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?)

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% per decade (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
• ~15–20% lifetime SUDEP risk — one of the highest among all epilepsy syndromes
• 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 (LGS REQUIRES tonic seizures) — if tonic seizures develop, 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

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

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: 100–150 mg/kg/day; may increase to 200 mg/kg/day
• Retinal toxicity: irreversible bilateral concentric visual field constriction (25–50% with prolonged use); ophthalmologic monitoring required

Everolimus

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

EPISTOP

• Preventive vigabatrin at first EEG abnormality (before clinical seizures) in TSC infants
• Reduced risk of developing clinical seizures and improved developmental outcomes
• Supports serial EEGs every 4–6 weeks in the first year of life in all TSC infants

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)

• Part A (all 3 required): focal seizures (± EPC) + unilateral cortical deficit + unihemispheric EEG slowing/discharges + unihemispheric MRI atrophy
• Part B (any 2 of 3): clinical + EEG + MRI criteria, OR histopathology showing T-cell encephalitis with microglial nodules
• Key MRI findings: progressive unilateral cortical atrophy, T2/FLAIR signal changes, caudate head atrophy (early sign)