Review
Myoclonus: current concepts and recent
advances
John N Caviness and Peter Brown
Myoclonus presents as a sudden brief jerk caused by
involuntary muscle activity. An organisational framework is
crucial for determining the medical significance of the
myoclonus as well as for its treatment. Clinical presentations
of myoclonus are divided into physiological, essential,
epileptic, and symptomatic. Most causes of myoclonus are
symptomatic and include posthypoxia, toxic-metabolic
disorders, reactions to drugs, storage disease, and
neurodegenerative disorders. The assessment of myoclonus
includes an initial screening for those causes that are
common or easily corrected. If needed, further testing may
include clinical neurophysiological techniques, enzyme
activities, tissue biopsy, and genetic testing. The motor
cortex is the most commonly shown myoclonus source, but
origins from subcortical areas, brainstem, spinal, and
peripheral nervous system also occur. If treatment of the
underlying disorder is not possible, treatment of symptoms
is worthwhile, although limited by side-effects and a lack of
controlled evidence.
Lancet Neurol 2004; 3: 598–607
Myoclonus can be a puzzling subject for physicians. Its
phenomenology has been muddled by continued use of
historical conventions that often conflict with the notions of
neurology subspecialists and modern physiological findings.
Myoclonus is a clinical sign defined as sudden, brief, shock-
like, involuntary movements caused by muscular
contractions or inhibitions.1 Muscular contractions produce
so-called positive myoclonus, whereas muscular inhibitions
produce negative myoclonus or asterixis. Myoclonic
movements have now been recognised to have many
possible causes, anatomical sources, and pathophysiological
features.2 Myoclonus can be classified by presentation,
cause, examination findings, and clinical neurophysiology
testing. In our MEDLINE search, 60% of studies retrieved by
use of “myoclonus” as a keyword were designated as case
reports. These numerous isolated observations by different
medical specialties present a challenge for the organisation
of the physician’s concept of myoclonus. Nevertheless,
substantial progress continues to be made. An
organisational framework that links clinical diagnosis,
pathophysiology, and treatment is emerging. In this review,
we will emphasise important recent advances in the
understanding of myoclonus and its treatment.
Epidemiology
Only a few large inclusive clinical series have been reported.
Among these series, the demographics and relative
598
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Myoclonus
proportions of different diagnostic categories varies
substantially.3 Even so, these studies show that symptomatic
(secondary) causes of myoclonus are most common,
epileptic seizures and myoclonus are intertwined, and
essential (primary and non-progressive) myoclonus only
constitutes a small proportion of patients with myoclonus.
The only epidemiological study on myoclonus due to any
cause in a defined population was done in Olmsted County,
Minnesota, USA.4 The average annual incidence of
pathological and persistent myoclonus for 1976 to 1990 was
1·3 cases per 100 000 person-years. The lifetime prevalence of
myoclonus, as of January 1, 1990, was 8·6 cases per 100 000
population. Symptomatic myoclonus (72%) was the most
common aetiological category, followed by epileptic
myoclonus (17%) and essential myoclonus (11%). All studies
that attempt to assess the occurrence of myoclonus have
various biases. Nevertheless, that posthypoxia aetiology,
neurodegenerative disease, and epilepsy syndromes are
common causes of myoclonus is clear. Toxic-metabolic and
drug-induced cases are common, but most are transient, and
as a result are missed in epidemiological studies.
Clinical presentation and aetiology
The best possible clinical presentations of myoclonus are
best organised by use of the major clinical syndrome
categories of Marsden and colleagues1 and their
corresponding lists of known causes (panel 1). The
myoclonus presenting from the causes under a given
category will share syndrome properties corresponding to
that category. However, the same category may contain
forms of myoclonus with various physiological properties.
Furthermore, the same causal factor may produce vastly
different types of myoclonus. In addition, the same patient
may show more than one type of myoclonus.
Physiological myoclonus
Physiological myoclonus occurs in healthy individuals.1
There is little or no associated disability and the physical
examination reveals no relevant abnormality. These jerks
JNC is at the Mayo Clinic College of Medicine, Parkinson’s Disease
and Other Movement Disorders Center, Scottsdale, Arizona, USA;
PB is at the Sobell Department of Neurophysiology, Institute of
Neurology, and at the National Hospital of Neurology and
Neurosurgery, London, UK.
Correspondence: Prof John N Caviness, MD, Mayo Clinic College
of Medicine, Parkinson’s Disease and Other Movement Disorders
Center, Mayo Clinic Scottsdale, 13400 East Shea Blvd, Scottsdale,
AZ 85255, USA. Tel +1 480 301 8100; fax +1 480 301 8451;
email jcaviness@mayo.edu
Neurology Vol 3 October 2004 http://neurology.thelancet.com
 Myoclonus
Review

Panel 1. Classification of myoclonus HIV

Post-infectious encephalitis
I. Physiological myoclonus (healthy individuals) Miscellaneous bacteria (streptococcus, clostridium, other)
A. Sleep jerks (eg, hypnic jerks) Malaria
B. Anxiety induced Syphilis
C. Exercise induced Cryptococcus
D. Hiccough (singultus) Lyme disease
E. Benign infantile myoclonus with feeding Progressive multifocal leucoencephalopathy
II. Essential myoclonus (primary symptom, non-progressive history) F. Metabolic
A. Hereditary (autosomal dominant) Hyperthyroidism
B. Sporadic Hepatic failure
Renal failure
III. Epileptic myoclonus (seizures dominate, part of chronic seizure
disorder) Dialysis syndrome
A. Fragments of epilepsy Hyponatraemia
Isolated epileptic myoclonic jerks Hypoglycaemia
Epilepsia partialis continua Non-ketotic hyperglycaemia
Idiopathic stimulus-sensitive myoclonus Multiple carboxylase deficiency
Photosensitive myoclonus Biotin deficiency
Myoclonic absences in petit mal epilepsy Mitochondrial dysfunction
B. Childhood myoclonic epilepsy Hypoxia
Infantile spasms Metabolic alkalosis
Myoclonic astatic epilepsy (Lennox-Gastaut) Vitamin E deficiency
Cryptogenic myoclonus epilepsy (Aicardi) G. Toxic and drug-induced syndromes33
Awakening myoclonus epilepsy of Janz (juvenile myoclonic epilepsy) H. Physical encephalopathies
C. Benign familial myoclonic epilepsy (Rabot) Post-hypoxia (Lance-Adams)
D. Progressive myoclonus epilepsy: Baltic myoclonus (Unverricht- Post-traumatic
Lundborg) Heat stroke
Electric shock
IV. Symptomatic myoclonus (secondary, progressive, or static
encephalopathy dominates) Decompression injury
A. Storage disease I. Focal nervous system damage
Lafora body disease CNS
GM2 gangliosidosis (late infantile, juvenile) Post-stroke
Tay-Sachs disease Post-thalamotomy
Gaucher’s disease (non-infantile neuronopathic form) Tumour
Krabbe’s leucodystrophy Trauma
Ceroid-lipofuscinosis (Batten) Inflammation (eg, multiple sclerosis)
Sialidosis (cherry-red spot) (types 1 and 2) Moebius syndrome
B. Spinocerebellar degenerations Developmental
Ramsay-Hunt syndrome Idiopathic
Friedreich’s ataxia Peripheral nervous system
Ataxia-telangiectasia Trauma
C. Other spinocerebellar degenerations Haematoma
Basal ganglia degenerations J. Malabsorption
Wilson’s disease Coeliac disease
Torsion dystonia Whipple’s disease
Hallervorden-Spatz disease K. Eosinophilia-myalgia syndrome
Progressive supranuclear palsy L. Paraneoplastic encephalopathies
Huntington’s disease M. Opsoclonus-myoclonus syndrome
Parkinson’s disease Idiopathic
Multisystem atrophy Paraneoplastic
Corticobasal degeneration Infectious
Dentatorubropallidoluysian atrophy Other
D. Dementias N. Exaggerated startle syndrome
Creutzfeldt-Jakob disease Hereditary
Alzheimer’s disease Sporadic
Dementia with Lewy bodies O. Hashimoto’s encephalopathy
Frontotemporal dementia P. Multiple system degenerations
Rett’s syndrome Allgrove syndrome
E. Infectious or post-infectious DiGeorge syndrome
Subacute sclerosing panencephalitis Membraneous lipodystrophy
Encephalitis lethargica Q. Unknown
Arbovirus encephalitis Familial
Herpes simplex encephalitis Sporadic
Human T-lympnotropic virus I From Marsden and colleagues,1 with modification.

Neurology Vol 3 October 2004 http://neurology.thelancet.com 599

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 Review
have a range of amplitude across individuals, and not all
types of physiological myoclonus occur in everyone. Jerks
during sleep or sleep transitions are the most familiar
examples of physiological myoclonus.5 Examples include
sleep starts (hypnic jerks) and fragmentary myoclonus.
Another observer, such as a sleep partner, commonly detects
the physiological jerk occurrence. Increased medical scrutiny
for an unrelated reason may cause a patient to question the
significance of a physiological jerk.
Essential myoclonus
In essential myoclonus, the myoclonus is the most
prominent or only clinical finding. Thus, the myoclonus is
an almost isolated or so-called essential phenomenon, from
which the patient usually experiences some, even if mild,
disability. Essential myoclonus is idiopathic or genetic, and
progresses slowly or not at all.1 Cognition is normal.
Sporadic and hereditary forms of this type of myoclonus
exist. Cases of sporadic essential myoclonus are very
heterogeneous with regard to distribution, what exacerbates
the jerks, and other examination findings.6 Sporadic essential
myoclonus probably has various heterogeneous, yet
undiscovered, causes, and some patients may have false-
negative family histories.
Palatal myoclonus has recently been thought by some to
represent tremor rather than myoclonus per se.7 The
published literature contains both terms and the entity is
discussed here for completeness. Essential palatal myoclonus
is typically caused by contractions of the tensor veli palatini,
symptomatic palatal myoclonus is generally caused by the
levator veli palatini, and middle-ear myoclonus is caused by
contractions of the tensor tympani or stapedius muscles, or
both.8–11 Such disorders may be under-recognised causes of
tinnitus or ear clicking.12,13 Middle-ear myoclonus may
coexist with essential palatal myoclonus or tremor.14
Hereditary essential myoclonus has been clinically
characterised by the following: onset before age 20 years;
dominant inheritance with variable severity; a benign course
compatible with an active life and normal longevity; and
absence of cerebellar ataxia, spasticity, dementia, and
seizures.15 The myoclonus is usually distributed throughout
the upper body, exacerbated by muscle activation, and
substantially decreased with alcohol ingestion. The term
myoclonus-dystonia syndrome has been introduced because
of the common occurrence of dystonia in these cases.
Recent progress in the genetics of the myoclonus-
dystonia syndrome has provided insights into pathogenesis
and added information to the clinical picture. Mutations in
the -sarcoglycan gene have had the strongest association
with the myoclonus-dystonia syndrome.16 There are at least
15 mutations reported and the number is increasing. By
contrast to the other types of sarcoglycan,  sarcoglycan is
expressed in the brain and other non-muscle tissues, but its
function is unknown. Most mutations are loss-of-function
mutations and maternal imprinting has been associated with
reduced penetrance.17 Exactly how the loss of function of
 sarcoglycan results in myoclonus or dystonia is not known,
but -sarcoglycan dysfunction interferes with normal GABA
inhibitory receptors. Mutations in the dopamine D2-
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Myoclonus
receptor and torsin A each have an association with the
myoclonus-dystonia syndrome, but in both cases, a
mutation was also found in the -sarcoglycan gene.16,18 One
myoclonus-dystonia family was reported to have no
-sarcoglycan gene mutation but had genetic linkage to a
locus on chromosome 18.19 There are families with
hereditary essential myoclonus with unknown linkage.
Among patients with the various -sarcoglycan mutations,
the clinical phenotype is mostly consistent with what has
been described for hereditary essential myoclonus for many
years. Two-thirds of patients exhibit dystonia, mostly of the
neck or arm. However, there have been some interesting
variations. Obsessive-compulsive disorder, anxiety
disorders, and mild cognitive slowing have been variably
associated with -sarcoglycan mutation in this syndrome.20
Epileptic myoclonus
Epileptic myoclonus is the presence of myoclonus in the
setting of epilepsy, that is, a chronic seizure disorder.
Myoclonus can occur as only one component of a seizure,
the only seizure manifestation (myoclonic seizure), or as one
of multiple seizure types within an epileptic syndrome.
Seizures usually dominate the clinical picture in epileptic
myoclonus. The cause may be idiopathic, genetic, or a static
encephalopathy. Epilepsia partialis continua is a form of
focal spontaneous myoclonus; it occurs irregularly or
regularly with intervals of no longer than 10 s, is confined to
one part of the body, and continues for hours, days, or
weeks.21,22 Myoclonic seizures are epileptic seizures in which
the motor as well as the main manifestation is myoclonus.
The myoclonus is accompanied by a generalised ictal
epileptiform electroencephalographic discharge, but the
myoclonus itself may be generalised, segmental, or focal.
Juvenile myoclonic epilepsy (awakening myoclonus of Janz)
is the classic idiopathic syndrome in which myoclonic
seizures may occur in conjunction with generalised tonic-
clonic or absence seizures, but without other neurological
disability. In this disorder, myoclonus may occur as the first
symptom long before the other seizure types manifest. The
idiopathic myoclonic epilepsies (including juvenile
myoclonic epilepsy) are a subset of the disorders known as
idiopathic generalised epilepsies.
Remarkable progress has been made on the genetics of the
idiopathic myoclonic epilepsies. For many years, numerous
idiopathic myoclonic epilepsy syndromes with overlapping
phenotypic features and ages of presentation were described.
Genetic research on these syndromes is beginning to provide a
clear framework for organising the various syndromes into
clinicogenetic entities.23 For example, in juvenile myoclonic
epilepsy, myoclonic seizures without absence seizures are
much more likely to occur in families with mutation in
chromosome locus 6p12–11, whereas the seizure types are
mixed in people with mutations in chromosome 6p21 and
15q14.24–26 Across all idiopathic myoclonic epilepsy
syndromes, the hereditary transmission may be autosomal
recessive or dominant, or be more complex with the
involvement of oligogenic interaction models and locus
heterogeneity.23 Specific gene mutations have been found in
sodium-channel components and the GABAA receptor. The
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 Myoclonus
Panel 2. Drugs that are associated with myoclonus
Psychiatric medications
Cyclic antidepressants
Selective serotonin uptake inhibitors
Monoamine oxidase inhibitors
Lithium
Tardive syndrome (antipsychotic use)
Anti-infectious agents
Narcotics
Anticonvulsants
Anaesthetics
Contrast media
Cardiac medications
Calcium channel blockers
Antiarrhythmics
Drug withdrawal
Other medications
discovery of other specific gene mutations should enable the
development of new treatments for these disorders.
Symptomatic myoclonus
Symptomatic (secondary) myoclonus manifests in the
setting of an identifiable underlying disorder, which can be
neurological or non-neurological. Myoclonus can be seen
across the vast spectrum of neurological disease (panel 1).
Often there is clinical or pathological evidence of diffuse
nervous system involvement. Multiple significant clinical
manifestations exist in these patients and may even be more
prominent than the symptom of myoclonus. Mental-status
abnormalities, seizures, ataxia, and other movement
disorders are common clinical associations in symptomatic
myoclonic syndromes. Chronic or subacute clinical
progression suggests symptomatic myoclonus, but other
presentations are common. The cortex is the most
commonly proven source of the myoclonic jerks.
The number of reports on drug-induced myoclonus
continues to increase. Such myoclonus is potentially fully
treatable because the myoclonus is almost always reversible
on withdrawal of the offending drug. All drugs, either in
isolation or combination, must be scrutinised for a potential
role in myoclonus (panel 2). There are different clinical
symptoms of motor cortex hyperexcitability in lithium-
induced myoclonus.27 At therapeutic concentrations or mild
lithium toxicity, isolated cortical action myoclonus can
occur with concomitant electroencephalographic
background rhythm changes. Instances of greater lithium
toxicity can show motor seizures or generalised convulsions,
or both. The synergistic relation between myoclonus-causing
drugs in the setting of polypharmacy in complex psychiatric
cases has become very apparent.28,29 Quinolone antibiotics
cause myoclonus, in both the presence and absence of
seizures.30 Paradoxically, the antiseizure drug gabapentin and
the related drug pregabalin have been associated with
myoclonus.31,32 Gordon33 gives a comprehensive discussion of
toxic and drug-induced myoclonus.
New findings have shown that cortical myoclonus can
occur in all Lewy-body disorders.34,35 Small amplitude
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Review
cortical myoclonus in Parkinson’s disease (PD) occurs
during muscle activation and may seem repetitive and
rhythmic enough to resemble action tremor. However, the
movement is irregular both in timing and amplitude, so
thus deserves the term myoclonus. The myoclonus in PD is
less common than in dementia with Lewy bodies, in which it
occurs in at least a third of cases. The myoclonus in
dementia with Lewy bodies is of larger amplitude and much
more likely to occur at rest than the myoclonus in PD. The
source of the myoclonus is cortical with similar
physiological properties to that of the myoclonus in PD.36 In
one family with hereditary Lewy-body disease caused by
overexpression of  synuclein, a similar cortical myoclonus
has been found.37 Even though the parkinsonism in these
disorders arises subcortically, the cortical myoclonus
signifies that the sensorimotor cortex is not functioning
properly. The fact that the dementia and myoclonus are
more prominent in dementia with Lewy bodies than in PD
may suggest that cortical myoclonus is a marker for cortical
dysfunction in Lewy-body disorders and is related to the
presence or development of cognitive dysfunction.
Recent observations have drawn attention to instances in
which the phenomenological border between tremor and
myoclonus may not be so clear.38 In corticobasal
degeneration, it has been noted that the myoclonus is
preceded by increased tremor or jerky tremor.39,40 Two series
of multiple system atrophy have reported small-amplitude,
jerky, postural arm tremor in 20%41 and 55%42 of patients.
Salazar and colleagues43 argued, on both clinical and
electrophysiological grounds, that the jerky postural tremor
movements were best characterised as myoclonus rather
than tremor. Chronic progression and insidious onset
characterise neurodegenerative diseases. Before the
repetitive action myoclonus of neurodegenerative disease is
easily identified as myoclonus, the abnormal physiology may
pass through a stage when the electromyographic discharges
produce a movement elicited by action that appears as a
small amplitude tremor. The term cortical tremor was first
coined by Ikeda and colleagues.44 The movement in their
patients was described as “shivering-like tremor” and “fine
shivering-like twitchings”, but the electromyographic
discharges were found to have classic characteristics of
cortical myoclonus. Other studies on cortical tremor have
since been published,45–47 including Toro and colleagues45
who asserted that such a phenomenon was a common
manifestation of cortical myoclonus. Pathological
exaggerations of central rhythms may play a part in
producing myoclonus.48,49 Because central rhythms are also
thought to be important in tremor, this observation reveals a
pathophysiological analogy between the two movement
phenotypes.
Psychogenic jerks
Jerks that occur in patients with a conversion disorder or
malingering may appear quick enough to be confused with
myoclonus. Monday and Jankovic50 have outlined character-
istics of psychogenic jerks: (1) inconsistent character of the
movements (amplitude, frequency, and distribution) and
other features incongruous with typical organic myoclonus,
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 Review
(2) associated psychogenic symptomatology, (3) pro-
nounced reduction of the myoclonus with distraction, (4)
exacerbation and relief with placebo and suggestion, (5)
spontaneous periods of remission, (6) acute onset and
sudden resolution, and (7) evidence of underlying
psychopathology.
Assessment and clinical neurophysiology
The guidelines for the assessment of a patient with
myoclonus may be broken up into four parts (panel 3).
Part 1: history, physical examination, and clinical
syndrome classification
Part 1 encompasses the history, physical examination, and
identification of which major clinical syndrome category
best reflects the circumstances of the patient. Guidelines for
the determination of the clinical syndrome category are
given above and in panel 3. Other useful hints for the
determination of the aetiological subcategory for the broad
major clinical syndrome category of symptomatic
myoclonus are given below.
The syndrome of progressive myoclonic epilepsy (PME)
in childhood or young adulthood suggests a storage disease
or other inherited disorder. Main syndrome components of
PME are seizures, myoclonus, ataxia, and dementia, which
lead to severe mental impairment and death in many cases.
The progressive nature of the illness and cognitive decline
differentiate PME diagnoses from more benign epileptic
syndromes. Some of these disorders better fit a related
syndrome of progressive myoclonic ataxia (PMA), in which
ataxia and myoclonus are the more prominent or sole
components.51 In PMA, there is a much slower clinical
progression. Sialidosis, Unverricht-Lundborg syndrome,
and mitochondria disorders are much more likely to present
with a PMA syndrome than PME. The PMA syndrome is
not limited to classic metabolic disorders, and coeliac
disease, a malabsorption syndrome, can present as PMA.
Myoclonus is a variable manifestation of spinocerebellar,
basal ganglia, and cortical dementia disorders. Prominent
progressive ataxia accompanied by other variable
neurological and possibly non-neurological features alerts
the physician to the presence of a spinocerebellar
degeneration. Progressive parkinsonism and dystonia are
characteristic in the basal ganglia syndromes that may
manifest as myoclonus. Dementia in myoclonus syndromes
may present with memory loss or begin as a focal cognitive
dysfunction which then generalises. In most cases, there is
an insidious onset of the main neurological symptom and
myoclonus is absent early in the course or is very small. The
likelihood of obvious myoclonus increases in middle and
late stages of the disease. The myoclonus in all of these
disorders has a varied presentation profile and is normally
multifocal but can be generalised. Generalised myoclonus in
Creutzfeldt-Jakob disease is commonly sensitive to sound.
The acute or subacute onset of myoclonus should trigger
the screening for early signs of both medical and
neurological inflammatory disorders, including infectious,
post-infectious, paraneoplastic, demyelinating, and other
autoimmune disorders. Sometimes, the myoclonus is the
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Myoclonus
Panel 3. Assessment of myoclonus
Part 1: History, physical examination, and clinical syndrome
classification
Full history
Must include mode of myoclonus onset, presence of other neurological
problems, history of seizures, current and past drug or toxin exposure,
past or current medical problems, and family history.
Physical examination
Distribution (may be focal, segmental, multifocal, hemi, generalised)
Temporal profile (includes rhythmic or irregular)
Continuous
Intermittent (sporadic or trains)
Activation profile
Rest (spontaneous myoclonus)
Voluntary movement (action myoclonus)
Reflex stimuli (any combination of touch, light, sound, muscle
stretch)
Determine major clinical syndrome category1
I. Physiological myoclonus (normal subjects)
II. Essential (primary symptom, non-progressive history)
III. Epileptic (seizures dominate, part of chronic seizure disorder)
IV. Symptomatic (secondary, progressive, or static encephalopathy
dominates)
Part 2: Basic ancillary testing
Electrolytes (± including bismuth)
Glucose
Renal function tests
Hepatic function tests
Paraneoplastic antibodies
Drug and toxin screen (if history suggests)
Brain imaging
Electroencephalography
Spine imaging (if focal or segmental)
Thyroid antibodies and function
Part 3: Clinical neurophysiology testing to determine physiological
classification (panel 4 and table)
Part 4: Advanced testing for rare and specific diagnoses
If not otherwise ruled out, the following testing should be considered:
Body imaging for occult cancer (even if paraneoplastic antibodies are
absent)
Cerebrospinal fluid exam (for infectious and inflammatory disorders, 14-
3-3 protein for Creutzfeld-Jakob disease, etc.)
Tests for malabsorption disorders (eg, coeliac sprue, Whipple’s disease)
Enzyme assays for deficiency (eg, neuraminidase, biotinidase, etc.)
Tissue biopsy of skin or leucocytes (eg, Lafora bodies, ceroid inclusions,
etc.)
Copper studies for Wilson’s disease
Alpha-feto protein, cytogenetic analysis, radiosensitivty of DNA synthesis
(ataxia-telangiectasia)
Genetic testing for inherited disorders (eg, EPM1 gene, mitochondria
genes, huntingtin gene, etc)
Mitochondria function studies (lactate, muscle biopsy, etc.)
Other testing may be needed
only early clue to some of these disorders. This is especially
true for paraneoplastic syndromes and malabsorption
syndromes such as coeliac disease. Action myoclonus is very
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 Myoclonus
Panel 4. Physiological classification of myoclonus
Cortical
Includes post-hypoxic action myoclonus, some examples of drug-
induced and toxic-metabolic myoclonus, cortical epilepsia partialis
continua, some cases of asterixis, progressive myoclonic epilepsies,
progressive myoclonic ataxias,* and the myoclonus in
neurodegenerative disease with cortical involvement such as Alzheimer’s
disease, Creutzfeldt-Jakob disease, corticobasal degeneration, and
Lewy-body disorders
Cortical-subcortical
Includes absence seizures, primary generalised myoclonic seizures,
primary generalised epileptic myoclonus
Subcortical-supraspinal
Includes essential myoclonus, reticular reflex myoclonus, opsoclonus-
myoclonus syndrome, hyperekplexia
Spinal
Includes propriospinal myoclonus and segmental spinal myoclonus
Peripheral
Includes hemifacial spasm
More than one mechanism may be present in a given patient or disease.
*Progressive myoclonic epilepsy=progressive syndrome of prominent epilepsy and
cognitive decline with myoclonus: progressive myoclonic ataxia=slowly progressive
syndrome of myoclonus and ataxia with little epilepsy or cognitive decline.
prominent in coeliac disease and the opsoclonus-myoclonus
syndrome. The myoclonus in encephalitis is commonly
accompanied by seizures and alteration in mental status. The
onset of myoclonus secondary to drugs, toxins, and organ or
gland failure is also typically acute or subacute. On history,
the relation of the drug to the myoclonus may be offset by
days, weeks, or longer. Metabolic disorders due to liver or
kidney failure may produce myoclonus by the inhibiting of
drug metabolism.
Rhythmic myoclonus in a brainstem or spinal segmental
distribution raises the concern for a focal lesion at or near
that segment of the brainstem or spinal cord. Generalised
jerks may arise from diseases that affect the cerebral cortex.
However, exaggerated startle syndromes (eg, hyperekplexia),
myoclonus arising from the brainstem reticular formation,
and lesions in the spinal cord causing propriospinal
myoclonus are important considerations.
Part 2: basic ancillary testing
If the cause of the myoclonus is unclear, then basic ancillary
diagnostics should be done. Such testing covers the most
common disturbances of electrolyte balance and acquired
metabolic disorders. Electroencephalography is very useful
for the identification of both ictal and interictal patterns in
epileptic myoclonus. For example, generalised spikes and
3–6 Hz spike and wave pattern is typical for primary
generalised myoclonic epilepsy, and 3 Hz spike and wave is
seen in absence epileptic syndromes. Loss of a normal
background rhythm and abnormal slow waves suggests that
a diffuse encephalopathy is present. Such diffuse slowing of
electroencephalographic frequencies is non-specific but
suggests a case of symptomatic myoclonus with widespread
CNS pathology. The imaging of the brain and spinal cord
may lead to the discovery of a focal lesion. Atrophy of diffuse
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Review
or focal brain regions suggests symptomatic myoclonus,
such as the diffuse atrophy of a global dementia or the focal
atrophy seen in genetic and sporadic forms of
frontotemporal dementia.
Part 3: clinical neurophysiology testing to determine
physiological classification (panel 4, table)
Clinical neurophysiology testing can reveal a
neuroanatomical localisation for myoclonus and certain
patterns have some aetiological specificity. Of note, the
neuroanatomical origin of the myoclonus provides some
guidance as to the treatment approach. For example, with
the exception of clonazepam, drugs that provide the best
chance of treatment response in cortical myoclonus are not
nearly as effective in segmental myoclonus. At a minimum,
clinical neurophysiology testing is recommended if a
diagnosis is not forthcoming after parts 2 and 3 of the
assessment options in panel 3 have been done.
The main aim of clinical neurophysiological testing is to
define the physiological classification of the myoclonus.
Major categories of the physiological classification used here
primarily refer to the neuroanatomical source of the
myoclonus. The main physiological classification categories
for myoclonus are cortical, cortical-subcortical, subcortical-
supraspinal, spinal, and peripheral (panel 4). The cortical-
subcortical designation refers to a physiology involving
abnormal paroxysmal and excessive oscillation in
bidirectional connections between cortical and subcortical
sites. More elaborate physiological classification schemes
based on neuroanatomical source combined with generator
mechanism have been developed.52,53 In practical
terms, physiological classification is derived from findings
on a battery of methods that generally include—
but are not limited—to electroencephalography, surface
electromyography, simultaneous electroencephalographic-
electromyographic studies with back-averaging, evoked
potentials, and long-latency electromyographic responses to
peripheral-nerve stimulation (eg, C reflex). Back-averaging
of simultaneous electroencephalography-electromyography
allows the detection of small electroencephalographic
potentials time-locked to electromyographic events such as a
myoclonus electromyographic discharge. Somatosensory
evoked potentials record electroencephalographic potentials
in response to upper or lower limb electrical stimuli. The
grouped findings for each major category of the
physiological classification are given in the table. Details on
how these methods are applied to myoclonus investigation
are given elsewhere.52,53
Part 4: advanced testing for rare and specific
diagnoses
When all other testing does not show a cause for the
myoclonus, advanced testing for specific and rare diagnoses
should be considered. The choice and order of such testing is
guided by the circumstances when a specific diagnosis or
group of causal factors is suspected or should be ruled out.
Part 4 of panel 3 contains examples of this testing, but is not
complete. The options for this testing will continue to
rapidly expand in the future.
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 Review Myoclonus

Electrophysiological findings in physiological types of myoclonus*

Physiological type Common gross EEG EMG Back-averaged Somatosensory Reflex responses
findings EEG transients evoked potential
Cortical Variable, may show Bursts typically Variable, but focal Enlarged cortical +/– C reflex at rest
epileptiform discharges less than 75 ms sharp wave 10–40 ms component common
and slow waves before jerk is
characteristic
Cortical-subcortical Generalised spike Bursts <100 ms Time-locked Enlarged cortical +/– C reflex at rest
and wave association component possible
Subcortical-supraspinal No consistent Variable burst No correlate Normal Sometimes reflex response to
abnormalities properties; burst sound
duration varies
among subtypes
Spinal Normal Bursts >100 ms No correlate Normal Variable, can be very short
and +/– rhythmic; in latency, incompatible with
may be denervation supraspinal loop
Peripheral Normal Variable burst No correlate Normal Normal
duration; may be
denervation

*Characteristics among the subtypes of each category have significant differences. EEG=electroencephalography; EMG=electromyography.

Pathophysiology The spinal motor system is organised on two levels.

Results from clinical neurophysiology testing give important
insight into the generation of the myoclonus. However, other
considerations should be realised about the pathophysiology
of myoclonus. The clinical features of myoclonus are largely
determined by the nature of the affected motor systems.
Thus, cortical myoclonus predominantly affects those body
parts with the biggest cortical representations, the hands and
face, and, as the motor areas of the cerebral cortex are most
involved in voluntary action, the jerks are most manifest on
action. The motor cortex in particular is involved in the
execution of fractionated rather than mass actions, and is
characterised by rhythmic activity in the beta (~20 Hz) and
gamma (~40 Hz) bands. Accordingly, cortical myoclonus is
multifocal, typically involving fractionated movement of the
fingers, and may involve high-frequency rhythmic bursts.54 In
its purest manifestation, this results in so-called cortical
tremor55 when the hands are bilaterally involved or epilepsia
partialis continua when involvement is unilateral. Long-loop
cutaneous and stretch reflexes are an important element in
the cortical organisation of movement and in cortical
myoclonus light touch and stretch may sometimes lead to
reflex jerks of the stimulated area. The increased gain in these
reflex pathways also manifests itself in the
electroencephalograph as giant cortical components of the
evoked potential. Action jerks may similarly be preceded at
short latency (10–40 ms) by time-locked cortical correlates in
the electroencephalograph or magnetoencephalograph,
sometimes they are evident as spike and wave in routine
recordings, but back-averaging is commonly needed to detect
them.
Brainstem motor systems are particularly involved in
axial and bilateral movements, and are tightly linked to
subcortical reflex centres. Thus, brainstem myoclonus is
generalised, especially axial, and very sensitive to stimulus.
Indeed its hallmark is auditory reflex jerks, as in
hyperekplexia and brainstem reflex myoclonus.56
Spinal segmental systems may become hyperexcitable, often
by viral irritation or the isolation of anterior horn cells from
inhibitory influences by disorders such as syringomyelia,
glioma, or spinal ischaemia. The result is myoclonus
involving one or two contiguous spinal myotomes that is
peculiarly resistant to supraspinal influences, such as
voluntary movement or sleep. The propriospinal system is a
slowly conducting intraspinal pathway that connects
multiple segmental levels. Involvement of this system leads
to predominantly axial jerks that, unlike brainstem
myoclonus, spare the face and are not provoked by sound.
Electrophysiologically propriospinal myoclonus is
characterised by long duration electromyographic bursts
that spread relatively slowly up and down from the level of
spinal hyperexcitability.57
Finally, psychogenic jerks closely parallels voluntary
movement in its organisation. Indeed, a slow negative
electroencephalographic potential, rising over 1–2 s in
electroencephalographs averaged before the myoclonus, and
little different to that associated with voluntary self-paced
movement, may precede spontaneous psychogenic
myoclonus.58
Treatment
The best strategy for the treatment of myoclonus is, of
course, the treatment of the underlying disorder. Some
causes of myoclonus can be reversed partially or totally, such
as an acquired abnormal metabolic state, a medication or
toxin, or an excisable lesion. There is some evidence that
psychogenic jerks respond to psychotherapy and
pharmacological psychiatric treatment.50,59 However, in most
myoclonus cases, such treatment of the underlying disorder
is not possible. Ideally, an approach to symptomatic
treatment is derived from its physiological classification.
Multiple drug trials are sometimes necessary to find the best
drug for a certain patient. Combination treatment regimens

604 Neurology Vol 3 October 2004 http://neurology.thelancet.com

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 Myoclonus
may be beneficial, particularly in cortical myoclonus.
However, myoclonus treatment is unsuccessful from many
patients’ points of view. High expectations for a decrease or
total elimination in the myoclonus are unrealistic. No drug
has been manufactured for the specific purpose of treating
myoclonus to date. As a result, there is little controlled
evidence on the treatment of myoclonus. Side-effects are
commonly dose-limiting. The discussion of treatment below
is outlined under the physiological classification of the
myoclonus origin.
Cortical myoclonus
Drug treatment is primarily aimed at bolstering deficient
inhibitory processes. In particular, a reduction of 25–50% of
GABA concentration has been reported in the CSF of
patients with posthypoxic myoclonus and progressive
myoclonic epilepsy, and GABAergic drugs form the
cornerstone of treatment. Of these, sodium valproate is the
most effective, and increases cortical GABA concentrations
as well as potentiating GABA postsynaptic inhibitory
activity. The drug is introduced slowly, with most patients
needing daily doses of 1200–2000 mg. Transient
gastrointestinal upset may occur during initial treatment,
usually with nausea and vomiting, but sometimes with
abdominal pain and diarrhoea. Hair loss, tremor,
hepatotoxicity, and drowsiness may also occur.
Benzodiazepines and barbiturates facilitate GABAergic
transmission by effects on the GABA receptor-ionophore
complex. Clonazepam is the most useful antimyoclonic
agent. Large doses of clonazepam are often necessary (as
much as 15 mg per day). Undue drowsiness and ataxia are
the only major side-effects and can be largely overcome by
gradually increasing the dose. Abrupt reductions and
withdrawals can result in a marked deterioration in
myoclonus and withdrawal seizures. Tolerance may develop
over a period of several months in some patients. Primidone
and phenobarbital are occasionally useful.
Piracetam and levetiracetam are related drugs that have
proven useful. Both drugs have had limited controlled
study.60–65 Their mechanism of action is unknown, although
both are well tolerated and generally non-sedating. They are
normally prescribed as add-on therapy, but can be effective
when given alone. Therapeutic daily doses of piracetam
have a range of 2·4–21·6 g and for levetiracetam of
1000–3000 mg. Abrupt withdrawal may precipitate a severe
worsening of myoclonus, and seizures may occur in the case
of piracetam.
Phenytoin and carbamazepine are helpful in only a
small proportion of patients. In others, particularly those
with Unverricht-Lundborg disease, phenytoin may
exacerbate myoclonus. Zonisamide has helped in some
cases.66,67 Vigabatrin, an irreversible inhibitor of GABA
transaminase, surprisingly does not seem very useful. It may
lead to a paradoxical increase in myoclonus in some
patients, or, occasionally, myoclonus in its own right.
In summary, the treatments of first choice in cortical
myoclonus are sodium valproate and clonazepam.68
Increasing evidence is showing that piracetam and
levetiracetam are useful adjuncts. Although no studies have
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For personal use. Only reproduce with permission from Elsevier Ltd
Review
tested sodium valproate or clonazepam versus piracetam or
levetiracetam, one of these latter two drugs may eventually
become the initial treatment of choice for cortical
myoclonus. However, most patients only gain adequate
relief from their myoclonus when drugs are used in
combination. Gait disturbance tends to be the most resistant
feature and a bouncy unsteady gait with frequent falls may
persist despite control of action and reflex myoclonus in the
upper limbs. The combination of clonazepam, sodium
valproate, and either primidone or piracetam, or both, may
be necessary to provide substantial relief of myoclonus.69
Polytherapy is generally well tolerated, but ataxia and
drowsiness may limit doses. Piracetam and levetiracetam
have particular advantages in these circumstances, as their
addition to existing treatments is rarely accompanied by
sedation.
Cortical-subcortical myoclonus
The myoclonus in primary generalised epilepsies falls under
this physiological classification. Valproic acid is the major
drug of choice for these disorders.70 The controlled evidence
for efficacy is mostly for juvenile myoclonic epilepsy.71,72 Less
impressive results are seen in other childhood myoclonic
epilepsy syndromes.73 Lamotrigine may be used alone or
used as an adjunct to valproic acid.74 Ethosuximide,
zonisamide, and clonazepam are mainly used as adjuncts.70
Polypharmacy may be useful but is limited by side-effects.
Paradoxically, antiseizure treatments sometimes increase
seizures in these syndromes. Intravenous valproic acid can
be useful in myoclonic seizure status.75
Subcortical-supraspinal myoclonus
Standard antiepileptic treatments are not helpful in
subcortical myoclonus. In essential myoclonus (including
myoclonus-dystonia), treatments such as clonazepam and
benzhexol generally do not match the amelioration seen with
alcohol, and as a result there is a real danger of alcoholism in
this disorder. Deep brain stimulation of the thalamus has had
success in a case report and awaits confirmation in more
patients.76 Reticular reflex myoclonus and opsoclonus-
myoclonus respond partially to clonazepam. The opsoclonus-
myoclonus syndrome has recently been reported to be
responsive to intravenous immunoglobulin therapy.77,78 In the
childhood form of opsoclonus-myoclonus, treatment
considerations differ from the adult form.79,80 Clonazepam is a
useful treatment in hyperekplexia.81
Palatal myoclonus is difficult to treat. The list of drugs
with anecdotal success in palatal myoclonus includes, but is
not limited to, clonazepam, carbamazepine, baclofen,
anticholinergics, tetrabenazine, valproic acid, phenytoin,
lamotrigine, sumatriptan, and piracetam.8,9,82,83 Because the
ear clicking is so disabling when it occurs in palatal
myoclonus, surgical treatments including tensor veli palatini
tenotomy and occlusion of the eustachian tube have been
tried with varying degrees of success.84 Botulinum toxin
injections have worked in some cases.10,85,86 Middle-ear
myoclonus has been treated with tensor tympani and
stapedius tenotomy as well as placement of ventilation
tubes.11–13
605
 Review Myoclonus

Spinal myoclonus
Symptomatic treatment is normally disappointing.
Clonazepam is the drug of first choice in propriospinal and
spinal segmental myoclonus, and may lead to partial
improvement in over half of cases in propriospinal
myoclonus. In daily doses of up to 6 mg, it may diminish or
abolish spinal segmented myoclonus. Diazepam,
carbamazepine, tetrabenazine, and levetiracetam have been
useful in a few cases. There are reports that use of
botulinum toxin injections for the pain and movements of
spinal segmental myoclonus have had some success.87,88
Search strategy and selection criteria
References for this review were identified by searches of
MEDLINE between January 1, 1996 and April 1, 2004 and
references from relevant articles; numerous articles were also
identified through searches of the extensive files of the authors.
The search terms “myoclonus”, “myoclonic epilepsy”,
“myoclonic seizures”, “treatment”, “piracetam”, “levetiracetam”,
“diagnosis”, “therapy” were used. Abstracts and reports from
meetings were also included. Only papers published in English
were reviewed. The final reference list was generated based on
originality and relevance to the topics covered in the review.

Peripheral myoclonus
For the quick movements in hemifacial spasm, botulinum
toxin injections are known to work well. Other causes of
peripheral myoclonus have also responded to botulinum
toxin injections.89 Drugs for peripheral myoclonus are
usually unsatisfactory, but carbamazepine may have some
effect.
Conclusion
Myoclonus has seen tremendous progress in recent years
with regard to description of myoclonus syndromes, clinical
neurophysiology, and pathophysiology. Despite this
progress, this disabling movement disorder still awaits more
major advances before better treatments are more widely
available. Physicians desperately need treatments specifically
designed for myoclonus rather than those intended for other
disorders. Further discovery of genetic mutations will yield
more specific information with regard to the neurochemical
and molecular pathophysiology of myoclonus, which, in
turn, will allow development of more specific treatments. In
addition, the delineation of the neuronal networks that
malfunction to produce myoclonus will lead to better
therapeutic targets. Finally, more double-blinded and
randomised controlled studies involving coordinated
investigator groups will be needed to systematically assess
old and new drugs for the treatment of myoclonus.
Authors’ contributions
JNC made the general plan of the review, did the literature search, and
contributed to all aspects of the review. PB contributed to all aspects of
the review.
Conflict of interest
We have no conflicts of interest.
Role of the funding source
No funding sources were involved in the writing of this review or in the
decision to submit it for publication.

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