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: most variants are de novo missense with dominant-negative or strong loss-of-function effects causing severe DEE; inherited haploinsufficiency typically causes self-limited BFNE (though exceptions exist); 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
🚩 Don’t Miss — Test-Day Priorities
- Pyridoxine trial in ANY refractory neonatal seizure: 100 mg IV under EEG monitoring (ALDH7A1) — missing this is a board-exam & clinical never-event
- CSF glucose <40 mg/dL or CSF:serum ratio <0.4 → GLUT1 deficiency (SLC2A1): fasting LP required; ketogenic diet is both diagnostic and therapeutic — don’t delay
- Burst-suppression EEG awake AND asleep → Ohtahara; burst-suppression mainly in sleep with erratic fragmentary myoclonus → EME (metabolic)
- KCNQ2-DEE = paradoxical Na-channel-blocker responder: carbamazepine/oxcarbazepine/phenytoin work (opposite of Dravet) — precision medicine pearl
- SCN2A is bidirectional: gain-of-function (early onset, <3 mo) responds to Na blockers; loss-of-function (later onset) is WORSENED by Na blockers
- KCNT1 migrating partial seizures of infancy → quinidine trial (channel-specific therapy)
- CDKL5-DEE = X-linked, girls, Rett-like: ganaxolone is FDA-approved for CDKL5 seizures
- Biotinidase deficiency: partial-tonic seizures + lactic acidosis + alopecia + rash → biotin reverses; on universal newborn screen
- Always order metabolic workup early: lactate, ammonia, plasma amino acids, urine organic acids, CSF glycine, GAA — before labeling as "genetic DEE"
- Genetic testing is essential for DEE management: changes both prognosis counseling AND drug choice (precision therapy)
🔍 Buzzwords & Pathognomonic FindingsEEG · Clinical / etiology · Genetics / treatment
EEG signs
- Burst-suppression awake AND asleep → Ohtahara syndrome (EIEE)
- Burst-suppression mainly in sleep, less consistent awake → Early myoclonic encephalopathy (EME)
- Hypsarrhythmia (chaotic high-voltage multifocal spikes) → West syndrome / IESS
- Multifocal migrating ictal discharges shifting hemispheres → EIMFS / MPSI (KCNT1)
- Slow spike-and-wave <2.5 Hz + paroxysmal fast activity → LGS evolution from Ohtahara/West
Clinical / metabolic clues
- Erratic fragmentary asynchronous myoclonus (face, fingers, limbs) → EME (nonketotic hyperglycinemia, PDE)
- Tonic spasms in clusters, neonatal onset → Ohtahara syndrome
- Low CSF glucose <40 mg/dL, CSF:serum ratio <0.4, fasting → GLUT1 deficiency (SLC2A1)
- Drug-resistant seizures + movement disorder + intellectual disability → GLUT1 deficiency
- Refractory neonatal seizures + lactic acidosis + alopecia + rash → Biotinidase deficiency
- Regression + hand-wringing stereotypies + breath holding, girl → Rett syndrome (MECP2)
- Rett-like girl with early infantile DEE → CDKL5-DEE (X-linked)
Genetics / treatment pearls
- KCNQ2 gain-of-function/dominant-negative + Na-channel blocker responder → KCNQ2-DEE (paradoxical, unlike Dravet)
- KCNT1 + quinidine trial → EIMFS / MPSI
- Ganaxolone FDA-approved → CDKL5-DEE
- STXBP1 → Ohtahara → West → atypical DEE spectrum
- ARX, neonatal/infantile DEE in boys, X-linked → ARX-related DEE (XLAG)
- ALDH7A1 + pyridoxine 100 mg IV reverses seizures → Pyridoxine-dependent epilepsy (PDE)
- Folinic-acid-responsive seizures (allelic to PDE) → ALDH7A1 (overlapping phenotype)
- Ketogenic diet diagnostic AND therapeutic → GLUT1 deficiency (SLC2A1)
- SCN2A bidirectional: early GoF helped, later LoF worsened by Na blockers → SCN2A-DEE precision pearl
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)
ILAE 2022 Note
Per ILAE 2022, both syndromes are now unified under EIDEE (early-infantile DEE).
| 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 is hypothesized to have a mechanistic rationale (acts on SV2A in the same presynaptic pathway) but is not yet proven as preferred therapy; broad-spectrum ASMs are standard.
West Syndrome / Infantile Epileptic Spasms Syndrome
Classic Triad
- Epileptic spasms in clusters — brief tonic contractions, typically upon awakening
- Hypsarrhythmia on EEG — chaotic, high-amplitude (>200–300 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 (Lux 2004): hormonal therapy superior to vigabatrin for non-TSC (73% vs. 54%); exception = TSC responds better to vigabatrin
- ICISS (2017): hormonal + vigabatrin improved early spasm cessation vs hormonal alone (72% vs 57%). For boards, still know hormonal therapy first-line for non-TSC and vigabatrin first-line for TSC; combination therapy can be considered, especially in high-risk or local-protocol pathways.
- EPISTOP (2021): preventive vigabatrin in TSC at first EEG abnormality (before clinical seizures) was associated with improved seizure outcomes (reduced incidence and severity of epilepsy) and possible developmental benefit; the seizure-prevention effect is well established, the neurodevelopmental signal is less definitive
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 — approximately 15–30% in infants with prolonged use (higher in adults)
💎 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 supports surveillance EEG in infants with TSC and preventive vigabatrin when epileptiform EEG abnormalities appear before clinical seizures, especially in specialized epilepsy/TSC care pathways
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; seizures typically resolve within days to weeks (by 6 months of age) |
| 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. Most KCNQ2-DEE variants are de novo missense with dominant-negative or strong loss-of-function effects; inherited haploinsufficiency typically causes self-limited BFNE, though exceptions exist
- 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, may repeat every 5–10 min up to 500 mg total under EEG/cardiorespiratory monitoring — seizures may cease within minutes; followed by oral maintenance 15–30 mg/kg/day (max ~500 mg/day)
- 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; seizures typically resolve within days to weeks (by 6 months of age) | 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.
Dravet Syndrome (SCN1A)
- Gene: SCN1A loss-of-function (LOF; ~80% of cases) — impairs Nav1.1 channel function in inhibitory interneurons
- Onset: typically ~6 months in a previously healthy infant; first seizure often febrile and prolonged (hemiclonic status epilepticus)
- Hallmark: fever sensitivity — seizures triggered by fever, vaccination, hot baths, ambient heat
- Evolution: multiple seizure types emerge (myoclonic, atypical absence, focal), developmental slowing/regression after the second year
- Drugs to AVOID: sodium channel blockers worsen seizures — carbamazepine (CBZ), oxcarbazepine (OXC), phenytoin (PHT), lamotrigine (LTG)
- FDA-approved adjuncts: stiripentol, cannabidiol (CBD), fenfluramine (each shown to reduce convulsive seizure frequency in RCTs)
- First-line foundation: valproate + clobazam, with stiripentol/CBD/fenfluramine added as needed; ketogenic diet for refractory cases
- Increased SUDEP risk compared with other childhood epilepsies — family counseling required
💎 Board Pearl
- Healthy infant + prolonged febrile hemiclonic seizure around 6 months → think SCN1A Dravet and AVOID Na channel blockers
- Three FDA-approved Dravet adjuncts: stiripentol, cannabidiol, fenfluramine
GLUT1 Deficiency Syndrome (SLC2A1)
- Gene: SLC2A1 — encodes GLUT1, the glucose transporter across the blood-brain barrier; autosomal dominant (often de novo)
- Mechanism: impaired glucose transport into brain → chronic neuroglycopenia
- CSF hallmarks: low CSF glucose (<40 mg/dL) with normal serum glucose; low CSF:serum glucose ratio (<0.45); CSF lactate low-normal
- Seizures: early-onset absence-like seizures, myoclonic seizures, atypical absences; often drug-resistant to standard ASMs
- Movement disorder: paroxysmal exercise-induced dyskinesia (PED), ataxia, spasticity
- Other features: acquired microcephaly, intellectual disability, gait disturbance — symptoms often worsen with fasting and improve after meals
- Treatment: ketogenic diet is first-line — provides ketones as an alternative brain fuel that bypasses GLUT1; should be started as early as possible
💎 Board Pearl
- Early-onset absences + exercise-induced dyskinesia + acquired microcephaly → check fasting CSF/serum glucose and SLC2A1; start ketogenic diet
PCDH19 Epilepsy (X-linked Female-Limited Epilepsy)
- Gene: PCDH19 (protocadherin-19) on Xq22 — encodes a cell-adhesion molecule important for cortical neuron sorting
- Unusual inheritance: X-linked but affects heterozygous females and mosaic males (cellular interference / mosaic loss-of-function); hemizygous males are typically spared — a paradoxical inheritance pattern
- Clinical: fever-triggered focal seizure clusters in infancy/early childhood (onset 6–36 months); seizures occur in tight clusters over days then quiescent periods; intellectual disability variable (mild to severe), autistic features common
- EEG/imaging: often normal between clusters; no characteristic interictal pattern
- Treatment: broad-spectrum ASMs, often clobazam, levetiracetam, or topiramate; bromides sometimes used; ganaxolone studied (neurosteroid GABA-A modulator)
- Board pearl: classic pedigree — "father transmits to daughters who are affected; sons are unaffected" (the carrier father is unaffected because he is hemizygous, while his heterozygous daughters develop epilepsy)
💎 Board Pearl
- Fever-triggered focal seizure CLUSTERS in a female infant 6–36 months + paradoxical inheritance (affected daughters, unaffected fathers and sons) → think PCDH19
- Mechanism = cellular interference: a mixture of wild-type and mutant cells disrupts cortical organization, so heterozygous females and mosaic males are affected but hemizygous males (uniformly mutant) are spared
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 | Broad-spectrum ASMs (standard); levetiracetam has mechanistic rationale (SV2A) but not proven preferred |
💎 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) or somatic X-mosaicism.
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: hormonal + vigabatrin improved early spasm cessation vs hormonal alone (72% vs 57%). For boards, still know hormonal therapy first-line for non-TSC and vigabatrin first-line for TSC; combination considered in high-risk or local-protocol pathways.
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.
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