Study Group Notes - Chapter 57 - Strokes in Children

 

Strokes in children depend on developmental, genetic, and environmental factors.

 

Epidemiology:

 

Neonates:

• Neonates higher risk
• Delicate germinal matrix susceptible to IVH in preterms (<36 weeks)
• Intracranial hemorrhage – 1 in 100 term neonates
• Term/near-term higher risk of arterial ischemic infarctions – 1 in 4000 - 1.36 in 100,000
• CSVT rate 0.67 per 100,000 children, 43% neonates

Children:

• 2.5-13 per 100,000 children per year
• Hemorrhagic – 1.2-5 per 100,000 per year
• Ischemic 0.6-8 per 100,000 per year

High risk subgroups:

• AV malformations, cavernous malformations (familial)
• Vasospasm and resultant ischemic stroke may be rarer in children
• Bleeding disorders, e.g., hemophilia – 4% intracranial bleeds, of which 48% intracerebral
• Sickle cell anemia – ischemic strokes – 285 per 100,000 per year
  • 11% children with sickle cell anemia have strokes, 17% silent infarcts
  • Also aneurysms with hemorrhage (more in adults)
• ECMO treatment – high risk of hemorrhage and ischemic – 0-26%, 50-52% post-mortem
• Complex congenital heart disease – cardioembolic, thrombotic, watershed, CSVT
  • Severity of lesion, number of surgeries, anesthetic technique, length of followup
  • Infarction in 6/20 children with MRI within 2 years
  • Heart transplant – 6.5% cerebrovascular complications
  • Risk greatest during surgery or catheterization
• Cancer – hemorrhage or infarcts
  • Hemorrhage – thrombocytopenia, brain metastases
  • Ischemia/CSVT – leukostasis, L-asparaginase (low antithrombin, fibrinogen, plasminogen), meningitis/arteritis, radiation vasculopathy, surgery complications
• Down syndrome – higher rate of leukemia, moyamoya, congenital heart disease, and atlantoaxial instability (vertebral dissection)
• NF1 – moyamoya, radiation vasculopathy
• Connective tissue disorders (Marfan’s, Ehlers-Danlos, pseudoxathoma elasticum) – cervicocephalic arterial dissection or aneurysms
• Metabolic syndromes damaging endothelium – homocystinuria, Fabry’s disease, familial hyperlipidemias

 

Presentations:

 

Neonates:

• Seizures most common (65% IVH, 80% AIS, 70% CSVT)
• Apnea, irritability, jitteriness, lethargy, bulging fontanelle
• Hemiparesis may not be evident until 6 months

Children:

• Seizures, focal signs, severe headache
• Focal signs may be missed by parents, sometimes considered behavioural
• In older children, focal signs missed due to low suspicion for stroke
• Some children have no acute symptoms – gradual developmental delay (silent infarcts)

 

 

 

 

Causes:

 

Cardiac

• Abnormal cardiac anatomy predisposes to intracardiac thrombi
• Septal defects allow right-to-left shunts allowing thrombi to cross to arterial side
• Surgery and catheterization can disrupt the endothelium and lead to thrombosis
• Cardiac surgery can lead to temporary prothrombotic state
• Abnormal heart valve can be nidus for bacterial vegetations
• Chronic hypoxemia à polycythemia à increased viscosity à thrombosis
• PFO – right-to-left shunting leading to arterial infarctions in children and adults

 

Hematologic

• Lower vit K-dependent factors in neonates
• Accidental warfarin injestion (also low vit K-dependent factors)
• Congenital coagulation factor deficiencies – factor VIII (hemophilia A), factor IX (hemophilia B), vWF
• Coagulation difficulties causing pediatric ischemic stroke
  • Protein C, protein S, antithrombin III
  • Activated protein C resistance from factor V Leiden mutation
  • Prothrombin gene 20210 mutation
  •  Methylene tetrahydrofolate reductase (MTHFR) gene defect
  • Elevated lipoprotein (a)
  • Plasminogen activator inhibitor promoter polymorphism (PAI 1)
  • Elevated APLA, lupus anticoagulant
  • Elevated factor VIII, low plasminogen, high fibrinogen leels
• Blood cell problems causing pediatric stroke
  • Low platelet count from autoimmune thrombocytopenia or bone marrow suppression
  • Increased viscosity from sickle cells, polycythemia, chronic hypoxia à arterial or venous infarct
  • Dehydration à CSVT and AIS (increased viscosity)
  • Anemia à AIS or CSVT (altered hemodynamics and imbalances in thrombotic pathways

 

Trauma

• Direct injury to vessels leading to hemorrhage or thrombosis
• Neonates – forceps injury
• Infants – subdural, subarachnoid hemorrhages, ischemic infarctions – accidental and nonaccidental injury
• 95% injury in infants due to abuse, 5% children returned to abusive parents w/o intervention are killed
• Abnormalities of vertebrae or vessel walls can predispose to traumatic injury
• Prothrombotic state or DIC can worsen trauma outcome

 

Infection

• Bacterial meningitis can lead to DIC and vasculitis à arterial or venous infarction
• GBS meningitis important in neonates – vertical or nosocomial infection
• First 2 months – maternal or environmental flora – GBS, G- enteric bacilli, Listeria monocytogenes
• After 2 months – Streptococcus pneumoniae, Neisseria meningitides, (Haemophilus influenza B)
• Immunosuppressed (HIV+)
  • Aspergillus
  • HIV arteriopathy of medium or small vessels, aneurysms
• TB meningitis – vasculitis and infarction
• Lyme disease – infectious vasculitis and infarction
• VZV – direct infectious vasculitis or postinfectious vasculitis (weeks to months later)

 

Vascular malformations/vasculopathy/migraine

• Vascular malformation à hemorrhage, vasospasm à ischemia
• Primary angiitis of the CNS (requires aggressive immunosuppresion), VZV vasculopathy (ASA only)
• Migranous infarction (?arterial vasospasm)

 

 

Drugs/toxins

• Maternal cocaine use à fetal vasospasm and infarction
• Cocaine ingestion à hemorrhage or ischemia
• Amphetamines increase risk of infarction from sudden HTN and vasospasm
• Accidental overdose of antithrombotic medications

 

Metabolic causes

• Mitochondrial disease + stress (nonvascular distribution)
• Arterial damage – homocystinuria, MTHFR gene defect
• Fabry’s disease – X-linked lysosomal storage disorder – deficiency of alpha-galactosidase – accumulation of glycolipids in the endothelial wall in males and female heterozygotes
• Alpha-1-antitrypsin deficiency – decreased structural integrity from disrupting balance of proteases and antiproteases à aneurysms, arterial dissection, fibromuscular dysplasia
• Hyperlipidemias à atherosclerotic vascular changes in children

 

Combination of multiple factors is common, e.g., trauma and hemophilia, heart disease and prothrombotic disorder.

 

Differential diagnosis:

• Seizures à Todd’s paresis (can persist for days!)
• Migraine à temporary deficits or migranous infarction, e.g., CACNA1A, chr.19p13 calcium channel mutation in familial hemiplegic migraine
• Alternating hemiplegia of childhood – progressive neurodegenerative condition ?mitochondrial
• Brain tumour – edema, bleed, shifts
• Encephalitis/meningoencephalitis
• Metabolic – glutaric aciduria, carbohydrate-deficient glycoprotein syndrome à stroke-like episodes
• ADEM / multiple sclerosis – more at grey-white junction, periventricular areas

 

Investigation:

 

History

• Hand preference before age 1
• Developmental delay
• Previous hemorrhages, abnormal bruising, petechiae, thromboses
• Congenital heart disease, renal failure, sickle cell disease
• Family history of abnormal bleeding, strokes <45 years, peripheral arteriopathy, DVT
• History of multiple miscarriages (APLA syndrome)

Examination

• Dysmorphic features
• Head circumference
• Bruising, petechiae, livedo reticularis (Sneddon’s sundrome, SLE, autoimmune disorders), NF1 café au lait spots, TS hypopigmented macules, Ehlers-Danlos skin laxity, cyanosis for heart failure/anoxia, pallor for anemia
• Vascular and cardiac bruits, murmurs, arrhythmias, peripheral pulses, renal bruits
• Focal neurological deficits – may be difficult in young children

Imaging

• U/S in assessing PVL or carotid flow, low sensitivity for strokes (<50%)
• Power Doppler for CSVT in neonates
• CT for assessing hemorrhage, but may not detect AIS until 24h
• MRI is tool of choice in childhood stroke, esp. DWI sequences – 2 weeks in children, pseudonormalization in 1 week in neonates. Sequences include DWI, FLAIR, T2, MR angiography
  • MR proton spectroscopy, single photon emission CT – regional blood flow in moyamoya
  • MRS – earliest detection of ischemia
• Conventional angiography – most accurate in vasculitis and dissection

Prothrombotic evaluation

• INR/PTT, CBC (platelets)
• Protein C/S, AT III, APC resistance, plasminogen, fibrinogen, homocysteine
• APLA screen, lipoprotein (a) level, cholesterol panel
• Genetic factor V Leiden mutation, prothrombin 20210A gene, MTHFR mutation

Cardiac evaluation

• ECG with rhythm strip, TTE with bubble study for PFO à TEE and Holter monitor if suspicious

Other tests

• EEG in seizures, VEP and BAER
• Factor I, VII, VIII, IX, XIII, vWF deficiency, polycythemia, thrombocythemia, anemia
• Serum lactate (mitochondrial disease)
• Serum study for plasma alpha-galactosidase (Fabry)
• Serum ammonia, amino acids, organic acids (hyperhomocysteinemia, mitochondrial diseases)
• Skin biopsy (collagen vascular disease)
• Muscle biopsy (mitochondrial disease)

 

Therapy:

 

Acute

• Close monitoring in first hours
• Hemophilia à factor replacement, blood transfusion
• Large hematomas à surgery
• Evaluation for other sites of injury
• IA or IV tPA à sparse evidence in case reports, not as useful in neonates (low plasminogen)
  • Should only be done when 24h access to CT, pediatric neurosurgeon/OR access
• Heparin in AIS or CSVT à good results in recent studies, also LMWH
• Sickle cell anemia à exchange transfusion (regular transfusions decrease risk by 90%)
• CoQ10 and antioxidants for mitochonrdrial disorders (varying results)
• Folate, B6, B12 in homocystinuria and MTHFR
• Alpha-galactosidase enzyme replacement in Fabry’s
• Pilot studies in coagulation pathway protein replacement, e.g., protein C, antithrombin III

 

Chronic

• Hemophilia à regular transfusions, protective helmets for ataxic children
• Genetic prothrombotic deficits à long term LMWH or warfarin
• Arterial dissection or CSVT à LMWH for 3-6 months, warfarin or ASA for longterm therapy
• Warfarin – concerns of dietary vitamin K, bony changes, possible teratogeniity
• ASA – Reye’s syndrome
• One study showed LMWH not superior to ASA after first ischemic stroke in child
• Moyamoya disease à encephalodurosynangiosis or arterial bypass
• Vascular aneurysms or vascular malformations à surgery

 

Other considerations

§         Pregnancy should be planned, teratogenicity of warfarin and antiepileptics

§         Oral contraceptives risk in prothrombotic disorders (incr peripheral and cerebral venous thrombosis)

§         Hemophiliac – reduce contact sports

 

Outcome:

• Risk for future cognitive impairment, motor impairment, epilepsy
• Preterms at higher risk
• Difficult to predict motor and language outcome based on imaging
• Evidence of corticospinal tract degeneration and midbrain asymmetry on MRI predicts hemiplegia
• Larger/multiple infarcts more likely to cause impairment
• Most children fall within normal range, but may require extra help in school
• Injury of cortex, internal capsule, and basal ganglia together more likely to cause motor impairment
• Progressive cerebrovascular disease, e.g, moyamoya or sickle cell diease, more significant