive
use
• Pregnancy and postpartum
• Malignancy
• L-asparaginase and other
chemotherapeutics
Cardiac disorders
• Congenital heart disease, especially with
right-to-left shunt
• Cardiac catheterization or surgery
• Extracorporeal membrane oxygenation
• Left ventricular assist devices
• Endocarditis
• Valvular abnormalities
• Cardiomyopathy
Genetic/metabolic disorders
• Mitochondrial encephalomyopathy,
lactic acidosis, and stroke-like episodes
(MELAS)
• Cerebral autosomal dominant
arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL)
• Homocystinuria
• Fabry disease
• Organic acidemias
– Glutaric aciduria type II
– Methylmalonic acidemia
– Propionic acidemia
– Isovaleric acidemia
• Congenital disorders of glycosylation
• Adenosine deaminase 2 deficiency
• Sulfite oxidase deficiency
Infection
• Meningitis
– Streptococcus pneumoniae
– Tuberculosis
– Aspergillus species
• Varicella vasculopathy
• Sinusitis
• Mastoiditis
• Sepsis
 Medical Conditions Associated With
Childhood Hemorrhagic Stroke

Vascular anomalies: Coagulation disorders:

• Arteriovenous malformation
• Arteriovenous fistula
• Aneurysm
• Cavernous malformation
• Capillary telangiectasia
• Venous angioma
Vasculopathy:
• Sickle cell disease
• Moyamoya syndrome
• Thrombocytopenia
• Hemophilia
• Hepatic failure
• Vitamin K deficiency
• Anticoagulant therapy
Other:
• Brain tumor
• Hemorrhage due to CSVT*
• Hemorrhagic transformation of
ischemic infarction*

*See tables of associated conditions

Figure: Hemorrhagic stroke due to
ruptured arteriovenous malformation.
A 14-year-old previously healthy boy
developed headache and emesis that
progressed to obtundation. Axial CT
scan with contrast (A) shows a right
temporal arteriovenous malformation
(arrow) fed by branches of the middle
cerebral artery (arrowheads), with
intraparenchymal hemorrhage
(asterisk). Axial T2-weighted MRI (B)
better delineates the nest of abnormal
vessels (arrow) fed by an enlarged
middle cerebral artery (arrowheads)
and adjacent intraparenchymal and
intraventricular hemorrhage (asterisk).
Hemorrhage is also visible on
postoperative axial susceptibility-
weighted MRI (C). Conventional
angiography (D) shows the
malformation (arrow) with rapid
contrast filling of a draining vein
(arrowheads). He has a left
hemiparesis and hemianopia.
 Sickle Cell Disease and Stroke
• Sickle cell disease (SCD) affects 1 in 365 children of African
ancestry in the U.S.
– Ischemic stroke occurs in 11% of patients with SCD by age 20
• “Silent strokes” are detected on MRI in up to 30%
– Risk of recurrence is 70%
• Mechanisms that contribute to ischemic and hemorrhagic
stroke in SCD:
– Sickled cells cannot pass easily through small arterial and capillary
beds, leading to vaso-occlusion in the brain
– Anemia and diminished oxygen carrying capacity contribute to
ischemia
– Chronic inflammation and vascular damage can lead to narrowing of
large arteries, aneurysm formation, or vessel rupture
 Sickle Cell Disease and Stroke
• The standard of care for stroke prevention in children
ages 2-16 years with SCD is annual screening with
transcranial Doppler ultrasonography (TCD)
– Children with high-risk TCDs should be screened more
frequently
• Stroke Prevention Trial in Sickle Cell Anemia (STOP)
– Monthly transfusion of children with high-risk TCD velocity
greater than 200 cm/second versus standard care
– Transfusion decreased annual stroke risk from 10% to less
than 1%
 Cardiac Disorders and Stroke
• The second most common risk factor for pediatric AIS
– In 18% of neonates and 31% of non-neonates
– Especially high risk periprocedure or while requiring extracorporeal membrane
oxygenation or ventricular assist devices
• Cardioembolic strokes arise from either intracardiac thrombi
or paradoxic embolism of venous thrombi via right-to-left
shunts
• Conditions especially predisposing to ischemic or hemorrhagic
stroke:
– Cyanotic congenital heart disease with right-to-left shunt
– Endocarditis, valvular disease, cardiomyopathy
– Anticoagulation
• May require long-term antiplatelet or anticoagulation therapy
 Prothrombotic and Proinflammatory
Conditions and Stroke
• 13% of children with arterial stroke and 67% with venous stroke have a
hereditary thrombophilia  testing for specific conditions is reasonable
• Migraine with aura, but not without aura, may double the risk of stroke in
adolescents
• Estrogen-containing oral contraceptive pills are associated with a 2- to 2.5-
fold increased risk of ischemic stroke and should be avoided in young
women at increased risk of thrombosis
• Both cancer and its treatment (especially cranial irradiation, indwelling
catheters, and L-asparaginase chemotherapy) increase stroke risk in
children
• Concurrent infection may be present in up to 1 in 3 children with stroke
– Meningitis results in stroke in 1 in 4 cases
 Acute Care for Pediatric Stroke
• The average delay from onset to diagnosis for pediatric stroke exceeds 24 hours
• Recognition of symptoms and rapid triage to a center with appropriate expertise is
important to institute neuroprotective care and avoid or treat complications
• MRI with MRA of head and neck is the definitive imaging modality
– MRI/MRA demonstrates ischemia within minutes of onset, identifies vascular occlusions or
abnormalities, and excludes hemorrhage
– CT may be normal in the early phase of stroke
• Thrombolytic therapy (tissue plasminogen activator/tPA) and endovascular
therapies may be appropriate in some cases of AIS
• Consensus-based guidelines exist for initial management of AIS, including the
selection of aspirin versus anticoagulation in the acute period
• For CSVT, anticoagulation is reasonable to prevent clot propagation, even in the
presence of some associated hemorrhage
Figure: Suggested diagnostic approach to ischemic stroke in children. The diagnosis of acute ischemic
stroke (within hours of onset) in children is ideally established by urgent stroke-protocol MRI and MRA of the
head and neck. CT with CTA showing a vessel occlusion is an alternative when MR is unavailable. Supportive
and diagnostic measures should be instituted simultaneously.
Figure: Acute perinatal arterial
ischemic stroke. A term infant with
uncomplicated pregnancy and
delivery presented with right eye
twitching within 24 hours of birth.
Axial MRI showed restricted diffusion
indicating acute ischemia (bright on
trace image, [A] and dark on apparent
diffusion coefficient [ADC] map, [B])
occupying the entire left middle
cerebral territory (arrows). Sulcal
effacement and obliteration of the
gray-matter/white-matter junction
are seen on the axial T2 sequence (C).
MRA (D) showed absent flow signal in
the expected location of the left MCA
due to occlusion (solid arrows
indicate expected course as
compared to white outlined arrows
that indicate course of right MCA). He
developed infantile spasms at 5
months. At 13 months, he had a
spastic hemiparesis, could sit but not
crawl, and had no specific words.
 Selected Differential Diagnoses
of Pediatric Stroke
• Complicated migraine
• Seizure/postictal symptoms not due to stroke
• Hemorrhage (hemorrhagic stroke, traumatic hemorrhage)
• Intracranial infection (meningitis, abscess)
• Trauma
• Tumor
• Demyelinating disease (multiple sclerosis, acute disseminated
encephalomyelitis)
• Posterior reversible encephalopathy syndrome (PRES)
• Toxic exposure
• Metabolic derangement
• Idiopathic intracranial hypertension (pseudotumor cerebri)
• Postinfectious process (cerebellitis, acute cerebellar ataxia)
• Musculoskeletal cause of weakness
• Somatoform disorder
 Neonatal and Perinatal Stroke
• Incidence: 1 in 1,600-4,000 neonates
– 20 weeks’ gestation to 28th postnatal day, but most thought to occur
within several days of birth
• Presentation:
– Focal or generalized seizures 12-72 hours after delivery – the second
most common cause of seizure in term babies
– May also demonstrate encephalopathy and poor feeding
– A unilateral motor deficit is rarely seen
• “Presumed perinatal” strokes:
– Identified after 28 days without a clinically recognized acute event
– Often discovered as hand preference before age 1 year, delayed motor
milestones, or seizures
 Selected Conditions Associated with
Perinatal Arterial Ischemic Stroke
Maternal factors:
• Infection
• Thrombophilia including antiphospholipid antibodies
• Preeclampsia
• Cocaine use
• Smoking
• History of infertility

Fetal/infant factors:
• Infection
• Thrombophilia
• Congenital heart disease
• Need for resuscitation or low Apgar score at 5 minutes
• Arterial injury during delivery from mechanical forces on the head and neck

Placental factors:
• Infarction
• Abruption
• Insufficiency
• Chorioamnionitis
Figure 5: Presumed perinatal arterial ischemic stroke. A previously healthy 6-year-old girl presented with first
lifetime right-sided seizure. Exam showed hyperreflexia and Babinski sign on the right as well as right arm
posturing when running. She had been left-handed since before age 1 year. Axial CT (A) and axial FLAIR MRI of
the brain (B) showed left parieto-occipital encephalomalacia in the territory of a branch of the left middle
cerebral artery (arrows). Neuropsychological evaluation showed mild intellectual disability with global deficits
in both verbal and nonverbal skills as well as difficulty with processing and integration.
 Prognosis
• Stroke recurrence varies by etiology
– 1%-2% for perinatal stroke
– 66% for children with arteriopathy such as SCD
• Cerebrovascular disease is among the top 10 leading causes of
death for U.S. children: mortality is 3%-20% for AIS, 12% for
CSVT, and up to 40% for hemorrhagic stroke
• Up to 90% morbidity, with moderate-to-severe deficits in 41%
– Spastic and/or dystonic hemiparesis – the leading cause of hemiplegic
cerebral palsy
– Cognitive deficits
– Mood and attention disorders
– Epilepsy in 70% of neonates and 30% of older children