Neonatal Epilepsy Syndromes By Age

Published: 2026-09-28 23:53:35

Neonatal Epilepsy Syndromes by Age

John Giang, MD

Why it matters

In the neonate the onset day, the EEG background and the child's state between seizures narrow the diagnosis faster than any single test. A well-baby with frequent focal seizures on day 3 and a hypotonic, hiccupping baby with burst suppression on day 1 have different genes, different treatments and different futures, and the EEG reader is often the first to see the difference.

Key points

Onset window 1: first hours to days (day 0–3), sick baby, abnormal background. Think treatable metabolic and channelopathy DEEs before settling on HIE.

Disorder	Peak onset	Most prominent EEG	Clue
Pyridoxine-dependent epilepsy (ALDH7A1) and PNPO deficiency	Median 9 h, range 1h-6 d; may begin in utero	Burst suppression in 62% during the first 5 days (bursts 50-250 µV, IBI 1-10 s); otherwise, excessive discontinuity with multifocal sharps; focal side-shifting electrographic seizures; no hypsarrhythmia	Refractory to standard ASMs; responds to pyridoxine (ALDH7A1) or P5P (PNPO)
Folinic acid-responsive seizures	First days of life	Same as PDE	Allelic to ALDH7A1; treat with both cofactors
Non-ketotic hyperglycinemia	First hours to days (85% of neonatal presenters have severe NKH)	Burst suppression, myoclonic seizures, then evolution to hypsarrhythmia over months	Progressive lethargy to coma, profound hypotonia, apnea needing ventilation, intractable hiccups
Holocarboxylase synthetase deficiency	Hours to weeks	Nonspecific: multifocal discharges or burst suppression	Lethargy, hypotonia, metabolic acidosis; biotin-responsive
Zellweger spectrum (peroxisomal)	Neonatal period	Multifocal spikes with disorganized slow background; may evolve to hypsarrhythmia	Profound hypotonia, poor feeding, dysmorphism
KCNQ2 (and SCN2A) neonatal DEE	Mean 1.8 days, first week	Burst suppression in about half of first-week EEGs; multiple daily tonic seizures	Encephalopathic between seizures; seizures often stop by 1-3 yr but development remains impaired
Mitochondrial (PDH deficiency, mtDNA depletion, respiratory chain)	Neonatal in severe forms	Burst suppression or multifocal discharges with diffuse slowing; may be indistinguishable from EIDEE	Lactic acidosis, multiorgan involvement

Onset window 2: day 2–7, well baby, normal or near-normal background.

Self-limited (familial) neonatal epilepsy (SeLNE), KCNQ2 > KCNQ3: focal tonic or clonic seizures begin day 2–7 after a seizure-free interval; the neonate behaves normally between seizures. Interictal EEG is normal or shows focal central or centrotemporal sharps in about two thirds; ictal EEG shows attenuation for up to 20 s followed by repetitive spikes, often bilateral, asynchronous and shifting side between seizures. Most remit by 6 weeks, nearly all by 6 months; about a third have later seizures.
Self-limited familial neonatal-infantile epilepsy (SeLFNIE), mostly SCN2A: onset day 1 to 23 months, mixed neonatal and infantile onsets within a family, remission by 12–24 months.

Onset window 3: birth to 3 months, encephalopathic infant.

Early-infantile DEE (EIDEE; former Ohtahara and early myoclonic encephalopathy): onset at or before 3 months, frequent drug-resistant tonic, myoclonic or focal seizures; the background is abnormal in every state and must show either burst suppression (bursts 150–300 µV of spikes and sharps for 1–5 s, interbursts 3–10 s below 5 µV) or multifocal discharges with diffuse slowing. Structural causes are most common; genetic (KCNQ2, STXBP1, SCN2A, CDKL5) and metabolic causes follow, and pyridoxine and P5P disorders must be excluded early. May evolve into IESS or Lennox-Gastaut.
Epilepsy of infancy with migrating focal seizures (EIMFS), KCNT1 > SCN2A: mean onset about 1 month (range 1 hour to 4–6 months). EEG hallmark is a nearly continuous ictal pattern: focal rhythmic theta-alpha discharges that migrate from one region and hemisphere to another within and between seizures, with autonomic and motor signs; background slows progressively. High drug resistance and mortality.

Onset window 4: 1–24 months, peak 3–12 months.

Infantile epileptic spasms syndrome (IESS; West syndrome when spasms, hypsarrhythmia and regression coexist): clusters of epileptic spasms, often on waking. Hypsarrhythmia is a highly disorganized, high-voltage irregular slow background with multifocal spikes and polyspikes, most evident in drowsiness, sleep and on waking; the awake background can be normal early, and some infants have only focal or multifocal discharges. Ictal correlate is a high-amplitude slow wave followed by diffuse electrodecrement with fast activity. Neonatal-onset DEEs, NKH, Zellweger and KCNQ2 can all evolve into it.

Using age as the clue

Day 0–1 with burst suppression: metabolic until proven otherwise; start pyridoxine, P5P and folinic acid trials while awaiting glycine and genetics.
Day 2–7 with a well-baby and normal background: KCNQ2/KCNQ3 SeLNE; day 2–7 with an encephalopathic baby and burst suppression: KCNQ2 DEE.
Weeks 2–8 with side-shifting near-continuous seizures: EIMFS (KCNT1).
Months 3–12 with spasms and hypsarrhythmia: IESS; ask what preceded it.

Common pitfalls

Assuming a normal exam between seizures excludes a genetic cause; SeLNE babies look well and still carry KCNQ2 variants.
Attributing neonatal burst suppression to HIE alone and never running the pyridoxine, P5P and folinic acid trials.
Ending a pyridoxine trial after one dose; EEG and clinical response can be delayed, and PNPO deficiency needs P5P rather than pyridoxine.
Reading migrating seizures as ordinary multifocal seizures; the hallmark of EIMFS is one seizure's field moving across regions and hemispheres, not several independent foci.
Dismissing intractable hiccups with hypotonia and apnea as feeding trouble rather than a red flag for NKH.
Waiting for classic hypsarrhythmia before diagnosing spasms; early IESS may show a normal awake record with abnormality only in sleep or on waking.
Relabeling a DEE as "self-limited" because seizures stopped on medication; remission without developmental cost is what defines the self-limited syndromes.