Neonatal Seizures

Neonatal seizures are the most common neurological emergency in the newborn and a marker of underlying brain dysfunction rather than a disease in themselves. Because the immature brain seizes differently from the older child, recognition is difficult, the EEG is the gold standard, and treatment is urgent — uncontrolled seizures worsen the very brain injury that caused them.

Definition and the "why are they different" concept

A neonatal seizure is a paroxysmal alteration in neurological function (motor, behavioural, autonomic) due to excessive, synchronous electrical discharge of cortical neurones, occurring within the first 28 days of life (or up to 44 weeks post-menstrual age in preterm babies).

The neonatal brain has features that make its seizures unique:

• Incomplete cortical organisation and poor myelination → discharges cannot propagate widely, so generalised tonic-clonic seizures (GTCS) virtually never occur in neonates.
• Relative excess of excitatory (glutamate) over inhibitory (GABA) circuitry, and GABA is paradoxically excitatory in the immature brain (high intracellular chloride via NKCC1 transporter) — this explains why GABAergic drugs like phenobarbitone are less effective than in adults and underlies experimental use of bumetanide (NKCC1 blocker).
• Electroclinical dissociation / uncoupling: many electrographic seizures have no clinical correlate (especially after a loading dose of an antiseizure drug — "uncoupling phenomenon"), and many "clinical" subtle events have no EEG correlate (these may be brainstem release phenomena, not true seizures).

High-yield: True GTCS do NOT occur in neonates because of incomplete cortical myelination and synaptogenesis. If asked "which seizure type does not occur in a neonate" → generalised tonic-clonic.

Classification of seizure types (Volpe / clinical classification)

This is the single most tested area. Learn the table cold.

Type	Description	EEG correlate	Notes
Subtle	Eye deviation/blinking, oro-buccal-lingual movements (chewing, sucking, lip-smacking), pedalling/bicycling/swimming/boxing limb movements, apnoea	Often NO correlate	Most common type overall, esp. in preterm; many are non-epileptic brainstem release
Clonic	Rhythmic, slow (1–3/s) jerking; focal or multifocal	Usually GOOD correlate (true seizure)	Most common in term babies; cannot be suppressed by holding the limb
Tonic	Sustained posturing; focal or generalised (decerebrate-like)	Focal tonic → correlate present; generalised tonic → often NO correlate	Generalised tonic mimics decerebrate posturing
Myoclonic	Single/multiple rapid lightning jerks (flexor); focal, multifocal, generalised	Generalised myoclonic → best correlate; focal/multifocal → variable	Often signifies severe diffuse CNS pathology; seen in inborn errors

High-yield: Subtle seizures are the commonest type overall and in preterms; multifocal clonic is commonest in term neonates. Apnoea as a seizure is usually accompanied by other subtle features and, unlike apnoea of prematurity, is NOT accompanied by bradycardia (the heart rate is maintained).

Jitteriness vs seizure — a perennial favourite distractor:

Feature	Jitteriness	Seizure
Stimulus-sensitive	Yes (provoked by handling)	No
Dominant movement	Tremor (equal amplitude to-and-fro)	Clonic jerk (fast-slow)
Abnormal gaze/eye movement	Absent	Often present
Stops on passive flexion/holding limb	Yes	No
Autonomic changes (tachycardia, BP, apnoea)	Absent	May be present

High-yield: A movement that stops when you gently hold/flex the limb and is stimulus-provoked is jitteriness, not a seizure. Jitteriness is associated with HIE, hypoglycaemia, hypocalcaemia and drug withdrawal.

Etiology — the timeline approach (extremely high-yield)

The age of onset narrows the cause dramatically. Use this stepwise reasoning:

Day 1–3 (first 72 h) → think HIE (commonest cause overall, peaks 12–24 h), then hypoglycaemia, hypocalcaemia (early), intracranial haemorrhage, pyridoxine dependency, drug withdrawal.

Day 4–7 → think infection (meningitis/sepsis), hypocalcaemia (late, "cow-milk/high-phosphate"), inborn errors of metabolism, intracranial haemorrhage, developmental brain malformations, benign familial neonatal seizures.

> Day 7 (after 1 week) → infection, herpes encephalitis, inborn errors, benign idiopathic ("fifth-day fits"), kernicterus, ductal-dependent CHD/stroke.

High-yield: Hypoxic-ischaemic encephalopathy (HIE) is the single commonest cause of neonatal seizures (~50–60%), and seizures from HIE typically begin within the first 24 hours (often 12–24 h). In a term baby seizing within hours of a difficult delivery, HIE is the answer.

Causes grouped by mechanism:

• Hypoxic-ischaemic encephalopathy — perinatal asphyxia; commonest.
• Metabolic — hypoglycaemia (<45 mg/dL, symptomatic), hypocalcaemia (total Ca <7 mg/dL or ionised <4 mg/dL / <1 mmol/L), hypomagnesaemia (<1.5 mg/dL — refractory hypocalcaemia is often actually low Mg), hypo/hypernatraemia.
• Infection — bacterial meningitis (GBS, E. coli, Listeria), TORCH, HSV encephalitis (think herpes if seizures after day 5–7 with CSF lymphocytosis).
• Intracranial haemorrhage / stroke — IVH in preterm, subarachnoid/subdural in term, perinatal arterial ischaemic stroke (classically focal clonic seizures in an otherwise well term baby, left MCA territory).
• Structural / malformations — lissencephaly, polymicrogyria, schizencephaly.
• Inborn errors of metabolism — urea cycle defects, organic acidaemias, MSUD, non-ketotic hyperglycinaemia, pyridoxine (B6)-dependent epilepsy.
• Drug withdrawal / toxicity — maternal opioids, inadvertent fetal scalp local-anaesthetic injection.
• Benign syndromes — Benign familial neonatal seizures (KCNQ2/KCNQ3 channelopathy), benign idiopathic neonatal seizures ("fifth-day fits", typically day 4–6, self-limiting).

Pathophysiology in brief

Energy failure (HIE, hypoglycaemia) → loss of Na⁺/K⁺-ATPase function → membrane depolarisation, glutamate release, NMDA/AMPA receptor over-activation → Ca²⁺ influx → excitotoxic neuronal injury. Seizures themselves increase cerebral metabolic demand and may cause secondary injury, hence prompt termination matters. In the immature brain the high NKCC1/low KCC2 ratio keeps intracellular chloride high, making GABA depolarising — the molecular basis of poor phenobarbitone response and the rationale for NKCC1 inhibition.

Clinical features and bedside clues

• Term baby, difficult delivery, Apgar low, encephalopathy + multifocal clonic jerks day 1 → HIE.
• Jittery, irritable, well baby on day 5–7, mother on high-phosphate feeds → late hypocalcaemia.
• Lethargy, poor feeding, temperature instability, bulging fontanelle, seizures day 4+ → meningitis.
• Focal clonic seizures in a vigorous term baby with normal interictal exam → perinatal arterial ischaemic stroke.
• Seizures unresponsive to all standard drugs, no metabolic cause → trial of IV pyridoxine (B6-dependent epilepsy) under EEG.

Diagnosis and investigation of choice

Investigation of choice for confirming and monitoring neonatal seizures = EEG (conventional/video EEG); continuous amplitude-integrated EEG (aEEG) is the practical cot-side tool.

High-yield: EEG is the gold standard for diagnosis because of electroclinical dissociation. aEEG (cerebral function monitor) is used cot-side for continuous monitoring and also for selecting/monitoring babies for therapeutic hypothermia.

Stepwise diagnostic workup:

1. Bedside glucose (first!) → then send labs.
2. Biochemistry: blood glucose, serum calcium (total + ionised), magnesium, sodium, electrolytes, ABG.
3. Sepsis screen + lumbar puncture (CBC, CRP, blood culture; CSF cytology/biochem/culture; consider HSV PCR in CSF).
4. EEG / aEEG to confirm electrographic seizures and assess background (burst-suppression and inactive backgrounds carry poor prognosis).
5. Cranial USG (first-line imaging for IVH in preterm) → MRI brain is the imaging of choice for HIE (diffusion-weighted), stroke, malformations and to prognosticate.
6. Metabolic workup if unexplained/refractory: serum ammonia, lactate, urine ketones/reducing substances, plasma amino acids, urine organic acids; trial of IV pyridoxine under EEG control.
7. TORCH screen as indicated.

High-yield: MRI (with DWI) is the imaging investigation of choice for HIE and best correlates with long-term outcome; cranial ultrasound is best for intraventricular haemorrhage in preterms.

Management — flow and drug of choice

Acute approach (memorise this flow):

ABC + check & correct glucose → correct electrolytes (Ca, Mg, Na) → if seizures persist, give Phenobarbitone IV → if persist, Phenytoin/Fosphenytoin (or Levetiracetam) → if persist, benzodiazepine (Midazolam infusion) → if refractory, trial Pyridoxine.

Step-by-step:

1. Supportive: secure airway, oxygen, IV access, maintain temperature and perfusion; do not delay for investigations.
2. Hypoglycaemia: IV dextrose 10% 2 mL/kg bolus (200 mg/kg) → followed by continuous infusion (glucose infusion rate 6–8 mg/kg/min, titrate up).
3. Hypocalcaemia: IV calcium gluconate 10% 2 mL/kg slowly with cardiac monitoring (watch for bradycardia/extravasation).
4. Hypomagnesaemia: magnesium sulphate 50% 0.25 mL/kg IM/IV — always check Mg in calcium-refractory tetany/seizures.
5. Antiseizure drug — drug of choice = Phenobarbitone.
   • Loading dose 20 mg/kg IV over 10–15 min; if no response, additional 10 mg/kg increments up to a total of 40 mg/kg.
   • Maintenance 3–5 mg/kg/day.
6. Second line: Phenytoin / fosphenytoin 20 mg/kg IV (fosphenytoin dosed as phenytoin-equivalents; phenytoin must NOT be mixed with dextrose — precipitates — and watch for arrhythmia/extravasation). Levetiracetam (40–60 mg/kg) is increasingly used as it is well tolerated, though older trials show phenobarbitone superior for seizure control.
7. Third line: Midazolam infusion or lignocaine infusion (not with phenytoin/cardiac disease).
8. Pyridoxine 100 mg IV under EEG monitoring for refractory seizures (B6-dependent epilepsy) — dramatic cessation is diagnostic.

High-yield: Phenobarbitone is the first-line drug of choice for neonatal seizures (loading 20 mg/kg, max 40 mg/kg). Phenytoin is second line. Despite GABA being depolarising in neonates, phenobarbitone remains the established first agent in guidelines/exams.

Therapeutic hypothermia (33.5°C for 72 h, started within 6 hours of birth) in moderate-to-severe HIE in term/near-term (≥36 weeks) babies reduces death and disability and reduces seizure burden — a frequently tested neuroprotective intervention.

High-yield: Therapeutic (whole-body/selective head) hypothermia must be initiated within 6 hours of birth in moderate-severe HIE to be neuroprotective.

Duration of therapy: if neurological exam and EEG normalise and cause is transient (metabolic), antiseizure drug can be stopped early; if the cause is structural/HIE with abnormal exam, continue and reassess.

Complications

• Acute: status epilepticus, aspiration, apnoea/hypoventilation, secondary excitotoxic brain injury, hyperthermia, metabolic derangement.
• Long-term neurodevelopmental sequelae: post-neonatal epilepsy, cerebral palsy, intellectual disability, microcephaly, sensorineural deficits, learning/behavioural problems.
• Prognosis is driven by aetiology and EEG background, not seizure type. Best outcome: late hypocalcaemia, benign familial/idiopathic seizures. Worst: HIE with burst-suppression/isoelectric EEG, structural malformations, severe IEMs.

Good prognosis	Poor prognosis
Late hypocalcaemia, benign familial/idiopathic ("5th-day") seizures	HIE (esp. stage III), structural malformations
Normal interictal EEG background	Burst-suppression or isoelectric EEG
Subarachnoid haemorrhage	Severe IVH (grade III–IV), meningitis with infarcts
Short seizure duration, prompt control	Status / refractory seizures, prolonged uncoupled electrographic seizures

Key differentials (non-epileptic mimics)

Distinguishing seizures from benign movements avoids unnecessary drugs:

• Jitteriness (see table) — stimulus-sensitive, stops on holding, no gaze deviation/autonomic change.
• Benign neonatal sleep myoclonus — myoclonic jerks only during sleep, stop on waking, normal EEG, normal development — NO treatment.
• Hyperekplexia ("stiff baby"/startle disease, glycine receptor GLRA1 mutation) — exaggerated startle, tonic stiffening on handling, relieved by forced neck flexion (Vigevano manoeuvre); treat with clonazepam.
• Apnoea of prematurity — apnoea with bradycardia and no other seizure features (seizure-related apnoea preserves heart rate).
• Sandifer syndrome / GORD posturing, opisthotonos of non-epileptic origin.

High-yield: Benign neonatal sleep myoclonus occurs only in sleep, abolished by arousal, has a normal EEG, and needs no treatment — a classic distractor against starting phenobarbitone.

Mnemonics and eponyms

• Causes mnemonic — "HIE MILD": HIE, Intracranial haemorrhage/stroke, Electrolyte/metabolic, Meningitis/sepsis, Inborn errors, Local anaesthetic/drug withdrawal, Developmental malformations.
• Metabolic quartet — "4 lows": low glucose, low calcium, low magnesium, low/high sodium.
• Vigevano manoeuvre — forced flexion of head/legs aborts the tonic spasm in hyperekplexia (life-saving, prevents apnoea).
• "Fifth-day fits" — benign idiopathic neonatal seizures, day 4–6, self-limiting.
• Sarnat & Sarnat staging — clinical grading of HIE (Stage I mild, II moderate, III severe); Stage II/III qualifies for cooling.

Recently asked / exam angle

• Commonest cause of neonatal seizures → HIE.
• Commonest seizure type overall / in preterm → subtle; commonest in term → multifocal clonic.
• Seizure type that does NOT occur in neonates → generalised tonic-clonic (immature cortex).
• Investigation of choice to confirm/monitor → EEG / aEEG; imaging of choice for HIE → MRI-DWI.
• Drug of choice / first-line → Phenobarbitone (loading 20 mg/kg); second line → phenytoin/fosphenytoin.
• Movement that stops on holding the limb and is stimulus-provoked → jitteriness, not a seizure.
• Myoclonus only in sleep, normal EEG, no treatment → benign neonatal sleep myoclonus.
• Refractory seizures responding to a vitamin → pyridoxine (B6)-dependent epilepsy.
• Time window for therapeutic hypothermia → within 6 hours of birth in moderate-severe HIE.
• Why GABA drugs work poorly in neonates → GABA is excitatory (high intracellular Cl⁻ via NKCC1); rationale for bumetanide.
• "Stiff baby" with exaggerated startle relieved by neck flexion → hyperekplexia (GLRA1), treat clonazepam.
• Apnoea without bradycardia in a seizing neonate vs apnoea of prematurity with bradycardia.

Rapid revision

1. HIE is the commonest cause of neonatal seizures; seizures usually start within 24 h.
2. Subtle seizures are commonest overall and in preterms; multifocal clonic is commonest in term babies.
3. Generalised tonic-clonic seizures do not occur in neonates (immature cortex).
4. EEG/aEEG is the gold standard for diagnosis due to electroclinical dissociation/uncoupling.
5. Always check glucose first; correct Ca, Mg, Na before escalating drugs.
6. Drug of choice = phenobarbitone 20 mg/kg loading (max 40 mg/kg); second line = phenytoin/fosphenytoin.
7. Hypoglycaemia treated with D10 2 mL/kg bolus; hypocalcaemia with calcium gluconate 10% 2 mL/kg slow IV.
8. Refractory seizures with no metabolic cause → trial IV pyridoxine under EEG.
9. Therapeutic hypothermia within 6 h for moderate-severe HIE (Sarnat II–III, ≥36 weeks).
10. Jitteriness stops on holding the limb, is stimulus-sensitive, and has no gaze/autonomic change.
11. Benign neonatal sleep myoclonus occurs only in sleep, normal EEG, no treatment.
12. Prognosis depends on aetiology + EEG background; burst-suppression = poor outcome.