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Myoclonus

What Do You Need to Know?

Definition: Brief, involuntary, shock-like jerks caused by sudden muscle contraction (positive) or sudden loss of tone (negative/asterixis)
Classification: By physiology (cortical > subcortical > spinal > peripheral); cortical myoclonus is the most common type
Cortical myoclonus: Action-sensitive, stimulus-sensitive; EEG shows giant SEPs and back-averaged cortical transients; enhanced C-reflex on EMG
Opsoclonus-myoclonus: In children → neuroblastoma (~50%); in adults → breast, lung, or ovarian cancer; anti-Ri antibody
PME syndromes: Unverricht–Lundborg (EPM1, cystatin B), Lafora disease (Lafora bodies, PAS+), NCLs, sialidosis (cherry-red spot)
Treatment: Levetiracetam, valproate, clonazepam, piracetam; avoid phenytoin and carbamazepine (worsen myoclonus)

Classification of Myoclonus

By Physiology (Generator Site)

Type	Generator	Distribution	Key Features
Cortical	Sensorimotor cortex	Focal / multifocal	Action-sensitive, stimulus-sensitive; giant SEPs, back-averaged cortical transient, enhanced C-reflex
Cortical–subcortical	Cortex + thalamus/brainstem (loop)	Generalized	Epileptic myoclonus (e.g., JME); bilateral synchronous jerks
Subcortical–brainstem	Reticular formation (medulla)	Generalized	Reticular reflex myoclonus; auditory startle, hyperekplexia
Spinal	Spinal cord segments	Segmental / propriospinal	Rhythmic, may persist in sleep; spinal cord lesions
Peripheral	Nerve root / plexus / nerve	Focal	Hemifacial spasm, nerve root compression

By Distribution

Focal: Single body region (e.g., one arm, face)
Multifocal: Multiple non-contiguous regions, asynchronous (classic for cortical myoclonus)
Segmental: Contiguous body segments (e.g., arm + shoulder); typical of spinal myoclonus
Generalized: Whole-body jerks; cortical–subcortical or reticular origin

By Etiology

Physiologic: Hypnic jerks (sleep starts), hiccups, exercise-induced — normal, no treatment needed
Essential: Isolated myoclonus without other neurological deficits; autosomal dominant or sporadic; benign course
Epileptic: Myoclonus as the predominant seizure type (JME, PME syndromes, Lennox–Gastaut)
Symptomatic (secondary): Due to identifiable underlying disease (neurodegenerative, metabolic, toxic, post-hypoxic)

💎 Board Pearl

Cortical myoclonus is the most common type overall — action-sensitive + stimulus-sensitive + multifocal = cortical origin
Boards love the physiologic classification — knowing the generator site determines the EEG/EMG findings and treatment approach

Cortical Myoclonus

Clinical Features

Most common type of pathologic myoclonus
Action-sensitive: Worsens with voluntary movement (action myoclonus) — highly disabling
Stimulus-sensitive: Triggered by touch, light, sound (reflex myoclonus)
Distribution: focal or multifocal, distal predominance (hands > face > feet)
Brief jerks (<50 ms EMG burst duration) — shorter than subcortical myoclonus
Often co-occurs with cortical reflex seizures

Electrophysiologic Diagnosis

EEG back-averaging: Time-locked cortical transient precedes the myoclonic jerk by 15–40 ms (arm) — confirms cortical generator
Giant somatosensory evoked potentials (SEPs): Enlarged P25–N33 amplitude (≥10 µV) — indicates cortical hyperexcitability
Enhanced C-reflex (long-loop reflex): Exaggerated late EMG response to peripheral nerve stimulation; cortical loop-mediated
EMG burst duration: <50 ms (short) — vs. >50 ms in subcortical myoclonus
EEG may show generalized spike-wave or polyspike-wave discharges in epileptic cortical myoclonus

Treatment

Levetiracetam: First-line for cortical myoclonus; broad efficacy, well-tolerated
Valproate: Effective for cortical and cortical–subcortical myoclonus; risk of hepatotoxicity, teratogenicity
Piracetam: High doses (up to 24 g/d); specifically effective for cortical myoclonus; limited availability
Clonazepam: Add-on; sedation limits use; effective for all myoclonus types
Avoid: Phenytoin, carbamazepine, gabapentin — may worsen cortical myoclonus

💎 Board Pearl

Back-averaging is the gold-standard technique to confirm cortical origin — shows a cortical transient preceding the jerk
Giant SEPs + enhanced C-reflex + short EMG bursts (<50 ms) = cortical myoclonus triad on electrophysiology
Phenytoin and carbamazepine are contraindicated — they worsen cortical myoclonus

Subcortical Myoclonus

Reticular Reflex Myoclonus

Generator: medullary reticular formation (nucleus reticularis gigantocellularis)
Generalized jerks; proximal > distal; often stimulus-sensitive (especially auditory)
EMG burst duration: >50 ms (longer than cortical)
Rostral spread pattern: activation begins in proximal muscles and spreads upward (brainstem origin)
EEG: no cortical correlate precedes the jerk (unlike cortical myoclonus)
Classic example: post-hypoxic myoclonus (Lance–Adams)

Hyperekplexia (Startle Disease)

Exaggerated startle reflex to unexpected stimuli (auditory, tactile) — pathologic startle
Major form: Neonatal hypertonia + exaggerated startle → risk of apnea; AR, GLRA1 gene (glycine receptor α1 subunit)
Also: GLRB, SLC6A5 (glycine transporter), GPHN, ARHGEF9
Nose-tap reflex: sustained head retraction — clinical hallmark; does NOT habituate
Treatment: Clonazepam (enhances GABAergic inhibition); valproate as adjunct
Vigevano maneuver: Forced flexion of head and hips terminates neonatal startle episodes — can be life-saving

Myoclonus–Dystonia (DYT-SGCE)

SGCE gene (epsilon-sarcoglycan); autosomal dominant with maternal imprinting (only paternal allele expressed)
Onset: childhood/adolescence; myoclonic jerks (neck, trunk, upper limbs) + dystonia (cervical, writer’s cramp)
Alcohol-responsive myoclonus — dramatic improvement with ethanol (similar to ET)
Psychiatric comorbidity: OCD, anxiety, depression, alcohol dependence
Treatment: clonazepam, levetiracetam, trihexyphenidyl; DBS (GPi or VIM) for refractory cases

💎 Board Pearl

Hyperekplexia = GLRA1 (glycine receptor); non-habituating startle + neonatal hypertonia; clonazepam is treatment of choice
Myoclonus–dystonia = SGCE with maternal imprinting — disease manifests only when inherited from father
Reticular myoclonus has no preceding cortical transient on back-averaging — distinguishes it from cortical myoclonus

Spinal Myoclonus

Segmental Spinal Myoclonus

Arises from one or a few contiguous spinal segments
Rhythmic, repetitive jerks in muscles innervated by affected segments
Persists during sleep — key distinguishing feature (most other myoclonus types disappear in sleep)
Not stimulus-sensitive; frequency typically 1–3 Hz
Causes: spinal cord tumors, myelitis, syringomyelia, trauma, infection (herpes zoster), radiation myelopathy

Propriospinal Myoclonus

Flexion jerks of trunk/hips/knees, originating from thoracic or upper lumbar cord segments
Slow propagation velocity (5–15 m/s) along propriospinal pathways — visible sequential activation of muscles
Occurs at rest, prominent in supine position; may disrupt sleep onset
EMG: long burst duration (50–300 ms); slow rostral and caudal spread from thoracic origin
Many cases are functional (psychogenic) — variable latency, distractibility; must exclude structural cause with MRI spine

Clinical Pearl

Myoclonus that persists during sleep → think spinal segmental myoclonus (most other myoclonus disappears in sleep)
Propriospinal myoclonus in a young patient with inconsistent EMG findings → consider functional etiology before extensive workup

Epileptic Myoclonus & PME Syndromes

Juvenile Myoclonic Epilepsy (JME)

Most common epileptic myoclonus syndrome; onset 12–18 years
Morning myoclonic jerks (arms > legs) — occur shortly after awakening; patients drop objects at breakfast
Also: generalized tonic–clonic seizures (~90%), absence seizures (~30%)
EEG: 4–6 Hz generalized polyspike-and-wave; photosensitivity common
Treatment: Valproate (most effective); levetiracetam; avoid: carbamazepine, phenytoin, gabapentin (worsen)
Lifelong treatment usually required — high relapse rate (>80%) when medications withdrawn

Progressive Myoclonus Epilepsies (PME)

Syndrome	Gene / Protein	Key Features	Pathology
Unverricht–Lundborg (EPM1)	CSTB (cystatin B); AR	Onset 6–16 yr; stimulus-sensitive myoclonus + GTC; mild cognitive decline; Finnish/Mediterranean	No storage material; cerebellar atrophy late
Lafora disease (EPM2)	EPM2A (laforin) or NHLRC1 (malin); AR	Onset 12–17 yr; rapidly progressive; occipital seizures; dementia	Lafora bodies (PAS-positive polyglucosan inclusions) in skin, liver, brain
Neuronal ceroid lipofuscinoses (NCLs)	CLN1–CLN14; AR	Variable onset; vision loss (retinal), myoclonus, seizures, cognitive decline	Curvilinear / fingerprint / GROD inclusions; lipofuscin storage
Sialidosis type I (cherry-red spot myoclonus)	NEU1 (neuraminidase); AR	Adolescent onset; cherry-red spot on fundoscopy + myoclonus + ataxia	Sialic acid-containing oligosaccharides; urine sialyloligosaccharides ↑
MERRF	MT-TK (tRNA-Lys); maternal	Myoclonus + epilepsy + ataxia + ragged-red fibers	Ragged-red fibers on Gomori trichrome; COX-negative fibers
Dentatorubral-pallidoluysian atrophy (DRPLA)	ATN1; AD; CAG repeat	PME in children; chorea/ataxia/dementia in adults; Japanese predominance	Neuronal loss in dentate, red nucleus, GP, STN

Cortical Tremor (FCMTE / BAFME)

Familial cortical myoclonic tremor with epilepsy (also called BAFME — benign adult familial myoclonic epilepsy)
Autosomal dominant; intronic TTTCA/TTTTA repeat expansions (SAMD12, TNRC6A, RAPGEF2, MARCH6)
Fine postural/action tremor resembling ET — but electrophysiology reveals cortical myoclonus
Giant SEPs + enhanced C-reflex + back-averaged cortical transient — same as cortical myoclonus
Infrequent GTC seizures; benign course; responds to valproate or clonazepam

💎 Board Pearl

Morning myoclonic jerks in a teenager + GTC + polyspike-and-wave on EEG = JME — lifelong treatment required
Lafora bodies (PAS-positive) = Lafora disease; skin biopsy confirms the diagnosis (apocrine sweat glands)
Cherry-red spot + myoclonus = sialidosis type I; also consider Tay–Sachs (but Tay–Sachs presents in infancy)
MERRF = myoclonus + ragged-red fibers — maternal inheritance (mitochondrial tRNA-Lys mutation)

Opsoclonus–Myoclonus Syndrome

Clinical Features

Opsoclonus: Involuntary, chaotic, conjugate, multidirectional saccades (“dancing eyes”) without intersaccadic intervals
Myoclonus: Generalized or multifocal action myoclonus
Ataxia: Truncal > appendicular (“dancing feet”)
Full triad: opsoclonus + myoclonus + ataxia (OMS / “dancing eyes–dancing feet”)

Pediatric OMS

~50% associated with neuroblastoma (neural crest tumor; adrenal or paraspinal)
Age of onset: 6 months–3 years; paradoxically, OMS confers better tumor prognosis (more differentiated tumors)
Mechanism: autoimmune — anti-neuronal antibodies (specific antibody often not identified)
Workup: urine catecholamines (VMA, HVA), CT/MRI abdomen/chest, MIBG scan
Long-term neurocognitive sequelae in >50% of children (cognitive, behavioral, motor) despite treatment

Adult OMS

Paraneoplastic: Breast cancer (most common), small cell lung, ovarian, other solid tumors
Anti-Ri (ANNA-2): Most associated antibody (breast, gynecologic cancers)
Also: parainfectious (viral), idiopathic (no tumor found in ~40%)
Workup: CT chest/abdomen/pelvis, PET-CT, paraneoplastic antibody panel

Treatment

Tumor removal when identified (neuroblastoma resection, etc.)
Immunotherapy: ACTH/corticosteroids + IVIG first-line; rituximab or cyclophosphamide for refractory cases
Relapsing–remitting course common; prolonged immunosuppression often necessary

💎 Board Pearl

Child with opsoclonus–myoclonus → must rule out neuroblastoma (urine catecholamines, abdominal imaging)
Anti-Ri (ANNA-2) is the classic antibody in adult paraneoplastic OMS — think breast cancer
OMS in neuroblastoma paradoxically predicts better tumor prognosis but worse neurologic outcome

Lance–Adams Syndrome (Post-Hypoxic Myoclonus)

Clinical Features

Chronic action myoclonus developing days to weeks after recovery from a hypoxic–anoxic event (most commonly cardiac arrest)
Distinguished from acute post-hypoxic myoclonus (status myoclonus within 24 hours = poor prognosis) — Lance–Adams occurs in survivors who regain consciousness
Action-sensitive: Severe intention/action myoclonus with relative sparing at rest
Stimulus-sensitive; exacerbated by emotional stress
Often accompanied by cerebellar ataxia, dysarthria

Pathophysiology

Cortical origin (similar to other cortical myoclonus): Giant SEPs, back-averaged cortical transients, enhanced C-reflex
Selective vulnerability of Purkinje cells and cortical interneurons to hypoxia
Serotonin deficiency may contribute — rationale for 5-HTP use

Treatment

Levetiracetam: First-line; most effective for post-hypoxic action myoclonus
Valproate + clonazepam: Commonly used as adjuncts
Piracetam: High doses effective for cortical myoclonus component
5-HTP (5-hydroxytryptophan) + carbidopa: historical treatment; limited availability
Often requires polytherapy; disability remains significant despite treatment

Clinical Pearl

Acute myoclonus within 24 hours post-arrest (especially status myoclonus) = poor prognosis marker; Lance–Adams = myoclonus in a patient who recovers consciousness
Do not confuse the two — Lance–Adams patients have meaningful recovery potential and deserve aggressive antimyoclonic therapy

Negative Myoclonus (Asterixis)

Definition & Mechanism

Negative myoclonus: Brief, involuntary loss of muscle tone (silence on EMG) causing a sudden postural lapse
Opposite of positive myoclonus (which is a sudden muscle contraction)
Asterixis (“hepatic flap”): The most common form of negative myoclonus — bilateral flapping tremor of dorsiflexed wrists
EMG: brief pauses in ongoing tonic EMG activity (50–200 ms silent periods) — diagnostic

Etiologies

Metabolic encephalopathies (most common):
- Hepatic encephalopathy — classic association (“liver flap”)
- Uremia, hypercapnia, hyponatremia, hypoglycemia, hyperammonemia
Drug-induced: Anticonvulsants (phenytoin, carbamazepine, gabapentin at toxic levels), benzodiazepines, lithium
Structural: Unilateral asterixis (contralateral thalamic or parietal lesion) — rare but localizing

Management

Treat the underlying metabolic derangement — asterixis resolves when the cause is corrected
No specific antimyoclonic therapy needed for metabolic asterixis
Lactulose + rifaximin for hepatic encephalopathy

💎 Board Pearl

Asterixis = negative myoclonus (EMG silence), NOT a tremor — tested frequently
Bilateral asterixis = metabolic encephalopathy (hepatic most common); unilateral asterixis = structural lesion (contralateral thalamus)
Always check ammonia, LFTs, BMP, and medication levels in a patient with new-onset asterixis

Treatment of Myoclonus

Pharmacotherapy by Myoclonus Type

Myoclonus Type	First-Line	Adjuncts / Alternatives	Avoid
Cortical myoclonus	Levetiracetam, valproate	Piracetam (high dose), clonazepam	Phenytoin, carbamazepine, gabapentin
Post-hypoxic (Lance–Adams)	Levetiracetam	Valproate + clonazepam, piracetam	Phenytoin, carbamazepine
JME (epileptic)	Valproate, levetiracetam	Lamotrigine (caution — may worsen myoclonus), topiramate	Carbamazepine, phenytoin, gabapentin
Reticular / subcortical	Clonazepam	Valproate, levetiracetam	—
Hyperekplexia	Clonazepam	Valproate	—
Myoclonus–dystonia	Clonazepam	Levetiracetam, trihexyphenidyl; DBS (GPi/VIM)	—
Spinal segmental	Clonazepam	Botulinum toxin (focal), levetiracetam	—
Negative (asterixis)	Treat underlying cause	Lactulose/rifaximin (hepatic)	—

General Principles

Identify and treat the underlying cause (metabolic correction, tumor removal, immunotherapy) before symptomatic treatment
Levetiracetam has largely replaced valproate as first-line due to better side-effect profile
Polytherapy is often required — combine agents with different mechanisms
Sodium channel blockers (phenytoin, carbamazepine, oxcarbazepine) worsen cortical myoclonus — critical to avoid
DBS (VIM thalamus or GPi) considered for refractory myoclonus–dystonia; limited evidence in other myoclonus types

💎 Board Pearl

Levetiracetam + valproate + clonazepam = the classic antimyoclonic triad; these are the 3 most effective drugs across all myoclonus types
Never use carbamazepine or phenytoin for myoclonus — they worsen it (sodium channel blockers exacerbate cortical hyperexcitability)

References

Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet Neurol. 2004;3(10):598-607.
Zutt R, van Egmond ME, Elting JW, et al. A novel diagnostic approach to patients with myoclonus. Nat Rev Neurol. 2015;11(12):687-697.
Kojovic M, Bhatt M, Bhatt A, et al. Myoclonus: electrophysiological workup and practical approach. Mov Disord Clin Pract. 2021;8(3):341-350.
Marsden CD, Hallett M, Fahn S. The nosology and pathophysiology of myoclonus. In: Movement Disorders. Butterworth-Heinemann; 1982:196-248.
Hallet M. Physiology of human posthypoxic myoclonus. Mov Disord. 2000;15(Suppl 1):8-13.
Frucht SJ, Leurgans SE, Hallett M, Fahn S. The Unified Myoclonus Rating Scale. Adv Neurol. 2002;89:361-376.
Bien CG, Bien CI. Opsoclonus-myoclonus syndrome. In: Autoimmune Neurology. Elsevier; 2016:133-146.
Kalviainen R. Progressive myoclonus epilepsies. Semin Neurol. 2015;35(3):293-299.