Neonatal & Infantile Encephalopathies
Neonatal & Infantile Epileptic Encephalopathies
What You'll Learn
- 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
HighYield Pearls
- 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)
🔍 Quick ReferenceEEG · 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
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