By Physiology (Generator Site)

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)

Clinical Features

• Most common subtype 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: 8–24 g/d; specifically effective for cortical myoclonus; not FDA-approved in the US — LEV is the practical substitute
• Clonazepam: Add-on; sedation limits use; effective for all myoclonus types
• Avoid: Phenytoin, carbamazepine, gabapentin — may worsen cortical myoclonus

Subcortical myoclonus arises from basal ganglia/thalamus (e.g., myoclonus–dystonia, thalamic lesions) and lacks a preceding cortical transient on back-averaging. Brainstem myoclonus arises from the reticular formation or pontomedullary nuclei and includes reticular reflex myoclonus, hyperekplexia, and palatal 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)
• Examples: brainstem/reticular myoclonus from medullary lesions. Note: diffuse post-hypoxic brain injury can produce both reticular and cortical forms of myoclonus; modern electrophysiology supports a predominantly cortical mechanism in most patients with Lance–Adams syndrome, so Lance–Adams is now usually classified as a cortical myoclonus.

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 (first-line; enhances GABAergic inhibition); clobazam or levetiracetam as more appropriate adjuncts (valproate is not preferred)
• Vigevano maneuver: Forced flexion of head toward trunk terminates tonic/apneic spells in neonatal hyperekplexia — can be life-saving

Palatal Myoclonus / Palatal Tremor

• Symptomatic palatal tremor:
  • Lesion in the Guillain–Mollaret triangle: central tegmental tract (from red nucleus) → contralateral inferior olive → cerebellar dentate nucleus (via superior cerebellar peduncle) → back to red nucleus
  • Hypertrophic olivary degeneration on MRI: T2/FLAIR hyperintensity and pseudohypertrophy of the inferior olive (develops weeks to months after the inciting lesion)
  • Involves the levator veli palatini (vagal/pharyngeal plexus); persists in sleep
  • Causes: brainstem/cerebellar stroke, MS, trauma, tumor
• Essential palatal tremor:
  • Ear clicks from rhythmic contraction of the tensor veli palatini (opens/closes the Eustachian tube)
  • No structural lesion; no olivary hypertrophy; benign course
  • Treatment: clonazepam, botulinum toxin to tensor veli palatini for disabling ear clicks

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; for refractory cases, DBS — GPi is the preferred target (VIM thalamus is an alternative)

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

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, oxcarbazepine, lamotrigine, gabapentin, tiagabine, vigabatrin (all may worsen myoclonus)
• Lifelong treatment usually required — high relapse rate (>80%) when medications withdrawn

Progressive Myoclonus Epilepsies (PME)

PME Treatment Principles

• Standard regimen: Valproate + levetiracetam + clobazam ± perampanel (AMPA antagonist; effective for myoclonic and GTC seizures in PME)
• Avoid sodium channel blockers — they worsen myoclonus and seizures in PME:
  • Phenytoin (also accelerates cerebellar degeneration in Unverricht–Lundborg)
  • Carbamazepine, oxcarbazepine, lamotrigine
• Also avoid: tiagabine and vigabatrin (GABA-reuptake inhibitor / GABA-T inhibitor; may precipitate or worsen myoclonus and nonconvulsive status)
• Acetazolamide and zonisamide may be adjuncts; piracetam (where available) for the cortical myoclonus component

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

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
• Antibodies: Anti-Ri (ANNA-2) most common (breast, gynecologic cancers); anti-Hu (SCLC), anti-Yo, anti-amphiphysin, anti-CRMP5 also reported
• 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

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: 8–24 g/d effective for cortical myoclonus component; not FDA-approved in the US — LEV is the practical substitute
• 5-HTP (5-hydroxytryptophan) + carbidopa: Historical treatment; carbidopa added to prevent peripheral decarboxylation; limited availability
• Often requires polytherapy; disability remains significant despite treatment

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), valproate (via hyperammonemia), benzodiazepines, lithium, cefepime, opioids, bismuth
• 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

Serotonergic Agents

• SSRIs, SNRIs, MAOIs, tramadol, linezolid, triptans — alone or in combination
• Serotonin syndrome triad: myoclonus + clonus (especially inducible/ocular) + hyperreflexia, with autonomic instability and altered mental status
• Lower-limb clonus and hyperreflexia > upper limb; diaphoresis, mydriasis, hyperthermia
• Treatment: discontinue offending agent; cyproheptadine (5-HT2A antagonist); supportive care

Opioids

• Morphine, meperidine, fentanyl, tramadol — multifocal myoclonus, especially at high doses or in renal failure (normeperidine and morphine-3-glucuronide accumulation)
• Tramadol also contributes via serotonergic mechanism and lowers seizure threshold

Antibiotics

• Cephalosporins (especially cefepime): Encephalopathy with myoclonus and nonconvulsive status, particularly in renal impairment; EEG may show generalized periodic discharges or triphasic waves
• Imipenem (and other carbapenems): Myoclonus and seizures, dose-related
• Penicillins at very high doses

Other Toxins / Drugs

• Lithium toxicity: Coarse tremor, myoclonus, ataxia, confusion (SILENT syndrome with persistent neuro deficits)
• Cyclosporine, tacrolimus: PRES-like encephalopathy with myoclonus
• Bismuth (subsalicylate, subnitrate): Subacute encephalopathy with myoclonus and ataxia
• Anticonvulsant paradox: Gabapentin, pregabalin, phenytoin, carbamazepine, lamotrigine may worsen or precipitate myoclonus, especially in PME and JME
• Bismuth, heavy metals (mercury), MDMA, cocaine

Pharmacotherapy by Myoclonus Type

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