Progressive Myoclonic & Reflex Epilepsies
Progressive Myoclonic Epilepsies & Reflex Epilepsies
What You'll Learn
- PME triad: progressive ACTION myoclonus + epileptic seizures (GTC) + neurological decline (ataxia, cognitive deterioration)
- Key rule: if myoclonus is getting WORSE, the diagnosis is NOT JME — evaluate for PME
- Giant SEPs confirm cortical origin of myoclonus in all PME syndromes
- Phenytoin is STRICTLY contraindicated in all PME — causes irreversible cerebellar atrophy (especially ULD)
- Lafora disease: PAS-positive Lafora bodies on SKIN BIOPSY; occipital seizures; fatal within ~10 years
- CLN2 (NCL): cerliponase alfa = only FDA-approved disease-specific therapy for any PME
- Photosensitive epilepsy: PPR Grade 1 = normal variant (no treatment); Grade 3–4 = clinically significant
- Reading epilepsy: ILAE-recognized; jaw myoclonus while reading; stop reading = abort seizure
- Startle epilepsy: almost always structural brain disease; distinguish from hyperekplexia (GLRA1, not epileptic)
HighYield Pearls
- Worsening myoclonus = NOT JME: progressive action myoclonus + cognitive/cerebellar decline → PME workup (genetics, skin biopsy, mtDNA)
- AVOID phenytoin in Unverricht-Lundborg: accelerates irreversible cerebellar degeneration; also AVOID all Na-channel blockers (CBZ, OXC, LTG, PHT) & tiagabine/vigabatrin — worsen myoclonus across all PMEs
- Lafora bodies: PAS-positive polyglucosan inclusions in eccrine sweat duct cells on AXILLARY SKIN BIOPSY — pathognomonic for Lafora disease (EPM2A laforin / EPM2B/NHLRC1 malin)
- CHERRY-RED SPOT + myoclonus + preserved cognition → sialidosis type I (NEU1, α-neuraminidase deficiency)
- MERRF = m.8344A>G in MT-TK: ragged-red + COX-negative fibers; maternal inheritance; AVOID VPA in mitochondrial disease (especially POLG — fatal hepatotoxicity)
- CLN2 (late-infantile NCL, TPP1): cerliponase alfa intraventricular ERT = only FDA-approved disease-specific PME therapy; CLN3 (juvenile Batten) presents with retinal degeneration FIRST
- Unverricht-Lundborg has BEST prognosis & PRESERVED cognition; Lafora is RAPIDLY fatal (death ≤10 yr) with dementia + occipital seizures + visual hallucinations
- Giant SEPs + back-averaging confirm cortical origin of myoclonus in all PMEs
- Photosensitive epilepsy: JME is the most common syndrome; Pokémon stroboscope (1997) is the classic trigger story; PPR Grade 3–4 on IPS is clinically significant
- Startle epilepsy ≠ hyperekplexia: startle epilepsy has structural brain lesions (often perinatal injury) ± ATP1A3; hyperekplexia is GLRA1 glycine receptor (non-epileptic, treat with clonazepam)
🔍 Quick ReferenceClinical · EEG / biopsy · Genetics / treatment
Clinical phenotype
- Baltic / Mediterranean myoclonus, adolescent, preserved cognition → Unverricht-Lundborg (EPM1)
- Teen with rapid dementia + occipital seizures + visual hallucinations, dead in 10 yr → Lafora disease
- Cherry-red macular spot + action myoclonus + preserved intellect → Sialidosis type I (NEU1)
- Myoclonus + Epilepsy + ataxia + dementia + LIPOMAS + short stature + hearing loss → MERRF
- Visual loss FIRST, then seizures + dementia in a child → CLN3 juvenile Batten
- Chorea + ataxia + myoclonus + dementia in a Japanese patient, anticipation → DRPLA (ATN1 CAG)
- Jaw / orofacial twitching while reading aloud, aborts on stopping → Reading epilepsy
- Seizure on immersion in hot bath (South India / Turkey) → Hot-water reflex epilepsy
- Pokémon stroboscope, video-game / TV-flicker GTC → Photosensitive epilepsy (often JME)
EEG / biopsy / imaging
- PAS-positive polyglucosan inclusions in eccrine sweat ducts on axillary skin biopsy → Lafora bodies
- Ragged-red fibers + COX-negative fibers on muscle biopsy; lactic acidosis → MERRF
- Curvilinear / fingerprint / granular osmiophilic deposits (GROD) on EM of skin or conjunctiva → NCL (Batten)
- GROD specifically → CLN1 (PPT1) infantile NCL; curvilinear bodies → CLN2 (TPP1); fingerprint profiles → CLN3 juvenile
- Giant somatosensory evoked potentials + back-averaged cortical correlate → Cortical myoclonus (any PME)
- Photoparoxysmal response on intermittent photic stimulation → Photosensitive epilepsy
- Autofluorescent lipopigment in neurons → NCL
- Cerebellar atrophy on MRI in a PME patient previously on phenytoin → Unverricht-Lundborg + iatrogenic PHT toxicity
Genetics / treatment
- CSTB dodecamer repeat expansion (chr 21q22.3), AR → Unverricht-Lundborg (EPM1)
- EPM2A (laforin) or EPM2B / NHLRC1 (malin), AR → Lafora disease
- mtDNA m.8344A>G in MT-TK, maternal inheritance → MERRF
- NEU1 (α-neuraminidase), AR → Sialidosis type I
- ATN1 CAG repeat, AD, anticipation → DRPLA
- Cerliponase alfa (intraventricular ERT) → CLN2 late-infantile NCL (TPP1)
- Perampanel + zonisamide adjuncts; piracetam 8–24 g/day antimyoclonic → Unverricht-Lundborg / PMEs
- AVOID phenytoin (cerebellar toxicity), Na-channel blockers, tiagabine, vigabatrin → All PMEs
- AVOID valproate (POLG hepatotoxicity); use CoQ10 / L-carnitine / riboflavin → Mitochondrial epilepsies including MERRF
- ATP1A3 mutations → Startle epilepsy with motor system abnormalities (also AHC, RDP, CAPOS)
Progressive Myoclonic Epilepsies — Overview
The PME Triad
- Progressive action myoclonus: action-sensitive + stimulus-sensitive; worsens over months to years; cortical origin
- Epileptic seizures: GTC most common; myoclonic seizures; atypical absences in some
- Neurological decline: cerebellar ataxia (gait → limb → dysarthria) + cognitive deterioration (variable by etiology)
PME vs. JME — Critical Distinction
- PME: myoclonus progressively worsens; EEG background deteriorates; cognitive/motor decline over time
- JME: myoclonus is stable with treatment; EEG background remains normal; NO neurological decline
- Worsening myoclonus despite appropriate ASMs = red flag for PME
- Family history of consanguinity or affected siblings = suspect AR inheritance (most PMEs)
Neurophysiology
- Giant SEPs: dramatically enlarged cortical somatosensory evoked potentials; confirms cortical myoclonus
- EEG: generalized spike-wave / polyspike-wave; progressive background slowing; photoparoxysmal response
- Back-averaging: demonstrates cortical correlate time-locked to myoclonic jerks
💎 Board Pearl
- Phenytoin causes irreversible cerebellar atrophy in ULD — historically devastating before genetic diagnosis was possible
- ALL sodium channel blockers (CBZ, OXC, PHT) worsen myoclonus in PME — AVOID across all etiologies
- Vigabatrin also contraindicated — worsens myoclonus AND causes irreversible visual field loss (especially harmful in NCL)
Major PME Etiologies — Comparison
| Disease | Gene | Inheritance | Onset | Hallmark Feature | Prognosis |
|---|---|---|---|---|---|
| Unverricht-Lundborg (EPM1) | CSTB | AR | 6–15 y | Action myoclonus; cognition PRESERVED; no storage material | Best PME prognosis; survive decades |
| Lafora Disease (EPM2) | EPM2A / NHLRC1 | AR | 6–19 y | PAS+ Lafora bodies on SKIN BIOPSY; occipital seizures | Fatal ~10 years from onset |
| NCL (Batten disease) | CLN1–CLN14 | AR (most) | Infancy–adult | Visual loss + seizures + dementia; autofluorescent lipofuscin | Progressive; variable by type |
| Sialidosis Type I | NEU1 | AR | 8–25 y | Cherry-red spot + action myoclonus; cognition PRESERVED | Slow; near-normal lifespan |
| MERRF | MT-TK (m.8344A>G) | Maternal | Any age | Ragged-red fibers; lipomas; hearing loss; lactic acidosis | Variable; slowly progressive |
| DRPLA | ATN1 (CAG repeat) | AD | Variable | Chorea + dementia + ataxia; anticipation; Japanese | Progressive; reduced lifespan |
Individual PME Syndromes
Unverricht-Lundborg Disease (EPM1)
- Gene: dodecamer repeat expansion in CSTB promoter (chr 21q22.3); cysteine protease inhibitor
- Epidemiology: most common PME worldwide; endemic in Finland (Baltic myoclonus) and Mediterranean
- Onset: 6–15 years; myoclonus usually the presenting symptom
- Cognition: relatively preserved for decades — dramatically better than Lafora
- Treatment: VPA, clonazepam, LEV, perampanel; piracetam (8–24 g/day) antimyoclonic
- PHT causes irreversible cerebellar atrophy — STRICTLY avoid
Lafora Disease (EPM2)
- Genes: EPM2A (laforin) / NHLRC1 (malin, EPM2B locus); ~40–50% each, with ~10% unsolved
- Pathology: Lafora bodies = PAS-positive, diastase-resistant polyglucosan inclusions
- Found in: neurons, myocytes, hepatocytes, eccrine sweat gland duct cells (basis for SKIN BIOPSY)
- Hallmark: occipital seizures with visual hallucinations early in course
- Course: rapid cognitive decline → dementia → status epilepticus → death ~10 years
- Diagnosis: axillary skin biopsy (~80% sensitivity); genetic testing first-line
- Emerging: antisense oligonucleotides targeting glycogen synthase; metformin (preclinical)
Sialidosis Type I (Cherry-Red Spot Myoclonus)
- Gene: NEU1 (neuraminidase 1); AR
- Key features: bilateral cherry-red spot (~95%) + severe action myoclonus + ataxia
- Cognition: generally PRESERVED (distinguishes type I from type II)
- No hepatosplenomegaly or dysmorphic features (type I)
- Diagnosis: elevated urine sialyloligosaccharides; deficient neuraminidase enzyme activity
MERRF
- Mutation: m.8344A>G in MT-TK (tRNALys); maternal inheritance
- Core features: myoclonus + GTC + ataxia + myopathy
- Red flags: hearing loss + lipomas + short stature + elevated lactate
- Muscle biopsy: ragged-red fibers (Gomori trichrome); COX-negative fibers
- VPA with CAUTION: hepatotoxicity risk in mitochondrial disease (especially POLG); LEV, clonazepam safer
DRPLA
- Gene: ATN1 — CAG trinucleotide repeat expansion; autosomal dominant
- Anticipation: longer repeats → earlier onset, more severe phenotype in successive generations
- Juvenile onset: PME phenotype (myoclonus, seizures, ataxia)
- Adult onset: chorea, dementia, ataxia, psychiatric features
- Epidemiology: predominantly Japanese; rare outside East Asia
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