Pediatric Stroke

Definition

Brain injury due to interruption of normal blood flow to the brain, through either vessel occlusion (ischemia) or rupture (hemorrhage), leading to loss of specific brain function relating to the affected area lasting for >24 hours (WHO) or ≤24 hours with brain imaging showing a new infarct of appropriate age and location.

Pediatric stroke can occur in two phases:

Perinatal phase: 20^th week of gestation to 28^th day after birth.

• Prenatal phase: 20^th week to birth
• Newborn phase: Birth to 28^th day

Acute Neonatal Stroke:

• Perinatal stroke can be acutely diagnosed as newborn stroke (birth to 28^th day)

Presumed Perinatal Ischemic Stroke (PPIS):

• Perinatal stroke can be diagnosed later in infancy when hemiparesis emerges gradually with maturation and imaging demonstrates remote infarct presumed to have occurred in the perinatal period

Childhood phase: 29^th day of birth to 18 years

Etiology

• Approximately 1/4^th-1/3^rd of all childhood strokes are idiopathic (40% of perinatal and 10% of childhood)
• As with adults, may be either ischemic or hemorrhagic

Hemorrhagic Stroke (~45%)

Primary mechanisms/causes:

• Cerebral sinovenous thrombosis (CSVT)
• Vascular malformation
• Brain tumour
• Periventricular hemorrhagic infarction
• Rupture of an arterial aneurysm
• Drug or alcohol abuse by the mother
• Neonatal alloimmune thrombocytopenia (NAIT)

Ischemic Stroke (~55%)

Primary mechanisms/causes:

• Cerebral Sinovenous Thrombosis (CSVT)
  • Incidence of CSVT is 0.7 in 100,000 children (Canadian Registry)
  • In the Canadian Pediatric Ischemic Stroke Registry, 6% of children died after ischemic stroke due to CSVT, 72% had residual neurologic deficits, and 22% fully recovered

Ref: deVeber G et al. N Engl J Med. 2001; 345:417-23

• Prothrombotic disorders (20-50%)
  • Protein C deficiency
  • Factor V Leiden mutation
  • Prothrombin gene mutation
  • Antiphospholipid antibodies
  • Methylenetetrahydrofolate reductase mutation
  • Prothrombotic medications (L-asparaginase, OCP)
• Maternal conditions
  • Preeclampsia
  • Diabetes
  • Cocaine abuse
  • Placental thrombosis
  • Placental abruption
  • Twin-twin transfusion
  • Amnionitis
• Arteriopathy (17%-53% )
  • Moyamoya disease
  • Transient Cerebral Arteriopathy (TCA): Idiopathic, nonprogressive focal or segmental, unilateral stenosis of the distal ICA or proximal MCA/ACA resulting in a lenticulostriate infarction. 20-30% of stroke due to arteriopathies are caused by TCA (other terms focal cerebral arteriopathy (FCA), post-varicella angiopathy (PVA) or non-progressive primary angiitis of the central nervous system (PACNS)
  • Progressive PACNS: Approx. 6% of arteriopathic strokes are due to PACNS which is rare, non-infectious, progressive arteriopathy isolated to the cerebral vessels without systemic involvement. It is characterized by bilateral distal and bilateral proximal cerebral artery narrowing
• Sickle cell disease(SCD): Approx. 10% children with SCD suffer stroke by age 20
• Cardiac diseases: Accounts for approx. 20-30% of stroke cases
  • Congenital
  • Acquired
• Arterial dissection: Approx. 7.5-20%
• Perinatal asphyxia is an association, may mimic stroke
• Neurofibromatosis (NF) type 1: Intracranial occlusive arterial disease is the neurovascular manifestation of NF type I in young patients; approx.6% of NF type 1 have vasculopathies
• Trauma to large arteries with dissection or occlusion
• Watershed strokes
  • Comprises 10% of all ischemic strokes
  • Occur in watershed or border-zone regions of brain supplied by major cerebral arteries
  • Divided into two types: Cortical watersheds and internal watersheds (latter more common with distal ICA occlusion e.g. moyamoya)

Risk factors for perinatal stroke:

Maternal risk factors:

• History of infertility
• Chorioamnionitis
• Premature rupture of membrane
• Preeclampsia
• Other maternal and placental disorders

Neonatal risk factors:

• Cardiac disorders
• Coagulation disorders
• Infection, trauma, drugs
• Perinatal asphyxia

Epidemiology

Incidence/Occurrence:

• Birth-18 years: Approx. 6-8 per 100,000 children/year (30% neonatal stroke)
• Ischemic > Hemorrhagic
• Males > Females
• Possible ethnic/genetic factors; incidence higher in African Americans than Asian, Caucasians
• Mean age of childhood presentation is 4-6 years
• Morbidity
  • 2/3 of neonatal and childhood stroke leads to motor deficit with lifetime disability and impairment
  • 15% have chronic seizure disorders
• Mortality
• Childhood stroke:
  • Approx. 10% following ischemic stroke and 25% following hemorrhagic stroke
  • Mortality rate in first year is 5.3 per 100,000 children/year
  • Pediatric stroke is one of the top ten causes of death in children

Incidence of Arterial Ischemic Stroke (AIS)

• Childhood: 2.4 per 100,000 children/year
• Neonatal/newborn: 20-30 per 100,000 newborns/year (~1/4000-5000 live births/year), although MRI detection of neonatal stroke suggests a higher incidence of ~1:2300 live births
• Perinatal AIS accounts for approximately 25-30 % of all AIS in children

Ref: Friedman, N Advances in Pediatrics. 2009, 56:271-299.

Incidence of Hemorrhagic Stroke

• Birth-18 years: 2.2 per 100,000 children/year
• Rate of hemorrhagic stroke for term infants is 6.7 per 100 000/year

Recurrence Rate

• Stroke recurrence risk is approximately 15-20%
• Recurrence rate for childhood AIS varies between 6-37% and is increased with arteriopathy
• AIS recurrence risk appears highest in the first 6 months after initial stroke

Pathophysiology

There is a low energy reserve in the brain; hence there is an absolute requirement for continuous oxygen and glucose. Any process that reduces cerebral perfusion leads to an oligemic state → ischemia → cell death via necrosis (infarction) or apoptosis (neuronal drop out).

Decreased cerebral perfusion triggers an “ischemic cascade” of events that mediate cell death. These changes include:

• Depletion of ATP
• Lactic acidosis
• Release of the excitatory amino acid glutamate → activation of glutamate receptors → membrane depolarization
• Loss of ionic homeostasis → changes in intracellular ion concentrations of sodium, potassium, and calcium
• Free radical (nitric oxide, superoxide) formation
• Membrane failure → cellular edema
• Activation of proteolytic enzymes and caspases
• Inflammatory cascade
• Ultimately leading to necrotic or apoptotic cell death

Clinical Presentation

Perinatal strokes:

In contrast to adult strokes, perinatal strokes may be asymptomatic initially, and deficits may only become apparent later on (PPIS see above). While it is uncommon to find focal deficits in acute newborn stroke, arterial and venous strokes often present with focal seizures, usually involving one limb.

Stroke may also be suspected in infants with

• Encephalopathy
• Asphyxiated appearance
• Signs of acute intercurrent illness

Caveat: Children with neurological symptoms present early as compared to adults (25% within 6 hours of onset). However, stroke is often not considered in the initial differential diagnosis in children, leading to delays in brain imaging; average delay in children is nearly 8 hours.

Ref: Bowers KJ et al. Journal of Child Neurology, 2011; 26: 1074-1100.

Signs/Symptoms in infants:

• Focal seizures (e.g. involving one limb)
• Perinatal distress, particularly in full-term neonates
• Problems feeding, breathing (gasping)
• Sudden hemi-body paresis or paralysis
• For those with delayed diagnosis (PPIS)
  • Early preference for use of one hand over the other (note: hand dominance is not normal until 12 months of age)
  • Delays in early milestones – rolling, sitting, pulling to stand, crawling, and walking
  • Hemiplegic cerebral palsy

Signs/symptoms in children older than 1 year:

• Recurrent focal seizures: >50% cases may present in this fashion
• Sudden onset of any of the following:
  • Hemi-body paresis or paralysis
  • Neglect (hemibody, hemispatial)
  • Difficulty with speech, swallowing
  • Memory difficulty and learning disabilities; schoolwork may be affected
  • Eye movement abnormalities
  • Visual impairment; partial or complete blindness, diplopia, blurred vision
  • Incoordination and impaired balance
  • Horner’s syndrome (may signify carotid dissection or brainstem stroke)
  • Severe headache
  • Nausea and/or vomiting

Differential Diagnosis

Structural lesions:

• Brain tumors
• Intracranial abscess

Infectious processes:

• Meningoencephalitis
• Bilateral meningitis
• Post-infectious cerebellitis
• Botulinum

Demyelinating conditions:

• Acute disseminated encephalomyelitis (ADEM)
• Multiple sclerosis
• Transverse myelitis

Conditions with vasospasm:

• Reversible posterior leukoencephalopathy syndrome
• Complicated/hemiplegic migraine

Other:

• Postictal state (Todd’s paralysis-transient unilateral paresis/plegia)
• Intoxication
• Traumatic brain injury

Investigation and Workup

Neuro-imaging:

The optimal imaging study is dependent on the child’s clinical stability.

• Cranial ultrasound:
  • Safe and quick
  • Requires an open anterior fontanel
  • Low sensitivity in detecting AIS and superficial lesions misses at least 33% of AIS
• Computed tomography (CT) scan (unenhanced):
  • Relatively quick
  • Useful for detecting hemorrhages, abscesses, and tumors
  • Low yield for AIS in initial 24 hours
  • Unable to assess venous thrombosis unless CT venogram
• CT-angiogram (CTA):
  • Detection of stenosis, occlusions, dissections
• CT-venogram (CTV):
  • Detection of cerebral sinovenous thrombosis (CSVT)
• Magnetic resonance imaging (MRI):
  • Very high yield for detecting AIS, differentiating structural and demyelination lesions
  • Also reliably detect hemorrhages
  • First study of choice for suspected childhood AIS when feasible
• Magnetic resonance angiography (MRA):
  • Detection of stenosis, occlusions, dissections, vascular malformations
• Magnetic resonance venography (MRV):
  • Detection of cerebral sinovenous thrombosis (CSVT)
• Transcranial Doppler (TCD):
  • Assessment of large vessel occlusive disease
  • Possible assessment of neonatal cerebral sinovenous thrombosis CSVT
• Catheter angiography:
  • Less commonly used
  • Used in certain conditions such as vascular malformations, or vasculitis

NOTE: MRI/MRA/MRV modalities provide the highest yield and are preferred.

Other procedures and investigations are guided by suspicion of underlying pathology.

Suspected cardiac source of embolism:

• Transthoracic echocardiogram (TTE) or Transesophageal echocardiogram (TEE) for older children e.g. >7 years:
  • Structural cardiac defects
  • Thrombus
  • Valve abnormalities (vegetations)
  • Cardiac tumors

Infectious workup (suspected sepsis/meningitis):

• Blood and urine cultures
• Chest x-ray
• Lumbar puncture (also used to rule/out subarachnoid hemorrhage)

Hypercoagulability:

May require a full battery of investigations that can include

• PTT, INR, D-Dimer
• Protein C, protein S or antithrombin deficiencies
• Factor V Leiden gene mutation
• Anticardiolipin antibodies/Lupus anticoagulant
• Dilute Russell viper venom time
• Prothrombin gene mutations
• Beta2-glycoprotein I antibodies (IgG and IgM)
• Homocysteine
• Elevated lipoprotein(a)
• Factor VIII activity

Vasculitis:

• CTA, MRA, conventional angiography
• Antinuclear antibodies (ANAs)
• Herpes virus serology (varicella, HVS-1 & 2, EBV, and cytomegalovirus)
• Cerebrospinal fluid (CSF) analysis

Genetic/Metabolic: MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke)

• Mimics vaso-occlusive arterial stroke though regional metabolic infarction
• Maternally inherited multisystem disorder that may include stroke
• MRI may detect stroke overlapping vascular territories
• Elevation in serum or CSF lactate
• Muscle biopsy used to detect red ragged fibers
• Gene analysis for mitochondrial mutation (if required as diagnosis can usually be achieved prior to this)

Treatment

Clinical Trials

• Delay to Diagnosis in Acute Pediatric Arterial Ischemic Stroke A prospective outcome study of neonatal cerebral sinovenous thrombosis
• Neonatal cerebral sinovenous thrombosis

Pipeline Agents

• Safety of anticoagulants in children with arterial ischemic stroke

Physician Resources

1. Tips for Patient Care

• Ensure parents and patient (whenever possible) are well informed about disease and its outcomes
• The patient (whenever possible) and family should be encouraged to express their main concerns about reintegration to the home, community and school environments
• Anemia, thrombocytopenia and factor deficiencies should be monitored and corrected
• Clinical or laboratory signs of inflammation are not always present in all individuals with vasculitis
• Pregnancy is considered a stroke risk factor in teenaged girls
• Signs and symptoms of stroke are more diffuse and less focal in neonates and infants as compared to older children
• New onset neurological symptoms or signs in children with sickle cell disease should be evaluated as potentially being due to stroke
• MRI is the most sensitive imaging technique for identifying ischemic brain lesions
• Sensory function in young children is difficult to assess

Medications:

• Consider concurrent risk factors and disease states with the prescribed therapy; example aspirin may worsen the symptoms of asthma
• It is reasonable to reduce aspirin dosage by 50% during influenza and varicella infections (to reduce risk of Reye’s syndrome)
• Large doses of vitamin K may be needed to correct factor deficiencies induced by maternal medications
• tPA generally is not recommended for children with AIS
• Anticoagulant therapy usually is not recommended in individuals with bacterial endocarditis

Social and Stress factors:

• Direct parents and patients to appropriate support services/counseling to help alleviate psychological stress, whenever its possible

Counseling

• Ensure family and/or caregivers as well as patient (whenever possible) are well informed about disease and potential triggers
• Thrombophilia screening may be offered to
  • Family members of children with ischemic stroke or CVST and known thrombophilic defects
  • Mothers of children with ischemic stroke that occurred before, during, or immediately after birth even if thrombophilia screening in the neonate is negative

Physical activity:

• Rehabilitation and physical therapy are among important measures to improve neurological outcome in individuals with perinatal stroke
• Include family or social support in lifestyle modification

Alerts

• Venous thrombosis and early acute ischemic stroke(AIS) is usually missed with CT
• Approximately 10% of seizures in term neonates are due to stroke
• Approximately 30% of intraventricular haemorrhage in term neonates is due to CSVT
• Stroke/ICH are major complications of sickle cell disease (Ref: Wu, Ferriero et al)
• Intracranial infections can cause vasculitis and imaging should be considered

Expected outcome

• Outcome of children with perinatal stroke ranges from normal to hemiparesis (subtle, moderate or severe) and mild neurocognitive delays
• Most survivors with neonatal AIS and CVST learn to walk independently before 2 years old
• Neonatal encephalopathy is predictive of poor outcome after AIS

2. Scales and Tables

• Protocol for Systemic Heparin Administration and Adjustment in Children
• Treatment of heparin-induced bleeding
• Warfarin Anticoagulation Protocol for Children
• Treatment of VKA-induced bleeding
• Comparison of AACP and AHA recommendation for management of childhood AIS
• Comparison of AACP and AHA recommendation for maintenance therapy following childhood AIS

References

Core Resources:

• Bowers KJ; DeVeber GA; Ferriero DM et al Cerebrovascular disease in children: Recent advances in diagnosis and management Journal of Child Neurology 2011;26(9):1074-1100
• Patty Lindsay et al. last publication of Canadian BPG’s which included Ped Stroke Guidelines consistent with this article
• Compendium of Pharmaceuticals and Specialties (CPS). Canadian Pharmacist Association. Toronto: Webcom Inc. 2012
• Lynch JK, Hirtz DG, deVeber G, Nelson KB. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002; 109: 116-23
• deVeber G, Andrew M, Adams C et al. Cerebral sinovenous thrombosis in children. Canadian Pediatric Ischemic Stroke Study Group. N Engl J Med. 2001;345:417-23
• Friedman, N Pediatric Stroke: Past, Present and Future. Advances in Pediatrics. 2009, 56:271-299
• Katzung BG, Masters SB, Trevor AJ, eds. Basic and Clinical Pharmacology. 11^th ed. New York: McGraw-Hill; 2009
• Lindsay P, Bayley M, Hellings C, et al. Canadian Best Practice recommendations for stroke care.CMAJ.2008; 179: S1-S25
• Monagle P, Chalmers E, Chan A, et al. Antithrombotic Therapy in Neonates and Children American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8^thEdition) CHEST 2008; 133: 887S-968S
• Monagle P, Chan A, Goldenberg NA et al. Antithrombotic Therapy in Neonates and Children: : Antithrombotic Therapy and Prevention of Thrombosis, 9^th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012;141;e737S-e801S
• Roach ES, Golomb MR, Adams R, et al. Management of Stroke in Infants and Children A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young Stroke 2008; 39: 2644-2691
• Saposnkik G. Barinagarrementeria F, Brown RD et al. Diagnosis and Management of Cerebral Venous Thrombosis; Stroke. 2011;42:1158-1192
• Skidmore-Roth L. ed. Mosby’s drug guide for nurses. 9^th ed. St. Louis: Elsevier-Mosby; 2011
• Skidmore-Roth L, ed. Mosby’s nursing drug reference. 24^th ed. St. Louis: Elsevier-Mosby; 2011
• Wu, Ferriero et al
• Online resources:
  • The Heart and Stroke Foundation
  • National Institute of Neurological Disorders and Stroke

Online Pharmacological Resources:

• e-Therapeutics
• Lexicomp
• RxList
• Epocrates

Journals/Clinical Trials:

• Agrawal N, Johnston SC, Wu YW. Et al. Imaging Data Reveal a Higher Pediatric Stroke Incidence Than Prior US Estimates. Stroke. 2009; 40: 3415-3421
• Alexiou GA, Mpairamidis E, Sfakianos G, Prodromou N. Surgical management of brain cavernomas in children. Pediatr Neurosurg. 2009;45:375-8
• Bensler SM, Silverman E, Aviv RI; Primary Central Nervous System Vasculitis in Children; Arthritis & Rheumatism 2006, 54,1291-1297
• Goldenberg NA, Bernard TJ, Fullerton HJ, Gordon A, deVeber G; International Pediatric Stroke Study Group. Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study. Lancet Neurol. 2009;8:1120-7
• Jordan LC, Hillis AE. Hemorrhagic Stroke in Children Pediatr Neurol. 2007 February; 36: 73-80.
• Kincaid PK, Duckwiler GR, Gobin YP, Viñuela F. Dural arteriovenous fistula in children: endovascular treatment and outcomes in seven cases. AJNR Am J Neuroradiol. 2001;22:1217-25
• Moharir MD, Shroff M, Pontigon A-M et al. A prospective outcome study of neonatal cerebral sinovenous thrombosis J Child Neurol. 2011; 26:1137-44
• Rafay MF, Pontigon A-M, Chiang J et al. Delay to Diagnosis in Acute Pediatric Arterial Ischemic Stroke Stroke. 2009; 40:58-64
• Schechter T, Kirton A, Laughlin S et al. Safety of anticoagulants in children with arterial ischemic stroke Blood. 2012; 119: 949-956