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

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

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)

Epidemiology

• Onset typically 18 months to 8 years (peak 3–5 years)
• Accounts for 1–4% of childhood epilepsies but ~10% of drug-resistant childhood epilepsy
• Male slight predominance

Diagnostic Triad

• (1) Multiple seizure types with MANDATORY tonic seizures (often nocturnal)
• (2) Slow <2.5 Hz generalized spike-and-wave on interictal EEG
• (3) Cognitive impairment — present at onset or progressive
• If tonic seizures absent → reconsider diagnosis (Doose? DEE-SWAS — Developmental & Epileptic Encephalopathy with Spike-Wave Activation in Sleep; see ESES/CSWS section below)

EEG

• Interictal: slow (<2.5 Hz) generalized spike-and-wave; diffuse background slowing
• Sleep: GPFA at 10–25 Hz during NREM — HIGHLY characteristic; may or may not accompany clinical tonic seizure
• Sleep EEG essential — waking EEG alone may miss hallmark features

Seizure Types

Etiology

• 20–40% evolve from infantile spasms (West syndrome)
• Structural: HIE, cortical dysplasia, TSC, perinatal stroke, CNS infections
• Genetic: STXBP1, DNM1, CHD2, SYNGAP1 (no single dominant gene)
• Unknown etiology ~20–30% (relatively better cognitive outcomes)

Treatment

Prognosis

• >90% drug-resistant; complete seizure freedom is rare
• Progressive intellectual disability in the majority
• Mortality ~5% (lifetime; varies by cohort) — SUDEP, status epilepticus, aspiration
• EEG may lose classic appearance in adulthood, but GPFA often persists
• Only 5–10% maintain normal or near-normal cognition

SCN1A & NaV1.1

• SCN1A loss-of-function in >80% (de novo in ~95%)
• NaV1.1 = predominant Na+ channel in GABAergic INHIBITORY interneurons (PV+ and SST+)
• Haploinsufficiency → reduced interneuron firing → decreased inhibition → E/I imbalance
• Temperature sensitivity: interneuron function disproportionately impaired at elevated temperatures

Genotype-Phenotype

• Truncating variants (~40–50%): more severe phenotype
• Missense variants (~35–40%): variable; some produce GEFS+ instead
• SCN1A-negative (~15–20%): consider GABRG2, GABRA1, STXBP1, PCDH19

Clinical Hallmark

• Prolonged hemiclonic FEBRILE seizures in the first year in a previously healthy infant
• Seizures may alternate sides; often present as febrile status epilepticus
• Age 1–4: afebrile seizures emerge (myoclonic, atypical absence, focal); developmental plateau/regression
• Age 4+: drug-resistant seizures; intellectual disability; crouch gait develops

EEG

• Often normal initially; evolves to generalized and focal/multifocal discharges
• Background slowing develops; photosensitivity in ~30%
• NOT slow spike-and-wave (distinguishes from LGS)

Pharmacotherapy

Emerging Therapy

• STK-001 (ASO): targets nonproductive SCN1A splice variant to increase NaV1.1 expression; intrathecal; phase 3

Prognosis

• Drug-resistant epilepsy in >90%; moderate-to-severe ID in the majority
• Overall mortality ~15–20%; SUDEP accounts for ~half of Dravet deaths (Dravet-specific SUDEP risk ~9–10%, among the highest of any epilepsy syndrome)
• Crouch gait progresses; requires orthotics/assistive devices

Clinical Features

• Onset age 2–6 years in a previously normally developing child; male predominance (2:1)
• Hallmark: myoclonic-atonic drop attacks — brief myoclonic jerk followed by atonic drop
• Other: GTC (~70%), myoclonic, atypical absence, NCSE; explosive onset over days to weeks

KEY Distinction From LGS

• NO tonic seizures — tonic seizures are highly characteristic of LGS (present in the vast majority, often captured only on sleep EEG); if tonic seizures emerge later in the course, reconsider toward LGS
• EEG: 2–6 Hz spike-wave; theta rhythms; NO GPFA
• Normal MRI (LGS often shows structural abnormalities)

Treatment & Prognosis

• Ketogenic diet often first-line — 50–80% respond; especially if SLC2A1 (GLUT1 deficiency)
• Valproate: first-line pharmacotherapy; ethosuximide: adjunct for absences
• AVOID: CBZ, OXC, PHT (worsen myoclonic and absence seizures)
• 60–70% remit within 1–3 years (MUCH better than LGS)
• 30–40% develop refractory epilepsy with cognitive decline

Concept & Terminology

• ILAE 2022: EE-SWAS (Epileptic Encephalopathy with Spike-Wave Activation in Sleep) and DEE-SWAS (Developmental and EE-SWAS, when premorbid delay is present) replace older terms ESES (electrical status epilepticus in sleep) and CSWS (continuous spike-and-wave during slow sleep).
• Landau-Kleffner syndrome (LKS) = a phenotype on this spectrum with predominant acquired auditory verbal agnosia → language regression.
• Onset typically 2–12 years (peak 4–8 years).

Defining EEG Feature

• Marked activation of (typically generalized) spike-and-wave discharges during NREM sleep
• Spike-wave index (SWI) > 85% of slow-wave sleep is the classical threshold (some authors use ≥50–85%); SWI = % of NREM occupied by spike-wave
• Awake EEG may be relatively normal — overnight or nap EEG is mandatory
• LKS often shows bilateral temporal/centrotemporal focus

Clinical Features

• Seizures: typically infrequent — focal motor (often nocturnal), atypical absences, atonic; tonic seizures are absent (helps distinguish from LGS)
• LKS: acquired auditory agnosia (cannot understand spoken language despite intact hearing) → expressive language regression; behavioral disturbance
• CSWS / EE-SWAS: global cognitive and behavioral regression — attention, executive function, motor; autistic-like features
• Regression is typically reversible if SWAS is controlled early; persistent SWAS → lasting deficits

Etiologies

• Structural: perinatal thalamic injury, polymicrogyria, congenital hemiparesis
• Genetic: GRIN2A (epilepsy-aphasia spectrum), SLC6A1, CNKSR2, KCNQ2, SCN2A
• Many cases idiopathic

Treatment

Key Concept

• Defined at the FAMILY level — requires ≥2 family members with seizure disorders within the GEFS+ spectrum
• Variable expressivity: same variant → different phenotypes in different family members
• A parent with “benign” FS may carry an SCN1A variant causing Dravet in their child

Genetics

• SCN1A — most common gene (missense → GEFS+; truncating → Dravet)
• SCN1B — first gene identified; GABRG2 — GABA_A γ2-subunit
• AD inheritance with variable penetrance; variant found in only ~20–30% of families

Clinical Spectrum

Treatment Considerations

• Most FS+ patients: benign course; may not need long-term ASMs
• Any child in a GEFS+ family worsening on Na+ channel blockers → urgently evaluate for Dravet

Genetics — Cellular Interference Model

• PCDH19 on Xq22.1 encodes protocadherin-19 (calcium-dependent cell-adhesion at synapses)
• Unusual X-linked inheritance pattern: affects heterozygous females and mosaic males; hemizygous males are SPARED
• Mechanism = cellular interference: in heterozygous females, X-inactivation creates a mosaic of PCDH19-positive and PCDH19-negative neurons that cannot properly adhere / signal — the mixture is pathogenic. Hemizygous males have uniformly PCDH19-null neurons → uniform tissue, no interference → unaffected.
• De novo in most; ~10–25% inherited from an unaffected transmitting (hemizygous) father

Clinical Features

• Onset 6–36 months (median ~10 months) in a previously developing girl
• Fever-triggered focal seizure clusters — flurries of brief focal seizures (often with affective/fearful semiology) over hours to days, separated by long seizure-free intervals
• Status epilepticus common during clusters
• EEG often normal interictally between clusters
• Variable cognitive outcomes: ~25% normal, ~50% mild–moderate ID, ~25% severe; autism / behavioral disturbance common
• Seizures often improve in adolescence; cognitive/behavioral phenotype persists

Treatment

• No single agent reliably effective; clobazam, bromides, steroids during clusters reported
• Na+ channel blockers are NOT contraindicated (unlike Dravet) — PCDH19 is not a sodium channelopathy
• Always send PCDH19 in girls with Dravet-like presentation but normal SCN1A

TSC1 vs. TSC2

mTOR Pathway

• TSC1-TSC2 complex = GAP for Rheb (Ras homolog enriched in brain)
• Normal: TSC1/2 → Rheb-GTP to Rheb-GDP → mTORC1 suppressed
• TSC: loss of TSC1/2 → constitutive Rheb-GTP → mTORC1 activation → increased protein synthesis (S6K1, 4E-BP1) → hamartomas
• Therapeutic target: mTOR inhibitors (everolimus, sirolimus)

Diagnostic Criteria

• Definite: pathogenic variant OR ≥2 major features OR 1 major + ≥2 minor
• Possible: 1 major, OR 1 major + 1 minor, OR ≥2 minor
• Major features include: hypomelanotic macules (≥3), angiofibromas (≥3), cortical tubers, SENs, SEGA, cardiac rhabdomyoma, renal AMLs (≥2), LAM
• ~10–15% have no mutation identified (mosaicism, deep intronic variants)

Epilepsy

• 85–90% develop seizures; 2/3 onset in first year; spasms ~40%, focal >60%
• Cortical tubers = primary epileptogenic foci; tuber burden correlates with severity
• 50–60% seizure-free with surgery (tuberectomy targeting dominant tuber)

Vigabatrin for TSC Spasms

• First-line; 65–95% spasm cessation (vs. 35–50% in non-TSC)
• Dose: initial 50 mg/kg/day, titrate to 100–150 mg/kg/day (FDA max 150 mg/kg/day for infantile spasms)
• Retinal toxicity: irreversible bilateral concentric visual field constriction (~25–35% with prolonged exposure; lower with short courses used for infantile spasms); ophthalmologic monitoring required

Everolimus

• Trough: 5–15 ng/mL; stomatitis most common SE; SEGA regrows if stopped

EPISTOP

• Supports surveillance EEG in infants with TSC and preventive vigabatrin when epileptiform EEG abnormalities appear before clinical seizures, especially within specialized epilepsy/TSC care pathways
• Improved seizure outcomes (reduced incidence and severity of clinical seizures) and may improve developmental outcomes (signal less robust than the seizure-prevention effect)
• Serial EEGs every 4–6 weeks in the first year of life are commonly used in TSC infants enrolled in such pathways

Surveillance

• EEG: every 4–6 weeks first year; Brain MRI: every 1–3 yr until 25
• Renal imaging q1–3 yr; cardiac echo at dx then q1–3 yr; chest HRCT at 18 for women (LAM)

Overview

• Rare chronic progressive inflammatory disorder affecting one cerebral hemisphere
• Typical onset age 2–10 years (median ~6); adult-onset ~10% (slower course)
• Almost always unilateral — bilateral involvement should prompt alternative diagnosis

Pathophysiology

• T-cell mediated unilateral hemispheric inflammation
• CD8+ cytotoxic T-lymphocytes + granzyme B-mediated neuronal apoptosis = primary mechanism
• GluR3 antibodies are SECONDARY (not primary cause); not in all patients; found in other epilepsies too
• Microglial nodules, astrogliosis, progressive neuronal loss confined to one hemisphere

Clinical Stages

Treatment

Diagnosis (European Consensus, Bien 2005)

• Diagnosis = Part A (all 3) OR Part B (any 2 of 3). Full-blown vasculitis or chronic viral encephalitis must be excluded.
• Part A — all 3 required:
  • Clinical: focal seizures (± EPC) and unilateral cortical deficit
  • EEG: unihemispheric slowing ± epileptiform discharges ± unilateral seizure onset
  • MRI: unihemispheric focal cortical atrophy AND at least one of grey/white-matter T2/FLAIR hyperintensity OR ipsilateral caudate head hyperintensity/atrophy
• Part B — any 2 of 3 required:
  • Clinical: EPC OR progressive unilateral cortical deficit
  • MRI: progressive unihemispheric focal cortical atrophy
  • Histopathology: T-cell encephalitis with microglial nodules + reactive astrogliosis (and NO numerous parenchymal macrophages, B-cells, plasma cells, or viral inclusions — i.e., full-blown vasculitis or chronic viral encephalitis excluded)
• Key MRI signs: progressive unilateral cortical atrophy, T2/FLAIR signal changes, caudate head atrophy (early sign)