Childhood Epileptic Encephalopathies

What You'll Learn

LGS triad: (1) multiple seizure types with MANDATORY tonic seizures, (2) slow <2.5 Hz spike-and-wave, (3) cognitive impairment; GPFA 10–25 Hz during NREM = highly characteristic
Dravet: SCN1A loss-of-function (>80%); NaV1.1 in inhibitory interneurons; Na+ channel blockers CONTRAINDICATED (CBZ, OXC, PHT, LTG, lacosamide)
Doose (MAE): myoclonic-atonic drops in previously normal child; NO tonic seizures (vs. LGS); ketogenic diet often first-line; 60–70% remit
GEFS+: defined at FAMILY level (≥2 members); SCN1A most common gene; same variant → FS in parent, Dravet in child
TSC: TSC1/TSC2 → mTOR hyperactivation; vigabatrin first-line for spasms (65–95%); everolimus for drug-resistant focal seizures (EXIST-3)
Rasmussen: T-cell mediated unilateral inflammation; EPC in 50–80%; hemispherectomy = definitive (70–80% seizure-free)

HighYield Pearls

West syndrome / IESS triad: infantile spasms + hypsarrhythmia + developmental regression/arrest; onset 3–12 mo (peak 4–7 mo); urgent treatment preserves cognition; lead time matters more than agent choice.
IESS first-line therapy by etiology: non-TSC → hormonal (ACTH or high-dose oral prednisolone); TSC → vigabatrin first (65–95% spasm cessation). ICISS showed hormonal + vigabatrin improved early spasm cessation vs hormonal alone; combination therapy can be considered, especially in high-risk or local-protocol pathways, but is not universal first-line.
Dravet = prolonged FEBRILE hemiclonic seizures in 1st year in previously healthy infant; SCN1A loss-of-function in >80%; AVOID Na+ channel blockers (CBZ, OXC, PHT, LTG, lacosamide); first-line VPA + clobazam ± stiripentol, cannabidiol, fenfluramine; SUDEP risk ~9–10%.
LGS triad: multiple drug-resistant seizure types with MANDATORY tonic seizures + slow <2.5 Hz spike-and-wave + cognitive impairment; GPFA 10–25 Hz NREM highly characteristic; treat with VPA, clobazam, rufinamide, cannabidiol, fenfluramine; corpus callosotomy for drop attacks.
Doose / EMAS: previously normal child 1–5 yr → myoclonic-atonic drops + GTC + atypical absence; NO tonic seizures (vs. LGS); ketogenic diet often first-line; 60–70% remit.
Landau-Kleffner = acquired auditory verbal agnosia in previously normal 3–8 yr old → language regression; ESES/SWAS pattern in sleep; treat with steroids/IVIG/clobazam; AVOID CBZ — can precipitate or worsen SWAS.
EE-SWAS / DEE-SWAS (ESES/CSWS): spike-wave index >85% of NREM + cognitive/behavioral regression; nocturnal EEG mandatory; high-dose steroids or pulse benzodiazepines first-line.
Ohtahara (now EIDEE): neonatal onset; burst-suppression in BOTH wake AND sleep; tonic spasms; structural malformations + STXBP1, KCNQ2, ARX; evolves to West → LGS.
EME (now EIDEE): neonatal onset; erratic fragmentary myoclonus; burst-suppression mainly in SLEEP; predominantly metabolic (nonketotic hyperglycinemia, pyridoxine-dependent); always trial pyridoxine / P5P / folinic acid.
Ketogenic diet indications: GLUT1 deficiency (SLC2A1, urgent), PDH deficiency (urgent), refractory infantile spasms, Doose, LGS, FIRES — do not delay genetic testing for GLUT1.

🔍 Quick ReferenceEEG · Clinical · Genetics / etiology / treatment

EEG signs

Hypsarrhythmia (chaotic high-voltage polymorphic delta + multifocal spikes, no normal background) → West / IESS
Slow <2.5 Hz generalized spike-and-wave + paroxysmal fast activity (GPFA 10–25 Hz NREM) → Lennox-Gastaut
Burst-suppression in BOTH wake AND sleep → Ohtahara (classical EIDEE)
Burst-suppression in SLEEP only (fragmented when awake) → EME (classical EIDEE)
Generalized 2–6 Hz spike-and-wave + theta, NO GPFA → Doose / EMAS
Spike-wave index ≥85% of NREM sleep → ESES/CSWS / EE-SWAS / Landau-Kleffner
Bilateral temporal / centrotemporal SWAS focus → Landau-Kleffner

Clinical signs

Flexor/extensor “jackknife” spasms in clusters on awakening + developmental regression at 4–7 mo → West / IESS
Prolonged hemiclonic FEBRILE seizures in 1st year in previously healthy infant → Dravet
Crouch gait in older child with drug-resistant epilepsy → Dravet
Drop attacks + multiple seizure types + intellectual disability → Lennox-Gastaut
Previously normal child with myoclonic-atonic drops + GTC, no tonic seizures → Doose / EMAS
Previously normal child losing language with intact hearing (verbal auditory agnosia) → Landau-Kleffner
Intractable focal seizures + cortical tubers + cardiac rhabdomyoma → TSC
Fever-triggered focal seizure CLUSTERS in girls with long seizure-free intervals → PCDH19

Genetics / etiology / treatment pearls

SCN1A loss-of-function → Dravet (AVOID Na+ channel blockers); missense often → GEFS+
KCNQ2 + neonatal seizures responsive to Na+ channel blockers (CBZ, PHT) → KCNQ2 encephalopathy (paradox vs. Dravet)
CDKL5 in girls with early-onset DEE (X-linked) → CDKL5 encephalopathy
STXBP1 → Ohtahara / EIDEE (also LGS); ARX X-linked + malformation → Ohtahara, West
MECP2 + hand stereotypies + breath holding in girls → Rett
SLC2A1 + low CSF glucose (<40 or CSF:serum <0.4) → GLUT1 deficiency → ketogenic diet
Pyridoxine-dependent (ALDH7A1) + neonatal seizures responsive to B6 trial → pyridoxine-dependent epilepsy; also folinic acid–responsive seizures & biotinidase deficiency
TSC + tubers + SEGA + cardiac rhabdomyoma → vigabatrin first for spasms; everolimus (mTOR inhibitor) for refractory focal seizures + SEGA + AML
Vigabatrin >6 mo → visual field constriction screening (irreversible bilateral concentric VF loss)
Stiripentol in Dravet only with VPA + clobazam backbone (STICLO 71% vs. 5%); inhibits CYP2C19/3A4 → reduce CLB dose

Early Infantile DEE (EIDEE)

Ohtahara (EIEE) & EME — merged under EIDEE (ILAE 2022)

Concept & ILAE 2022

ILAE 2022 merged Ohtahara (EIEE) and Early Myoclonic Encephalopathy (EME) into a single syndrome: Early Infantile DEE (EIDEE), recognizing substantial overlap and shared genetic etiologies.
Onset in the first 3 months of life (often first weeks); severe encephalopathy and drug-resistant seizures.
High early mortality; survivors have profound developmental impairment; many evolve to West syndrome → LGS.

Classical Ohtahara (EIEE)

Predominant seizure type: tonic spasms (singly or in clusters), ± focal seizures
EEG: burst-suppression present in BOTH wakefulness AND sleep (continuous)
Etiologies: structural (cortical malformation, hemimegalencephaly) and genetic — STXBP1, KCNQ2, ARX, SCN2A, SLC25A22

Classical EME

Predominant seizure types: erratic / fragmentary myoclonus, plus focal seizures
EEG: burst-suppression in SLEEP only (may be absent or fragmented when awake)
Etiologies: predominantly metabolic — nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, sulfite oxidase / molybdenum cofactor deficiency, mitochondrial disorders, propionic/methylmalonic acidemia

Workup & Treatment

Trial of pyridoxine, pyridoxal-5-phosphate, folinic acid in any neonate with refractory seizures
Targeted gene panel / WES; metabolic screen (CSF glycine, lactate, amino acids; urine organic acids; serum acylcarnitines)
MRI for structural cause; consider hemispherectomy if hemimegalencephaly
Pharmacotherapy guided by genotype: KCNQ2 → Na+ channel blockers (CBZ, PHT) often effective; STXBP1 variable response; ACTH/vigabatrin if spasms predominate

West Syndrome / Infantile Epileptic Spasms Syndrome (IESS)

Triad, EEG, Etiologies & Treatment

Triad

(1) Epileptic spasms — brief, symmetric, axial flexion/extension/mixed; occur in clusters, often on awakening
(2) Hypsarrhythmia on interictal EEG
(3) Developmental regression or arrest
Note: ILAE 2022 term is Infantile Epileptic Spasms Syndrome (IESS); West syndrome = classic full triad
Onset typically 3–12 months (peak 4–7 months); incidence ~1/2,000–4,000 live births

Hypsarrhythmia & Modified Variants

Classic hypsarrhythmia: chaotic, high-voltage (>200–300 μV) disorganized slow waves with multifocal spikes and sharp waves; no normal background
Modified hypsarrhythmia variants: increased interhemispheric synchronization, asymmetric (focal lesion), episodes of attenuation, consistent focus of discharges, or preserved background
Ictal correlate: generalized high-voltage slow wave followed by electrodecrement

Etiologies

Structural (~50–60%): HIE, perinatal stroke, periventricular leukomalacia, cortical malformations, TSC, lissencephaly, hemimegalencephaly
Genetic (~15–25%): ARX, CDKL5, STXBP1, SCN2A, SPTAN1, FOXG1; trisomy 21
Metabolic: pyridoxine-dependent, biotinidase, PKU, NKH, mitochondrial
Unknown (~10–20%) — better prognostic group

First-Line Therapy

Non-TSC etiology: hormonal therapy first-line — ACTH (high-dose IM) or high-dose oral prednisolone (40–60 mg/day)
TSC: vigabatrin first-line (65–95% spasm cessation) — superior to hormonal therapy in TSC specifically
Short lead-time-to-treatment is critical — delay >1–2 months worsens developmental outcome regardless of which agent achieves spasm cessation

Key Trials

Trial	Comparison	Result
UKISS	Hormonal (tetracosactide or prednisolone) vs. vigabatrin	Hormonal > VGB for spasm cessation at 14 days (73% vs. 54%); developmental advantage at 14 mo only in non-structural cases (NOT sustained at 4 yr)
ICISS	Hormonal alone vs. hormonal + vigabatrin combination	Combination improved early spasm cessation (72% vs 57% by day 14–42); faster response; developmental benefit in subgroups. For boards, hormonal therapy remains first-line for non-TSC and vigabatrin first-line for TSC; combination considered, especially in high-risk or local-protocol pathways.

Prognosis

~20–30% evolve to LGS; many develop focal epilepsies
Long-term cognitive normal outcomes in only ~15–25% (best with unknown etiology + short lead time)
Mortality 5–15% in first decade (etiology-dependent)

💎 Board Pearl — IESS Therapy Choice

TSC infant with spasms → vigabatrin first. Non-TSC infant with spasms → hormonal therapy first (ACTH or high-dose oral prednisolone).
ICISS: hormonal + vigabatrin improved early spasm cessation vs hormonal alone. Combination therapy can be considered, especially in high-risk or local-protocol pathways — not universal first-line.
Lead time matters more than agent choice for developmental outcome.

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