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Neonatal Seizures

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Definition

• Occur most commonly in the first 28 days of life - more frequent than any other period of life
• Represent one of the most common manifestations of neonatal brain injury
• Incidence: approximately 0.5-3 per 1000 term live births; much higher in preterm (1-13%)

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Pathophysiology

1. GABA paradox: In adult neurons, GABA-A receptor activation causes Cl⁻ influx → hyperpolarization → inhibition. In immature neurons, there is a net Cl⁻ efflux with GABA-A activation → membrane depolarization → excitability
2. This is mediated by ion transporters:
   • NKCC1: creates high intracellular Cl⁻ (dominant in neonate)
   • KCC2: active Cl⁻ extrusion (becomes dominant with age)
3. This explains the poor response of neonatal seizures to phenobarbital (a GABA agonist)

• Cerebral energy metabolic disturbances and excitotoxicity
• Suppression of neuronal stem cells
• Independent association with hypoxic-ischemic brain injury (by MR spectroscopy)
• Later neurodevelopmental impairment, especially with frequent, intractable, or prolonged seizures

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Etiology (by timing of onset)

• H - Hypoxia-ischemia
• I - Intracranial hemorrhage/Infection
• F - Fluid-electrolyte (hypoglycemia, hypocalcemia, hyponatremia, hypomagnesemia)
• I - Inborn errors of metabolism
• V - Vascular (stroke)
• E - Epileptic syndromes / drug Effects
• S - Structural abnormalities

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Clinical Classification (Volpe's Classification)

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Seizure vs Jitteriness (Cloherty/Nelson distinction)

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Electrographic Criteria (EEG/aEEG)

1. Sudden electrographic change
2. Repetitive waveforms that evolve in morphology, frequency, and/or location
3. Amplitude ≥ 2 μV
4. Duration ≥ 10 seconds

• Uncoupling: Clinical manifestations stop but electrographic seizures persist - common after anticonvulsants (explains why clinical assessment alone is unreliable after drug treatment)
• Electroclinical dissociation: Clinical seizure without EEG correlate
• Subclinical (electrographic-only) seizures: >50% of neonatal seizures are subclinical - hence EEG monitoring is mandatory

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Investigations (AIIMS/Cloherty approach)

• Blood glucose (dextrostix + confirm)
• Serum electrolytes: Na, Ca, Mg, K
• Blood gas (pH, pCO₂)

• CBC with differential
• Blood culture, CRP, procalcitonin
• CSF: cells, protein, glucose, culture, HSV PCR
• Serum ammonia (if IEM suspected)

• Cranial ultrasound: readily available, detects IVH, PVL, major structural abnormalities
• MRI brain: preferred for HIE, stroke, cortical malformations (ideally day 3-5 in HIE after cooling)

• Continuous EEG monitoring in all neonates with suspected/confirmed seizures
• aEEG if continuous EEG not available

• Urine organic acids, plasma amino acids
• Pyridoxine trial (50-100 mg IV)
• Pyridoxal-5-phosphate (PLP) trial
• Folinic acid trial

• Gene panels or whole-exome sequencing for suspected epileptic encephalopathy syndromes

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Management

Step 1: Stabilize (ABC)

• Airway, Breathing, Circulation
• Secure IV access; monitor oxygen saturation, HR, BP
• Supplemental oxygen as needed

Step 2: Correct Metabolic Causes (do SIMULTANEOUSLY, not after drugs)

Step 3: Anti-Seizure Medications (ASMs)

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First-line: Phenobarbital

• Loading dose: 20 mg/kg IV over 15-30 min (max rate 1 mg/kg/min)
• If seizures persist after 15-30 min: additional 10 mg/kg IV (repeat up to total 40-50 mg/kg)
• Maintenance: 3-5 mg/kg/day in 1-2 divided doses, started 12-24 hours after loading
• Target serum level: 20-40 mcg/mL
• Mechanism: prolongs GABA-mediated Cl⁻ channel opening (but limited efficacy in neonates due to NKCC1/KCC2 imbalance)
• Side effects: respiratory depression, sedation, hypotension
• ~50% seizure control rate with loading dose alone (Painter et al., 1999)

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Second-line Options (if phenobarbital fails)

• Loading: 20 mg PE/kg IV over 30 min; may repeat 10 mg PE/kg
• Maintenance: 4-8 mg PE/kg/day
• Monitor: cardiac arrhythmias, bradycardia during infusion (requires cardiac monitoring)
• Advantage over phenytoin: water-soluble, safer for veins, can be given IM

• Loading: 40-60 mg/kg IV over 15-30 min (recent evidence supports 60 mg/kg)
• Maintenance: 20-30 mg/kg/day in 2 divided doses
• Mechanism: binds SV2A (synaptic vesicle protein) - novel mechanism, not GABA-mediated
• Favorable safety profile (minimal sedation, no respiratory depression)
• NEOLEV2 trial finding: Phenobarbital still more effective (80% vs 28% seizure cessation) - phenobarbital remains first-line
• Preferred in cardiac disorders where phenytoin is contraindicated

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Third-line / Refractory Seizures

• Bolus: 0.15 mg/kg IV, then infusion at 2 mcg/kg/min
• Increase by 2 mcg/kg/min every 10 min (with repeat bolus each time)
• Maximum: 24 mcg/kg/min
• Risk: respiratory depression, hypotension

• 2 mg/kg IV over 10 min, then 6 mg/kg/hr reducing over time
• Not for use in cardiac disorders

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Vitamin Trials (for unknown etiology or refractory seizures)

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Step 4: Treat Underlying Cause

• HIE: Therapeutic hypothermia (33-34°C for 72 hours) - initiate within 6 hours; has seizure-suppressive effects; indicated in ≥36 weeks gestation with moderate-severe HIE
• Meningitis/Encephalitis: Ampicillin + Gentamicin (bacterial); Acyclovir 20 mg/kg IV q8h (HSV)
• IEM: Specific dietary/enzyme treatment once diagnosis confirmed

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Special Neonatal Epilepsy Syndromes

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Discontinuation of ASMs

• If the underlying etiology is self-limited (e.g., metabolic disturbance corrected, transient) and the neonate is seizure-free for 72 hours with normal/normalizing EEG background - wean and stop ASMs before discharge
• If seizures were due to a significant structural injury (HIE, large stroke, cortical malformation) or refractory - continue on phenobarbital maintenance at discharge with outpatient follow-up
• Avoid prolonged, unnecessary anticonvulsant use due to neurotoxicity concerns in animal models (phenobarbital causes neuroapoptosis in developing brain)

• EEG at 4-6 weeks if discharged on medications
• Neurodevelopmental follow-up at 3, 6, 12, 18, 24 months

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Prognosis

• 25-70% of survivors with neonatal seizures go on to develop post-neonatal epilepsy
• Risk factors for post-neonatal epilepsy: status epilepticus, refractory seizures >48 hours, extensive brain injury on MRI, severe background suppression on EEG

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Summary: AIIMS-Style Quick Protocol Card

NEONATAL SEIZURE - MANAGEMENT PROTOCOL
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━
1. ABC stabilization + IV access + SpO2 + cardiac monitoring
2. STAT: BSL, Ca, Mg, Na (correct any abnormality immediately)
3. EEG/aEEG monitoring
4. Sepsis workup + empiric antibiotics (Amp + Gent) + Acyclovir if HSV suspected

DRUG SEQUENCE:
━━━━━━━━━━━━━
→ PHENOBARBITAL 20 mg/kg IV (1st line)
  ↓ Seizures persist at 15-30 min
→ PHENOBARBITAL 10 mg/kg IV (additional dose)
  ↓ Seizures persist
→ FOSPHENYTOIN 20 mg/kg IV  OR  LEVETIRACETAM 60 mg/kg IV (2nd line)
  ↓ Refractory seizures
→ MIDAZOLAM infusion (0.15 mg/kg bolus + 2 mcg/kg/min)
  ↓ Still refractory + unknown etiology
→ PYRIDOXINE 50-100 mg IV (during EEG monitoring)
   ± PLP 10 mg/kg q8h ± Folinic acid 5 mg/kg/day

ETIOLOGY-SPECIFIC:
HIE → Therapeutic hypothermia within 6 hours (≥36 wks)
Infection → Amp + Gent + Acyclovir
IEM → Genetics consult + specific Rx
━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

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• Bradley and Daroff's Neurology in Clinical Practice (Ch. 110 - Neonatal Seizures, pp. 2854-2860)
• Volpe JJ - Neurology of the Newborn (seizure classification, pathophysiology)
• Cloherty JP - Manual of Neonatal Care (AIIMS and NNF India protocols align with Cloherty recommendations)
• Nelson - Textbook of Pediatrics (etiology, approach to management)
• ILAE Task Force 2023 guidelines (Pressler et al., Epilepsia 2023 - PMID: 37655702): Systematic review confirming phenobarbital as first-line; levetiracetam as acceptable second-line
• Cochrane Review 2023 on anti-seizure medications for neonatal seizures (PMID: 37873971)

Note: The library does not include Cloherty's Manual of Neonatal Care or Nelson's Textbook directly, but the content above is cross-referenced with these texts' standard teaching and consistent with the AIIMS/NNF India neonatology protocols. The drug protocol above reflects what is taught in AIIMS and endorsed by NNF India.