What are the causes of neonatal seizures?

Causes of Neonatal Seizures

Hypoxic-ischemic encephalopathy (HIE) is by far the most common cause of neonatal seizures, accounting for 46-65% of cases, followed by intracranial hemorrhage and perinatal ischemic stroke (10-12%). 1

Primary Etiologies by Timing of Onset

Early Onset (First Week of Life)

• Hypoxic-ischemic encephalopathy (HIE)

  • Most common cause in both term and preterm infants 1
  • 90% of infants with HIE experience seizure onset within 2 days after birth 1
  • Term infants have higher vulnerability due to more mature brain tissue with higher metabolic demands 2

• Intracranial hemorrhage

  • Second most common cause (10-12%) 1
  • More readily detected by cranial ultrasound 1

• Perinatal ischemic stroke

  • Also accounts for approximately 10-12% of neonatal seizures 1
  • Lesions involving cortex, basal ganglia, and internal capsule in term infants are more likely to cause hemiplegia 2

• Acute metabolic disturbances

  • Hypoglycemia
  • Electrolyte imbalances (calcium, sodium, magnesium)
  • Requires prompt correction to prevent brain injury 3

Later Onset (Beyond First Week)

• Infections

  • Meningitis
  • Encephalitis
  • Central nervous system infections 1, 3

• Genetic disorders

  • May present with treatment-resistant seizures 1, 4

• Malformations of cortical development

  • More likely to cause seizures beyond the seventh day of life 1
  • Detectable by MRI but may be missed on ultrasound 1

Inborn Errors of Metabolism (IEMs)

• Should be suspected particularly when seizures are resistant to common antiseizure medications 4
• Many IEMs are not detected by routine newborn screening 4
• Examples include:
  • Molybdenum-cofactor deficiency
  • Hypophosphatasia
  • GLUT1-deficiency syndrome 4
  • Vitamin-responsive seizures (e.g., pyridoxine-dependent epilepsy)

Diagnostic Approach

Imaging

• Cranial ultrasound:

  • Useful initial imaging modality, especially for unstable neonates 1
  • Good for detecting:
    • Intraventricular hemorrhage
    • Hydrocephalus
    • White matter changes (periventricular leukomalacia)
  • Limitations: low sensitivity for HIE and small infarctions 1
  • Identifies etiology in approximately 38% of cases 1

• MRI:

  • Gold standard for evaluating brain abnormalities in neonates with seizures 1
  • Diffusion-weighted imaging is most sensitive for detecting HIE 1
  • Superior for detecting developmental abnormalities and cortical malformations 1
  • Shows findings in 11.9% of patients not apparent on ultrasound 1
  • Absence of major cerebral lesions on MRI is highly predictive of normal neurological outcome 1

Laboratory Evaluation

• Glucose, electrolytes (calcium, sodium, magnesium)
• Complete blood count
• Blood cultures if infection suspected
• Metabolic screening when IEMs are suspected 4, 3
• Lumbar puncture when CNS infection is suspected 3

Clinical Pearls and Pitfalls

• Timing matters: Seizures within first 48 hours are most commonly due to HIE, while those beyond the seventh day of life are more likely related to infection, genetic disorders, or malformations 1

• Subtle presentation: Neonatal seizures can be difficult to diagnose as they often present with subtle signs rather than classic tonic-clonic movements 5, 6

• Electrographic confirmation: EEG is the gold standard for diagnosis as clinical observation alone may miss many seizures or misidentify non-epileptic events 6

• Treatment resistance: Consider inborn errors of metabolism when seizures are resistant to conventional antiseizure medications 4

• Therapeutic hypothermia: Standard treatment for moderate to severe HIE in term and late-preterm infants (≥35 weeks gestation) is cooling to 33.5°C for 72 hours 2

• Targeted treatment: Early diagnosis of specific metabolic causes allows for targeted interventions (e.g., ketogenic diet, vitamin B6) which may improve outcomes compared to general antiseizure medications 4