Neonatal & Infantile Encephalopathies
Neonatal & Infantile Epileptic Encephalopathies
What Do You Need to Know?
- ILAE 2022 terminology: DEE = developmental AND epileptic encephalopathy; EE = epileptic encephalopathy (seizures/EEG cause regression); DE = developmental encephalopathy (genetic cause, independent of seizures)
- Ohtahara (EIEE): tonic spasms, burst-suppression in wake AND sleep, structural/genetic causes (STXBP1, KCNQ2); evolves to West → LGS
- EME: erratic fragmentary myoclonus, burst-suppression in sleep > wake, metabolic causes (NKH, pyridoxine dependency)
- West syndrome: spasms + hypsarrhythmia + regression; onset 3–12 months; ACTH/prednisolone for non-TSC, vigabatrin first-line for TSC; neurologic EMERGENCY
- KCNQ2-DEE: dominant-negative = severe DEE; haploinsufficiency = self-limited BFNS; Na channel blockers paradoxically help (precision medicine)
- Pyridoxine trial is MANDATORY in ALL refractory neonatal seizures — 100 mg IV under EEG monitoring (ALDH7A1 gene)
- Precision therapy: gene-specific treatment now possible for KCNQ2, SCN2A, KCNT1, CDKL5, TSC, ALDH7A1, SLC2A1
ILAE 2022 DEE / EE / DE Terminology
- DEE (developmental AND epileptic encephalopathy): both the underlying etiology AND the epileptic activity contribute to neurodevelopmental impairment — most neonatal-onset syndromes fall here
- EE (epileptic encephalopathy): seizures/interictal EEG activity cause regression beyond what the underlying cause would produce alone
- DE (developmental encephalopathy): neurodevelopmental impairment is from the genetic/structural cause itself, independent of seizures
- "Early infantile DEE" now replaces both Ohtahara syndrome and EME in ILAE nomenclature (though eponyms remain widely used)
- "Self-limited" replaces "benign"; "familial" is added when family history is present
💎 Board Pearl
- DEE = dual mechanism (both gene + seizures harm development); EE = seizures are the main driver of regression; DE = gene alone causes impairment
- A child with TSC who has cognitive decline driven by both cortical tubers AND infantile spasms = classic DEE
Ohtahara Syndrome (EIEE) vs. Early Myoclonic Encephalopathy (EME)
| Feature | Ohtahara Syndrome (EIEE) | Early Myoclonic Encephalopathy (EME) |
|---|---|---|
| Onset | First 3 months (often first 10 days) | First month (often first week) |
| Hallmark seizure | Tonic spasms (brief, clusters) | Erratic fragmentary myoclonus (face, fingers, limbs — asynchronous) |
| Myoclonus | Rare or absent | Defining feature |
| Burst-suppression EEG | Wake AND sleep (constant) | Sleep > wake (may be less consistent awake) |
| Predominant etiology | Structural (cortical dysplasia, hemimegalencephaly) | Metabolic (NKH, pyridoxine dependency, organic acidurias) |
| Key genes | STXBP1, KCNQ2, ARX, SCN2A | ALDH7A1, PNPO, GLDC/AMT (NKH genes) |
| Evolution | Ohtahara → West → LGS (~75%) | Does NOT follow Ohtahara → West → LGS pathway |
| Treatable cause? | Rarely (surgery if focal cortical dysplasia) | Possibly (pyridoxine, PLP deficiency) |
| Prognosis | Extremely poor; high mortality | Catastrophic; ~50% die within weeks/months |
Clinical Pearl
STXBP1 (Munc18-1) is the most common single-gene cause of Ohtahara syndrome. It disrupts synaptic vesicle docking. Levetiracetam may have a preferential role because it acts on SV2A in the same presynaptic pathway.
West Syndrome / Infantile Epileptic Spasms Syndrome
Classic Triad
- Epileptic spasms in clusters — brief tonic contractions, typically upon awakening
- Hypsarrhythmia on EEG — chaotic, high-amplitude (>200 μV), asynchronous, multifocal spikes and slow waves
- Developmental regression — loss of social smile, visual attention, milestones
Key Features
- Onset: 3–12 months (peak 4–7 months)
- Neurologic EMERGENCY — delay worsens neurodevelopmental outcomes; treat within days
- Ictal EEG: electrodecremental response (sudden diffuse attenuation) during each spasm
- Asymmetric spasms suggest a focal structural lesion → evaluate for surgery
- Etiology identified in ~60–70%: structural (perinatal injury, cortical malformations, TSC), genetic (TSC1/2, CDKL5, STXBP1, ARX), metabolic
Treatment
| Etiology | First-Line | Response Rate |
|---|---|---|
| Non-TSC | ACTH or high-dose prednisolone ± vigabatrin | ~65–75% |
| TSC | Vigabatrin (FIRST-LINE) | ~65–95% |
| Combination (ICISS) | Hormonal + vigabatrin | 72% vs. 57% monotherapy |
Landmark Trials
- UKISS (2004–2005): hormonal therapy superior to vigabatrin for non-TSC (73% vs. 54%); exception = TSC responds better to vigabatrin
- ICISS (2017): combination (hormonal + vigabatrin) = 72% spasm cessation vs. 57% hormonal alone
- EPISTOP (2021): preventive vigabatrin in TSC at first EEG abnormality (before clinical seizures) reduced epilepsy risk and improved development — paradigm shift
Evolution & Outcomes
- 50–70% evolve to other epilepsy types; 20–40% evolve to LGS
- Normal development in only 10–25% (best in unknown etiology with rapid treatment)
- Vigabatrin adverse effect: irreversible bilateral concentric visual field constriction (25–50% with prolonged use)
💎 Board Pearl
- Vigabatrin = first-line for TSC-related spasms specifically; ACTH/prednisolone for everything else
- Electrodecremental response on EEG during a spasm = classic ictal correlate
- EPISTOP trial = treat TSC infants at first EEG abnormality, even before clinical seizures
KCNQ2-DEE (Precision Medicine Example)
Genotype-Phenotype Spectrum
| Feature | KCNQ2-DEE (Severe) | Self-Limited BFNS (Benign) |
|---|---|---|
| Mutation type | De novo missense → dominant-negative effect | Inherited LOF → haploinsufficiency |
| M-current loss | >50% (abnormal protein poisons normal channels) | ~50% (one allele lost) |
| EEG | Burst-suppression or multifocal discharges | Normal interictal |
| Seizure outcome | Drug-resistant; may improve over years | Self-limited; resolve by 6 weeks |
| Development | Moderate-severe intellectual disability | Normal |
Treatment Implication
- Na+ channel blockers (carbamazepine, phenytoin) PARADOXICALLY HELP — indirectly enhance residual M-current
- This is the opposite of typical neonatal epilepsy management (where Na blockers are often avoided)
- SCN2A gain-of-function (early onset): also responds to Na channel blockers — same precision medicine principle
- Novel KV7 channel openers (XEN496/XEN1101) in clinical development
💎 Board Pearl
- Same gene (KCNQ2) → two opposite phenotypes depending on variant type: dominant-negative = DEE, haploinsufficiency = benign BFNS
- Na channel blockers help KCNQ2-DEE (paradoxical) but must be AVOIDED in Dravet (SCN1A loss-of-function)
Pyridoxine-Dependent Epilepsy (ALDH7A1)
- Gene: ALDH7A1 (antiquitin) — autosomal recessive
- Mechanism: deficient antiquitin → accumulation of alpha-AASA and P6C → P6C inactivates PLP (active B6) → impaired GABA synthesis via GAD
- Onset: neonatal in ~75%; up to 3 years; prenatal seizures possible (fetal movements)
- Seizures: prolonged/status epilepticus, refractory to all standard ASMs
- Diagnosis: elevated urinary alpha-AASA (most sensitive), elevated plasma pipecolic acid, ALDH7A1 genetic testing
MANDATORY Vitamin Trial Protocol
- Pyridoxine 100 mg IV under continuous EEG monitoring — seizures may cease within minutes
- If pyridoxine fails → trial pyridoxal-5'-phosphate (PLP) 30–50 mg/kg/day enterally (for PNPO deficiency)
- If both fail → trial folinic acid 5 mg/kg/day (folinic acid-responsive seizures are allelic with PDE)
- Must trial in ALL refractory neonatal seizures — do NOT wait for genetic results
💎 Board Pearl
- IV pyridoxine bolus can cause apnea and cardiovascular collapse in responders — administer with resuscitation equipment ready
- Failure to give a vitamin trial is a PREVENTABLE cause of death in treatable neonatal epilepsy
- Lifelong pyridoxine supplementation required; ~75% still have some intellectual disability even with treatment
CDKL5 Deficiency Disorder
- Gene: CDKL5 (X-linked) — serine/threonine kinase critical for synaptogenesis
- Onset: first 3 months (median ~6 weeks) — earlier than classic Rett syndrome
- Seizure types: hypermotor/tonic-vibratory seizures, epileptic spasms, frequent status epilepticus
- Clinical features: severe ID, absent speech, stereotypic hand movements (Rett-like), cortical visual impairment
- Key distinction from Rett: earlier seizure onset, no period of normal development, MECP2-negative
- EEG: multifocal discharges; NO burst-suppression
- Treatment: profoundly drug-resistant; ganaxolone FDA-approved (neurosteroid, GABA-A modulator; Marigold trial)
- Emerging: AAV-mediated gene replacement therapy in early clinical trials
KCNT1 — Epilepsy of Infancy with Migrating Focal Seizures
- Gene: KCNT1 gain-of-function (~50% of cases)
- Onset: first 6 months (peak ~3 months)
- Hallmark: migrating focal seizures — ictal activity arises in one cortical region, subsides, then emerges in a different region on EEG (pathognomonic)
- Seizure features: prominent autonomic (facial flushing, apnea, cyanosis), eye deviation, clonic activity; frequent status epilepticus
- Treatment: extremely drug-resistant; quinidine trial (K channel blocker to reduce GOF effect) — mixed results, cardiac monitoring mandatory (QT prolongation)
- Prognosis: severe; profound disability; reduced life expectancy
Self-Limited Neonatal & Infantile Epilepsy Syndromes
| Feature | BFNS (KCNQ2) | BFNIS (SCN2A) | BFIS (PRRT2) |
|---|---|---|---|
| Onset | Day 2–7 ("fifth day fits") | 2 days – 7 months | 3–12 months |
| Seizure type | Generalized clonic/tonic, brief clusters | Focal ± secondary generalization | Clusters of focal seizures with eye deviation |
| Gene / Mechanism | KCNQ2 (LOF, haploinsufficiency) | SCN2A (GOF in early onset) | PRRT2 (interacts with SNAP25) |
| Inheritance | AD (~85% penetrance) | Autosomal dominant | Autosomal dominant |
| Interictal EEG | Normal (no burst-suppression) | Normal | Normal |
| Treatment | Self-limited; resolve by 6 weeks | Na blockers help early-onset GOF | Responds to OXC; NOT to LEV |
| Prognosis | Excellent; 16% later epilepsy | Excellent; remits by 12 months | Excellent; remits by 3 years |
| Special | — | SCN2A LOF (late-onset) = AVOID Na blockers | PRRT2 → PKD in teens, or ICCA syndrome |
Clinical Pearl
PRRT2: one gene → three phenotypes. The same PRRT2 variant can cause BFIS (infantile seizures), paroxysmal kinesigenic dyskinesia (PKD) in adolescence, and infantile convulsions with choreoathetosis (ICCA). Boards love this "one gene, multiple phenotypes" concept.
Precision Therapy by Gene
| Gene | Mechanism | Targeted Treatment |
|---|---|---|
| KCNQ2 | Dominant-negative K channel dysfunction | Na channel blockers (CBZ, PHT) |
| SCN2A (GOF, early onset) | Enhanced Na channel activity | Na channel blockers (CBZ, PHT) |
| SCN1A (Dravet) | Na channel LOF | AVOID Na blockers; VPA + clobazam + stiripentol, fenfluramine |
| CDKL5 | Kinase dysfunction | Ganaxolone (FDA-approved) |
| KCNT1 | K channel GOF | Quinidine (mixed results) |
| TSC1/TSC2 | mTOR pathway overactivation | Vigabatrin (spasms); everolimus (mTOR inhibitor) |
| ALDH7A1 | PLP inactivation → impaired GABA synthesis | Pyridoxine (lifelong) + lysine restriction |
| SLC2A1 (GLUT1) | Impaired glucose transport into brain | Ketogenic diet |
| STXBP1 | Impaired synaptic vesicle docking | Levetiracetam (acts on SV2A in same pathway) |
💎 Board Pearl
- SCN2A early onset (GOF) = Na blockers HELP; SCN1A Dravet (LOF) = Na blockers HARM — opposite responses despite both being Na channel genes
- Genetic diagnosis changes management in >70% of epilepsy patients — always pursue testing in early-onset DEE
Aicardi Syndrome
- Classic triad: infantile spasms + agenesis of the corpus callosum + chorioretinal lacunae
- Sex: females only — X-linked dominant, presumed lethal in males (gene not yet identified)
- Chorioretinal lacunae: round, depigmented lesions on fundoscopy — pathognomonic
- Additional features: polymicrogyria, heterotopia, vertebral anomalies (hemivertebrae, butterfly vertebrae), microphthalmia
- EEG: asynchronous burst-suppression or hypsarrhythmia between hemispheres ("split-brain" pattern from absent corpus callosum)
- Prognosis: severe ID, drug-resistant epilepsy, median survival to late childhood/early adolescence
Clinical Pearl
Board question classic: a female infant with spasms, absent corpus callosum on MRI, and round white lesions on fundoscopy = Aicardi syndrome. Remember: Agenesis of corpus callosum + Aicardi + chorioretinal lacunae. If it occurs in a "male," suspect 47,XXY (Klinefelter).
Board Pearls — Summary
💎 Board Pearl
- Burst-suppression in wake + sleep = Ohtahara; burst-suppression in sleep > wake = EME — the #1 tested EEG distinction
- Pyridoxine 100 mg IV trial is mandatory in ALL refractory neonatal seizures — failure to trial is a preventable cause of death
- Vigabatrin = first-line for TSC-associated spasms; ACTH/prednisolone for all other etiologies
- KCNQ2-DEE responds to Na channel blockers (paradoxical) — a defining precision medicine example
- SCN1A (Dravet) vs. SCN2A (GOF): Na blockers HARM in Dravet (LOF) but HELP in early-onset SCN2A (GOF)
- PRRT2 = one gene, three phenotypes: BFIS + PKD + ICCA
- ICISS trial: combination (hormonal + vigabatrin) = 72% vs. 57% monotherapy — now recommended first-line
References
- Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants. Epilepsia. 2022;63(6):1349–1397.
- Specchio N, Curatolo P. Developmental and epileptic encephalopathies: what we do and do not know. Brain. 2021;144(1):32–43.
- O'Callaghan FJ, et al. Hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS). Lancet Neurol. 2017;16(1):33–42.
- Kotulska K, et al. Prevention of epilepsy in infants with TSC in the EPISTOP trial. Ann Neurol. 2021;89(2):304–314.
- Lux AL, et al. UKISS: hormone treatment vs vigabatrin for infantile spasms. Lancet Neurol. 2005;4(11):712–717.
- Weckhuysen S, et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann Neurol. 2012;71(1):15–25.
- Mills PB, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12(3):307–309.
- Olson HE, et al. Cyclin-dependent kinase-like 5 deficiency disorder: clinical review. Pediatr Neurol. 2019;97:18–25.
- Knight EMP, et al. Ganaxolone for CDKL5 deficiency disorder: Marigold study. Lancet Neurol. 2022;21(10):891–901.
- Barcia G, et al. De novo gain-of-function KCNT1 mutations cause migrating partial seizures of infancy. Nat Genet. 2012;44(11):1255–1259.
- McTague A, et al. Genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304–316.
- Saitsu H, et al. De novo mutations in STXBP1 cause early infantile epileptic encephalopathy. Nat Genet. 2008;40(6):782–788.
- Ohtahara S, Yamatogi Y. Ohtahara syndrome: developmental aspects for differentiating from EME. Epilepsy Res. 2006;70(Suppl 1):S58–S67.
- Aicardi J. Aicardi syndrome. Brain Dev. 2005;27(3):164–171.