What are the causes and treatment options for neonatal seizures?

Neonatal Seizures: Causes and Treatment

Phenobarbital should be used as the first-line antiseizure medication for neonatal seizures regardless of etiology, with phenytoin, levetiracetam, midazolam, or lidocaine as appropriate second-line options when seizures are unresponsive to initial treatment. 1

Common Causes of Neonatal Seizures

Neonatal seizures are often symptoms of underlying central nervous system disorders. The main etiologies include:

1. Hypoxic-Ischemic Encephalopathy (HIE)

   • Most common cause of neonatal seizures 2
   • Results from perinatal asphyxia
   • Different injury patterns in term vs. preterm infants:
     • Term infants: Cortex, basal ganglia, internal capsule 3
     • Preterm infants: Periventricular white matter 3

2. Ischemic or Hemorrhagic Stroke

   • Occurs in approximately 1 per 4,000 live births 3
   • Accounts for approximately 10% of seizures in term neonates 3
   • Typically presents as focal motor seizures involving one extremity

3. Intracranial Hemorrhage

   • More common in premature infants
   • Intraventricular hemorrhage is particularly concerning

4. CNS Infections

   • Bacterial meningitis
   • Viral encephalitis
   • TORCH infections (Toxoplasmosis, Other infections, Rubella, Cytomegalovirus, Herpes simplex)

5. Metabolic Disturbances

   • Hypoglycemia
   • Hypocalcemia
   • Hypomagnesemia
   • Hyponatremia or hypernatremia

6. Genetic/Developmental Disorders

   • Genetic epilepsy syndromes
   • Brain malformations
   • Inborn errors of metabolism

7. Vitamin Deficiencies

   • Pyridoxine (vitamin B6) deficiency 4
   • Biotin deficiency 4

Clinical Features of Neonatal Seizures

Neonatal seizures often present differently from seizures in older children and adults:

• Tremors
• Irritability
• Increased wakefulness
• High-pitched crying
• Increased muscle tone
• Hyperactive deep tendon reflexes
• Exaggerated Moro reflex
• Frequent yawning and sneezing 4

Gastrointestinal symptoms may include:

• Poor feeding
• Uncoordinated sucking
• Vomiting
• Diarrhea 4

Autonomic signs include:

• Increased sweating
• Nasal stuffiness
• Fever
• Mottling
• Temperature instability 4

Diagnostic Approach

1. Electroencephalography (EEG)

   • Continuous EEG monitoring is essential for accurate diagnosis 5
   • Clinical observation alone leads to under-diagnosis of subclinical seizures and over-treatment of non-seizure events 6

2. Neuroimaging

   • MRI is the preferred imaging modality 3
   • CT scans should be limited to emergency situations for rapid assessment of hemorrhagic lesions 3
   • MR angiography (MRA) and venography (MRV) may be indicated for suspected vascular abnormalities 3

3. Laboratory Studies

   • Complete blood count
   • Electrolytes, glucose, calcium, magnesium
   • Blood cultures
   • Lumbar puncture if infection suspected
   • Metabolic screening
   • Genetic testing when appropriate

Treatment Algorithm

First-Line Treatment:

• Phenobarbital at 20 mg/kg IV loading dose 1, 5
  • Achieves therapeutic levels (15-30 μg/ml) within minutes 7
  • Effective in controlling seizures in approximately 43% of neonates 4

Second-Line Treatment (if seizures persist):

• Phenytoin/Fosphenytoin (15-20 mg/kg IV) OR
• Levetiracetam (20-40 mg/kg IV) OR
• Midazolam (0.05-0.1 mg/kg IV) OR
• Lidocaine (if available and appropriate) 1, 5

For Refractory Seizures:

• Consider continuous midazolam infusion 5
• For neonates with suspected vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASMs, a trial of pyridoxine may be attempted 1

Special Considerations:

• For neonates with cardiac disorders, levetiracetam may be the preferred second-line agent 1
• For suspected channelopathy (e.g., due to family history), phenytoin or carbamazepine should be used as first-line 1

Maintenance Therapy and Discontinuation

• Maintenance dose of phenobarbital: 3-4 mg/kg/day 7
• Following cessation of acute provoked seizures without evidence of neonatal-onset epilepsy, antiseizure medications should be discontinued before discharge home 1
• Early discontinuation after 1-2 weeks is generally possible 7

Adjunctive Treatments

• Therapeutic Hypothermia: Recommended as standard treatment for moderate to severe hypoxic-ischemic encephalopathy in term and late-preterm infants (≥35 weeks gestation) 3

  • May reduce seizure burden in neonates with HIE 1

• Supportive Care:

  • Treatment of dehydration and anemia 3
  • Correction of metabolic abnormalities
  • Management of increased intracranial pressure when present

Prognosis

The long-term outcome depends primarily on the underlying etiology:

• Seizures associated with HIE have variable outcomes based on severity
• Developmental delay after neonatal cerebral venous sinus thrombosis ranges from 28% to 58% 3
• Language delay occurs in approximately 25% of children with perinatal stroke 3
• Treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcomes 1

Important Caveats

1. Preterm vs. Term Infants: Preterm infants may have less severe withdrawal symptoms and seizures that are more difficult to control with standard medications 4

2. EEG Confirmation: Clinical observation alone is insufficient; EEG confirmation of seizures is essential to avoid under-diagnosis and over-treatment 6

3. Medication Side Effects: Monitor for adverse effects of phenobarbital including respiratory depression and hypotension 4

4. Subclinical Seizures: Many neonatal seizures have no clinical manifestations and can only be detected by EEG monitoring

5. Avoid Unnecessary Prolonged Treatment: For acute symptomatic seizures, discontinue antiseizure medications before discharge when seizures have resolved 1