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Therapeutic Advances in Neurological Disorders Review

Ther Adv Neurol Disord


Myoclonic disorders: a practical approach for (2011) 4(1) 4762
DOI: 10.1177/
diagnosis and treatment 1756285610395653
! The Author(s), 2011.
Reprints and permissions:
Maja Kojovic, Carla Cordivari and Kailash Bhatia http://www.sagepub.co.uk/
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Abstract: Myoclonus is a sudden, brief, involuntary muscle jerk. It is caused by abrupt muscle
contraction, in the case of positive myoclonus, or by sudden cessation of ongoing muscular
activity, in the case of negative myoclonus (NM). Myoclonus may be classified in a number of
ways, although classification based on the underlying physiology is the most useful from the
therapeutic viewpoint. Given the large number of possible causes of myoclonus, it is essential
to take a good history, to clinically characterize myoclonus and to look for additional findings on
examination in order to limit the list of possible investigations. With regards to the history, the
age of onset, the character of myoclonus, precipitating or alleviating factors, family history and
associated symptoms and signs are important. On examination, it is important to see whether
the myoclonus appears at rest, on keeping posture or during action, to note the distribution of
jerks and to look for the stimulus sensitivity. Electrophysiological tests are very helpful in
determining whether myoclonus is cortical, subcortical or spinal. A single pharmacological
agent rarely control myoclonus and therefore polytherapy with a combination of drugs, often in
large dosages, is usually needed. Generally, antiepileptic drugs such as valproate, levetira-
cetam and piracetam are effective in cortical myoclonus, but less effective in other forms of
myoclonus. Clonazepam may be helpful with all types of myoclonus. Focal and segmental
myoclonus, irrespective of its origin, may be treated with botulinum toxin injections, with
variable success.

Keywords: classification, clinical approach, myoclonus, treatment

Definition based on the presumed source of its generation. An Correspondence to:


Kailash Bhatia, FRCP, MD
Myoclonus is a movement disorder, which pre- alternative way of classifying myoclonus is based on Sobell Department of
sents itself with sudden, brief, shock-like jerks. the activity during which it occurs. It may occur at Motor Neuroscience and
Movement Disorders,
Most myoclonic jerks are due to a brief burst of rest, when maintaining a posture or during action. Institute of Neurology,
muscular activity, resulting in positive myoclonus A new category of orthostatic myoclonus has UCL, Queen Square,
London WC1N 3BG, UK
[Shibasaki and Hallett, 2005]. When jerks result recently been proposed by Glass and colleagues, k.bhatia@ion.ucl.ac.uk
from brief cessation of ongoing muscular activity, who described a heterogeneous group of 15 patients Maja Kojovic, MD
they are called negative myoclonus (NM). in which myoclonic jerks occurred predominantly Sobell Department of
Motor Neuroscience and
Positive myoclonus is generally more common, or exclusively on assuming an upright posture Movement Disorders,
while NM frequently occurs in hospital settings, [Glass et al. 2007]. Seven of these patients had neu- Institute of Neurology,
University College London,
as a result of toxicmetabolic causes. A combi- rodegenerative disease and two had a systemic ill- London, UK
nation of both forms may be present in the same ness that could cause myoclonus. Based on Carla Cordivari, FRCP,
disease, as in posthypoxic myoclonus or progres- aetiology, myoclonus may be classified as physiolog- MD
Department of Clinical
sive myoclonic epilepsies (PMEs). ical, essential, epileptic, symptomatic or psycho- Neurophysiology, National
genic [Marsden et al. 1982]. Hospital for Neurology and
Neurosurgery, London, UK
Classification and clinical presentation
Myoclonus can be classified in a number of ways. In a given patient, more than one form of myoc-
By distribution, myoclonus is classified as focal, lonus may occur. For instance, in posthypoxic
multifocal or generalized and by provoking factors myoclonus (LanceAdams syndrome), cortical
as spontaneous and reflex. Myoclonus can also be myoclonus may coexist with brainstem myoclo-
divided in cortical, subcortical, spinal or peripheral, nus [Borg, 2006].

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Therapeutic Advances in Neurological Disorders 4 (1)

Physiological classification of myoclonus is the myoclonic ataxias (PMAs) and neurodegenerative


most practical, since the presumed source of diseases.
myoclonus (cortical, subcortical, spinal or
peripheral) guides the physician towards the Negative myoclonus. NM occurs when there is
most effective treatment. For example, drugs sudden interruption of ongoing muscle contrac-
that provide the best likelihood of treatment tion (Figure 1). Clinically, it appears as a shock-
response in cortical myoclonus are not effective like involuntary jerk that causes postural lapses.
in segmental myoclonus [Caviness and Brown, When trunk or lower limbs are involved, as for
2004]. example in LanceAdams syndrome, NM will
cause a person to fall. NM may be of cortical
Individual diseases and conditions featuring or subcortical origin [Shibasaki, 1995]. NM of
myoclonus have been previously thoroughly an epileptic nature, or epileptic negative myoclo-
reviewed [Caviness, 2007; Borg, 2006; nus (ENM), is defined as an interruption of tonic
Defebvre, 2006]. This review is focused mainly muscle activity, which is time-locked to an epi-
on clinical aspects of myoclonus and its physio- leptic EEG abnormality, without evidence of an
logical classification. antecedent positive myoclonus [Rubboli and
Tassinari, 2006]. ENM can be observed in idio-
pathic, cryptogenic and symptomatic epilepsy,
Classification by underlying physiology
i.e. in PME. ENM is never an isolated sign, but
occurs in association with other types of seizures,
Cortical myoclonus. Cortical myoclonus is the
such as partial motor seizures (often of the rolan-
most common form of myoclonus, seen in both
dic type), absences or atonic seizures. NM may
outpatient and inpatient clinical settings. Cortical
also be of subcortical origin. For example, aster-
myoclonus mainly affects the distal upper limbs
ixis is a type of subcortical NM that occurs in
and face, which reflects the largest cortical repre-
toxicmetabolic encephalopathies. It is usually
sentations of these body areas [Caviness, 2009].
bilateral and rhythmic (611 Hz) [Rubboli and
It is often focal, but may be multifocal, bilateral Tassinari, 2006]. Unilateral asterixis may be
or generalized, as a consequence of intracortical seen in thalamic lesions [Tatu et al. 2000].
and transcallosal spreading of abnormal activity
[Brown et al. 1996, 1991a]. It typically occurs on Subcortical myoclonus. Subcortical myoclonus
voluntary action and may affect speech and gait. has its origin between the cortex and the spinal
Cortical myoclonic jerks are stimulus sensitive, cord. It may be divided into the nonsegmental
typically to touch, but sensitivity to visual stimuli and the segmental types.
is also described [Shibasaki and Neshige, 1987].
Most patients with cortical myoclonus have both Nonsegmental subcortical myoclonus. Startle/
positive myoclonus and NM, occurring either hyperekplexia and reticular reflex myoclonus are
independently or together as a complex of the considered to be classical examples of brainstem
two kinds of myoclonus [Shibasaki and Hallett, myoclonus. In addition, myoclonus dystonia and
2005]. If cortical myoclonus is prolonged and drug-induced myoclonus are also believed to be
lasts for hours, days or weeks, it is called epilepsia of subcortical origin, due to the absence of corti-
partials continua and is considered to be a cal correlates of myoclonic jerks [Li et al. 2008].
rare form of focal epileptic status [Bien and
Elger, 2008]. Focal cortical myoclonus almost Brainstem myoclonus is manifested by general-
always points to an underlining lesion of the sen- ized jerks and its most striking clinical feature is
sori-motor cortex, which produces hyperexcitabil- sensitivity to auditory stimuli. Two main types
ity (e.g. vascular, inflammatory or neoplastic). are (i) startle response, which may be physiologic
Recently, Alvarez and Caviness reported a case or pathologic (hyperekplexia), and (ii) reticular
series of seven patients aged over 65 with progres- reflex myoclonus.
sive cortical myoclonus, but no cause was identi-
fied after detailed investigations and they termed Physiologic startle is an example of physiological
the condition as primary progressive myoclonus brainstem reflex, which places the body in defen-
of aging [Alvarez and Caviness, 2008]. Examples sive posture, following an unexpected stimulus
of multifocal cortical myoclonus include posthy- such as sudden noise. Sensitivity to somatosen-
poxic myoclonus (LanceAdams syndrome), pro- sory stimuli delivered to the mantle area (e.g.
gressive myoclonic epilepsies (PMEs), progressive touching head, face and or upper chest) and

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M Kojovic, C Cordivari et al.

Figure 1. Negative myoclonus: cortical negative myoclonus. There is a sudden interruption of the muscle activity when the patient is
holding the left leg up against gravity. Duration of EMG silent period is 50100 ms.

visual stimuli may also be present. In startle may be distinguished from hyperekplexia by the
response, EMG activity starts in sternocleido- frequent occurrence of spontaneous myoclonus
mastoid muscles and is followed by face, trunk and sensitivity to somatosensory stimuli delivered
and limb involvement in an orderly fashion, as to distal limbs rather than to the mantle area. It
myoclonic activity spreads up the brainstem and may occur in posthypoxic encephalopathy, brain-
down the spinal cord. Startle involves proximal stem encephalitis and uraemia [Chadwick and
and distal muscles, bilaterally and synchronously, French, 1979].
and produces brief, shock-like movement com-
prising grimacing, arm abduction and flexion of Segmental subcortical myoclonuspalatal
the neck, trunk, elbows, hips and knees. myoclonus. Palatal myoclonus is a type of seg-
Hyperekplexia is pathological exaggeration of mental brainstem myoclonus, although it is con-
the normal startle response [Brown et al. sidered by some authors as a form of tremor
1991b], which does not habituate on repeated [Deuschl et al. 1994]. It consists of rhythmic
stimuli. Hyperekplexia may be familial as a (12 Hz) contractions of the soft palate, presum-
result of mutation in the alpha1 subunit of the ably due to a dysfunction (essential palatal myoc-
glycine receptor [Shiang et al. 1993], idiopathic lonus [EPM]) or a lesion (symptomatic palatal
or symptomatic of brainstem encephalitis, vascu- myoclonus [SPM]) in the GuillainMollaret tri-
lar lesions [Kimber and Thompson, 1997] or angle (GMT). The GMT comprises connections
multiple sclerosis [Ruprecht et al. 2002]. between dentate nucleus, red nucleus and infe-
rior olivary nucleus. EPM is a result of rhythmic
Brainstem reticular myoclonus is another rare contractions of the tensor veli palatini muscle,
form of generalized myoclonus. Clinically it which arises from the lateral wall of the

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Therapeutic Advances in Neurological Disorders 4 (1)

Eustachian tube. Repetitive opening and closing hundred milliseconds. Clinically, it can be distin-
of the tube, as the result of its contraction, pro- guished from brainstem myoclonus, which is also
duce an audible click [Deuschl et al. 1991], typ- axial in distribution, by sparing of the face and
ical for EPM. EPM disappears in sleep. In SPM, insensitivity to auditory stimuli. It typically
the main muscle involved is the levator veli pala- occurs spontaneously, especially in recumbent
tini. SPM is usually not accompanied by clicking position or may be provoked by tapping of the
and tends to persist in sleep [Pearce, 2008]. SPM abdomen or by eliciting tendon reflexes. As
is more common than EPM [Deuschl et al. opposed to segmental myoclonus, most patients
1990]. Important causes of SPM include vascular with propriospinal myoclonus have no clear
lesions, multiple sclerosis and brainstem aetiology. Symptomatic forms are reported in cer-
tumours. Another well-recognized cause of SPT vical trauma, tumour or viral myelitis [Brown,
is progressive ataxia palatal tremor syndrome 1996]. Psychogenic forms of propriospinal myoc-
(PAPT) [Pareyson et al. 2008]. PAPT may be lonus are now increasingly recognized [Williams
sporadic or familial. Familial PAPT is associated et al. 2008]. One recent study on a large cohort of
with marked brainstem and spinal cord atrophy patients with idiopathic spinal myoclonus,
and no evidence of olivary hypertrophy showed that at least 30% of patients had a definite
[Samuel et al. 2004]. Some familial cases of premovement (Bereitschaftspotential) potential,
PAPT are due to a GFAP mutation and represent indicating that the aetiology was psychogenic
adult onset of Alexander disease [Howard et al. [Esposito et al. 2009]. In another large series, a
2008; Pareyson et al. 2008]. A rare cause of psychogenic cause was suggested in 34 out of 35
SPT is autosomal dominant neuroferritinopathy patients with axial jerks, who were initially
due to ferritin light chain (NFL) gene mutation thought to have propriospinal myoclonus
[Wills et al. 2002]. Clinically, palatal myoclonus [van der Salm et al. 2010].
may sometimes be confused with palatal tics
[Adam et al. 2009]. Peripheral myoclonus. Peripheral myoclonus is
characterized by rhythmic or semirhythmic jerks
Spinal myoclonus. Spinal myoclonus may be secondary to plexus, nerve, root lesion or rarely
segmental or propriospinal, reflecting spinal seg- anterior horn cell disease. Hemifacial spasm is
mental organization and the presence of pro- the most common example of peripheral myoc-
priospinal pathways which connect different lonus, while other causes are relatively rare.
spinal segments [Brown et al. 1994]. It is gener-
Classification by aetiology
ally resistant to supraspinal influences such as
A classification of myoclonus is given in Table 1.
sleep (therefore it may persist in sleep) or volun-
tary action (therefore it is present at rest, inde- Physiological myoclonus. Physiological myoclo-
pendently of activation) and may or may not be nus occurs in healthy people. Jerks on falling
stimulus sensitive [Caviness and Brown, 2004]. asleep (hypnagogic myoclonus), hiccups and
physiological startle response are common
Spinal segmental myoclonus is usually symptom- examples.
atic of an underlying structural lesion such as
syringomyelia, myelitis, spinal cord trauma, vas- Essential myoclonus (myoclonus dystonia). In
cular lesion or malignancy [Brown et al. 1994; essential myoclonus, myoclonus is isolated or
Jankovic and Pardo, 1986]. It is confined to one the most prominent finding from which the
or few contiguous myotomes and may occur patient experiences some, even if mild disability
irregularly or quasirhythmically, with the fre- [Caviness and Brown, 2004]. It may be sporadic
quency as low as 12 per minute or as high as or hereditary.
100200 per minute. EMG myoclonic bursts are
prolonged up to 1000 ms. Hereditary essential myoclonus is synonymous
with myoclonus dystonia (DYT11), an autoso-
Propriospinal myoclonus is a form of spinal myoc- mal dominant disease with variable penetrance.
lonus where the spinal generator recruits axial Approximately 50% of clinically definitive
muscles up and down the spinal cord via long cases [Ritz et al. 2009] are due to mutations of
propriospinal pathways [Brown et al. 1994]. the epsilon-sarcoglycan gene on chromosome
Typically, there are axial flexion jerks involving 7q21 [Zimprich et al. 2001]. Myoclonus dystonia
the neck, trunk and hips with a frequency of is typically inherited from the father due to
16 Hz. EMG bursts are long, lasting several maternal genomic imprinting [Grabowski et al.

50 http://tan.sagepub.com
Table 1. Classification of myoclonus.

I. PHYSIOLOGICAL MYOCLONUS IV. SYMPTOMATIC MYOCLONUS IV-F Autoimmune Limbic encephalitis

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Hashimoto encephalopathy
Hypnic jerks IVA-Storage diseases Coeliac disease
Hiccoughs Neuronal ceroid lipofuscinosis* Eosinophilic encephalopathy
Sialidosis *
Physiologic startle IV-G Metabolic
Lafora body disease *
GM2 gangliosidosis (TaySachs disease) Hyperthyroidism
II. ESSENTIAL MYOCLONUS (+/ DYSTONIA) Gauchers disease type III Hepatic failure
Krabbes disease Renal failure
Myoclonic dystonia (DYT11) Dialysis syndrome
IVB- Spinocerebellar ataxias Hyponatraemia
Myoclonic dystonia (DYT15) Hypocalcaemia
RumsayHunt syndrome
Familial, no gene identified Friedreichs ataxia Hypomagnesaemia
Ataxiatelangiectasia Hypoglycemia
Sporadic SCA (2,3,17) Non-ketotic hyperglycemia
Biotin deficiency
IVC- Other neurodegenerative diseases Mitochondrial dysfunction
III. EPILEPTIC MYOCLONUS
Wilson's disease Hypoxia
Pantothenate kinase associated neurodegeneration (PKAN) Metabolic alkalosis
IIIA- Fragments of epilepsy Vitamin E deficiency
Progressive supranuclear palsy (PSP)
Isolated epileptic myoclonic jerks Dentatorubropallidoluysian atrophy (DRPLA) IVH-Toxic and drug-induced syndromes
Epilepsia partialis continua Multiple system atrophy (MSA)
BADFME Huntingtons disease (HD)
Photosensitive myoclonus IVI- Posthypoxic action myoclonus (Lance-Adams)
Alexanders disease
III-B Childhood myoclonic epilepsy IVD-Dementias IVJ-Paraneoplastic
Infantile spasms Prion disease
LennoxGastaut syndrome Corticobasal syndrome, including corticobasal degeneration IVL-Focal nervous system lesion
Severe myoclonic epilepsy of infancy (Dravet syndrome) Dementia with Lewy bodies Poststroke
Myoclonic astatic epilepsy (Doose syndrome) Parkinsons disease dementia Postthalamotomy
Cryptogenic myoclonus epilepsy (Aicardi) Alzheimers disease Tumour
III-C Idiopatic generalised myoclonic epilepsies Frontotemporal dementia linked to chromosome 17 Trauma
Inflammation
Myoclonic absence seizures IV-E Infectious or postinfectious
Juvenile myoclonic epilepsy Arbovirus encephalitis
Herpes simplex encephalitis V. PSYCHOGENIC MYOCLONUS
III-D Progressive myoclonus epilepsy:
Human T-lymphotropic virus I ( HTLV-I)
Baltic myoclonus (UnverrichtLundborg) HIV
MERRF (myoclonic epilepsy with ragged red fibres) Malaria
Syphilis
Cryptococcus
Lyme disease
Progressive multifocal leucoencephalopathy ( PML)
Whipples disease
Subacute sclerosing panencephalitis
Postinfectious encephalitis modified from Marsden et al. [1982]
Encephalitis lethargica
*Also classified as progressive myoclonic epilepsy

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Therapeutic Advances in Neurological Disorders 4 (1)

2003; Muller et al. 2002]. It typically starts in due to focal nervous system damage,
childhood, with myoclonic, lightning jerks in neurodegenerative diseases and hereditary meta-
combination with usually mild dystonia, while bolic diseases. Myoclonus due to toxicmeta-
other neurological deficits are absent. In a pro- bolic causes is usually accompanied by
portion of cases, psychiatric features such as anx- encephalopathy and additional neurological find-
iety, depression and obsessivecompulsive ings, such as ataxia or seizures. Borg has given an
disorders are part of the clinical picture [Hess exhaustive review of symptomatic myoclonus
et al. 2007; Misbahuddin et al. 2007; Saunders- [Borg, 2006].
Pullman et al. 2002]. Myoclonus and dystonia
affect mainly the head, neck and arms, but occa- It is important to recognize that the following
sionally falls caused by myoclonic jerks in the legs metabolic derangements may cause symptomatic
may be the main feature [Koukouni et al. 2008]. myoclonus: renal failure, hepatic failure, respira-
Typically, there is quite a dramatic response of tory failure, glycaemic disturbances, electrolytic
myoclonic jerks to alcohol. Stimulus sensitivity disturbances, hyperthyroidism, metabolic alkalo-
is not an important characteristic of this condi- sis or acidosis, vitamin E deficiency, Hashimoto
tion. Pathophysiology of myoclonus dystonia is encephalopathy and hypoxia [Borg, 2006].
not clear. Cortical somatosensory evoked poten- Symptomatic myoclonus is usually cortical,
tials are normal and back-averaging of EEG focal or multifocal and sensitive to stimuli.
activity preceding jerks reveals no cortical corre- However, NM (asterixis) and brainstem reticular
late [Li et al. 2008; Roze et al. 2008]. myoclonus may also be seen.

Epileptic myoclonus. This term is used to denote Toxic causes of myoclonus include chronic abuse
conditions where myoclonus occurs in the setting of alcohol and withdrawal, the dialysis syndrome
of epilepsy. Epileptic myoclonus may be positive due to aluminium toxicity, chronic toluene abuse,
or negative (lapses of postural tone). Epileptic methyl bromide and gasoline sniffing [Gordon,
myoclonus is accompanied by generalized epilep- 2002].
tiform discharges on EEG, but the myoclonus
itself may be focal, segmental or generalized Drugs that may cause myoclonus include
[Caviness and Brown, 2004]. Generalized myoc- levodopa, antidiarrhoeal bismuth subsalicylate,
lonus can occur in the syndromes of primary (idi- benzodiazepines, antidepressants (cyclic antide-
opathic) generalized epilepsy (e.g. juvenile pressants, selective serotonin uptake inhibitors,
myoclonic epilepsy) or in the secondary (symp- monoamine oxidase inhibitors), lithium, anti-
tomatic) generalized epilepsies (e.g. PME). infectious agents (quinolone antibiotics, cepha-
Focal myoclonus can occur in symptomatic epi- losporines), clozapine, opioids, anticonvulsants
lepsy, in the setting of infection, inflammation, (particularly gabapentin, pregabalin, lamotrigine,
vascular disease, trauma or tumours. phenytoin, phenobarbital), anaesthetic propofol,
cardiac medications (calcium channel blockers,
Familial cortical tremor, also known as benign antiarrhythmics) and contrast media [Caviness
autosomal dominant familial myoclonic epilepsy and Brown, 2004].
(BADFME), is a rare, although interesting disor-
der, because it clinically resembles essential Postanoxic myoclonus (LanceAdams syn-
tremor. It is a benign condition characterized by drome) is a distinct condition that may follow
fine, shivering-like tremor, which usually starts in severe cerebral hypoxia, usually after respiratory
the third or fourth decade. Generalized seizures rather than cardiac arrest [Werhahn et al. 1997].
are infrequent and there is no significant clinical Myoclonus is mainly cortical and multifocal
progression. The condition has been mapped to and there is a combination of positive myoclonus
chromosome 8q and to chromosome 2p and NM, but reticular reflex myoclonus and
[Guerrini et al. 2001; Plaster et al. 1999]. exaggerated startle may also occur. Action myoc-
lonus is the main disabling feature of this condi-
Secondary myoclonus. This type of myoclonus tion, although a variable degree of cognitive
occurs in the context of an underlying neurolog- impairment and seizures may be present in a pro-
ical or nonneurological disorder and is the most portion of patients. NM in proximal leg muscles
common form of myoclonus. The aetiology (bouncy legs) is very resistant to the treatment
includes posthypoxic myoclonus, drug-induced and may leave the patient wheelchair-bound.
myoclonus, toxicmetabolic causes, myoclonus Some patients may show late improvement and

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M Kojovic, C Cordivari et al.

eventually be able to walk unaided and to Polyminimyoclonus is stimulus-sensitive and


discontinue antimyoclonic drugs [Werhahn et al. accentuated during voluntary movements. A cor-
1997]. tical origin can be demonstrated by back-aver-
aging techniques, and somatosensory evoked
The progressive myoclonic epilepsy syndromes potentials (SSEPs) are sometimes giant
are a group of rare disorders, characterized by [Rodriguez et al. 1994].
myoclonic epilepsy, generalized tonic clonic sei-
zures, progressive ataxia and dementia. Six main Myoclonus occurs in 50% patients with cortico-
categories are recognized: UnverrichtLundborg basal degeneration (CBD) [Caviness, 2007].
disease, myoclonic epilepsy with ragged red fibres It appears focally in the affected arm, together
(MERRF), Lafora body disease, neuronal ceroid with apraxia, rigidity, dystonia and alien limb
lipofuscinosis, sialidosis and dentato-rubro-pala- phenomenon. At the beginning of the illness,
dal-Lysian atrophy (DRPLA). Myoclonus in it occurs in repetitive rhythmic fashion (jerky
PME is multifocal, typically involving the distal tremor) on an attempt to activate the arm or fol-
limbs and face and is provoked by posture or lowing somatosensory stimulation (reflex myoc-
action. It is sensitive to touch, noise and light lonus). As the disease progresses, spontaneous
[Shahwan et al. 2005]. Patients are typically myoclonus adjoins. A cortical origin has been
severely disabled by their action myoclonus. postulated [Thompson et al. 1994b], even
though an additional subcortical origin is possi-
Action myoclonusrenal failure syndrome is a ble [Grosse et al. 2003].
distinct type of PME, described by Badhwar
and colleagues, that is associated with renal In contrast to CBD, myoclonus is rare in progres-
impairment [Badhwar et al. 2004]. Mutation sive supranuclear palsy.
of the LIMP-2 gene has been recently identified
as a cause [Blanz et al. 2010] and the condition In relation to Huntingtons disease, myoclonus
is inherited in autosomal recessive fashion. may be seen in individuals with a juvenile onset
It usually starts with the tremor (age 1726), and longer CAG repeats [Thompson et al.
followed by action myoclonus, infrequent 1994a].
generalized seizures and cerebellar signs.
Proteinuria is invariably present in the course In Alzheimers disease (AD), myoclonus may
of the disease and the condition progresses to appear in the middle or late stages of disease, is
renal failure. usually multifocal, occurring both at rest and
during action. In patients with early onset AD
Progressive myoclonic ataxias, also known as and in familial cases, it may be present early in
RumseyHunt syndrome, include conditions the disease [Caviness, 2007].
with prominent myoclonus and ataxia, but little
in the way of epilepsy or progressive dementia. Myoclonus is typical finding in sporadic, familial
PMA include coeliac disease, some cases of mito- and new variant CreutzfeldtJakob disease.
chondrial diseases, vitamin E deficiency and Jerks, often limited and sporadic at the disease
some cases of UnverrichtLundborg disease. onset, become diffuse, generalized and relatively
rhythmic (0.61.5 Hz) as the disease progresses
Myoclonus is often linked to neurodegenerative
[Borg, 2006].
disorders.

Cortical myoclonus is present in about 15% of Psychogenic myoclonus. Psychogenic myoclo-


patients with dementia with Lewy bodies nus may occur spontaneously or following an
(DLB) [Caviness et al. 2003] or Parkinsons dis- external trauma. It may be focal (restricted to a
ease dementia, but is rare in Parkinsons disease few muscles) or generalized. Jerks are commonly
without dementia [Caviness et al. 2002]. distractible and inconsistent over time, with
sudden onset and offset and day-to-day variabil-
Patients with multiple system atrophy (MSA) ity. Usually, there is exaggerated stimulus sensi-
often display irregular, small-amplitude myo- tivity. Despite these characteristics, it may be
clonic movements (polyminimyoclonus) of difficult to distinguish psychogenic from organic
the hands and/or fingers on keeping out- myoclonus and electrophysiology may be helpful
stretched posture (jerky postural tremor). (as described in the following).

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Therapeutic Advances in Neurological Disorders 4 (1)

Approach to patients with myoclonus Family history with an autosomal recessive mode
On history taking, one should be interested in the of inheritance is present in syndromes of PME or
age at onset of myoclonus, the character of onset in hereditary metabolic disorders (e.g. GM1
(acute versus gradual), precipitating or alleviating gangliosidosis, Gaucher disease). Autosomal
factors, family history and associated symptoms dominant inheritance is seen in myoclonus dys-
such as epilepsy, ataxia and cognitive decline tonia, DRPLA or familial cortical tremor.
(present in symptomatic as opposed to essential Mitochondrial inheritance is characteristic for
myoclonus). It is also important to know whether MERRF.
the condition is static or progressive.
On examination, it is important to check whether
The age at onset is important as it may point out myoclonus appears at rest, on posture (keeping
to the major disease category. The onset of myoc- the arms outstretched) or during action and to
lonus in childhood or young adult, together with note its distribution. Myoclonus at rest indicates
generalized epileptic fits, cognitive decline and a spinal or brainstem source, whereas action-
progressive ataxia suggest the syndrome induced myoclonus points to a cortical origin.
of PME. On the other hand, in elderly patients, Focal and multifocal jerks, occurring during vol-
myoclonus and cognitive decline are seen untary action, are typical of cortical myoclonus.
DLB, CBD and later stages of AD or, if Spinal segmental myoclonus is also focal,
rapidly progressive, in prion diseases. although contrary to cortical myoclonus, it is
Opsoclonus myoclonus syndrome in childhood not action-induced and is occasionally stimulus
is typically associated with neuroblastoma or sensitive. Generalized myoclonus is usually sub-
medulloblastoma. In adulthood, it occurs as cortical (brainstem or propriospinal myoclonus)
paraneoplastic manifestation in lung small-cell or less frequently cortical. The amplitude of
carcinoma or melanoma, but may be postinfec- myoclonus varies considerably. Very small,
tious, associated with coeliac disease or may be hardly visible distal myoclonic jerks (mini poly-
drug related. myoclonus) are typical for MSA, whereas very
large amplitudes are typical for PME.
Regarding the nature of onset, the acute onset of
myoclonus is seen in toxicmetabolic disorders The next step in the examination is to look for
such as hepatic and renal failure, thyrotoxicosis, stimulus sensitivity. This can be done by gently
electrolyte disturbances (e.g. hyponatraemia, touching the outstretched fingers to trigger
hypoglycaemia, nonketotic hyperglycaemia), myoclonus. Clapping the hands may induce
some neuroinfectious diseases (herpes simplex myoclonus sensitive to auditory stimuli, but
encephalitis, neuroboreliosis), following hypoxic common sounds in the examination room (open-
brain injury, in paraneoplastic disorders and with ing or closing doors, loud speech) may be suffi-
drugs. The recent introduction of a new drug or cient to trigger myoclonus in susceptible patients.
increase in dosage should always be considered as
a possible cause of new onset myoclonus. More Finally, it is important to look for other neuro-
insidious onset followed by chronic progression logical signs, particularly for dementia, cerebellar
is characteristic of neurodegenerative diseases features, eye movement abnormalities and any
and PME. associated signs of systemic disease.

Precipitating factors are recognized in cases of Given the extensive list of different causes of
drug-induced myoclonus, intoxication and meta- myoclonus, it is important to take a good history
bolic disturbances. Spinal and peripheral myoc- and to use additional clinical findings, in order to
lonus may follow cord/plexus/root/nerve injury. avoid numerous, expensive and sometimes
Dramatic response to alcohol in myoclonus dys- unnecessary investigations. In unexplained cases
tonia is an example of a factor alleviating of myoclonus, the following tests are routinely
myoclonus. done: electrolytes, glucose, liver, renal and thy-
roid function, brain and spinal imaging and EEG.
The presence of additional neurological findings, Additional testing depends on clinical presenta-
such as dementia, cerebellar ataxia or epilepsy tion and may include spinal fluid examination,
automatically rule out essential myoclonus and paraneoplastic antibody testing, genetic tests or
prompt a search for symptomatic causes. enzyme activity assays.

54 http://tan.sagepub.com
M Kojovic, C Cordivari et al.

Neurophysiologic assessment conventional EEGEMG recording, EEG spikes


Electrophysiology is very helpful to detect associated with EMG myoclonic bursts suggest
whether myoclonus is cortical, subcortical or cortical origin. The absence of EEG spikes does
spinal/segmental. Polymyography is the first not exclude the possibility of a cortical aetiology
step in the neurophysiologic assessment of myoc- and back averaging of EEG, time locked to the
lonus and includes recording of duration, distri- onset of myoclonic jerks may disclose a cortical
bution and stimulus sensitivity of muscle jerks. spike, occurring approximately at an interval
Further investigations include combined appropriate for conduction in the fastest corti-
EEGEMG recording, EEG back averaging cospinal pathways.
and recording of SSEPs.
In contrast with cortical myoclonus, in subcorti-
Cortical myoclonus (Figure 2) may have the cal myoclonus there are no signs of hyperexcit-
following electrophysiological characteristics: (a) ability on the EEG and SSEP recordings.
it is represented by brief EMG discharges lasting
less than 70 ms, usually less than 50 ms Simultaneous recording of surface EMG (multi-
[Shibasaki, 2006]; (b) an EEG spike precedes channel surface EMG) from different muscles
the myoclonus by a short interval (20 ms for may give information on the distribution and
hand muscles and about 35 ms for the calf mus- mode of spread of myoclonus in the case of brain-
cles); (c) there is an enhancement of the early stem myoclonus (Figure 3). The first activated
cortical component of the SSEPs, called giant muscle is sternocleidomastoid or trapezius with
SSEPs [Kakigi and Shibasaki, 1987]. Also, subsequent spread of activity to rostral and
long loop reflexes mediated by the sen- caudal muscles.
sorymotor cortex (C-reflexes) are enhanced
and correspond to cortical reflex myoclonus In propriospinal myoclonus (Figure 4), myo-
[Hallett et al. 1979]. EMG recording from limb clonic bursts may last from 50 ms to 4 s. EMG
muscles may demonstrate spread of the jerks jerks arise from abdominal or cervical spinal seg-
from proximal to distal muscles with the velocity ments and spread slowly rostrally and caudally,
compatible with that of alpha motor fibres. On sparing the cranial muscles.

Figure 2. Cortical myoclonus: EMG and EEG trace in a case of cortical myoclonus.
(A) A magnification of a segment (20 ms/division) where myoclonic jerks are observed. Surface EMG shows
brief bursts of activity (of approximately 20 ms duration) with a typical rostrocaudal pattern of muscle activation
in the right upper limb.
(B) EEG back averaging of the right first dorsal interossei muscle. EMG burst demonstrates cortical spikes in
C3 derivation, starting 22 ms before the EMG myoclonic burst.

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Therapeutic Advances in Neurological Disorders 4 (1)

Figure 3. Brainstem reticular myoclonus. Multichannel EMG recording: Following acoustic stimulation there
was an initial activation of the right sternocleidomastoid muscle with a latency of 68 ms, followed by the spread
to rostral and caudal muscles.

Figure 4. Propriospinal myoclonus. With the patient in a recumbent position, surface multichannel EMG from
right-sided muscles shows a jerk of approximately 400 ms duration. This jerk is electrically evoked, starts with
a latency of 200 ms in the rectus abdominis muscle and is followed by activation of rostral and caudal muscles.

56 http://tan.sagepub.com
M Kojovic, C Cordivari et al.

Figure 5. Spinal segmental myoclonus. Multisurface EMG shows myoclonic bursts confined mainly to the
right triceps but affecting also a few adjacent myotomes.

In spinal segmental myoclonus (Figure 5), myo- intoxications or surgically treatable lesions, how-
clonic bursts are confined to one or two contig- ever in the majority of cases, the underlying cause
uous myotomes. is not correctable and symptomatic treatment is
the only possibility. A useful approach to the
Simple EMG recording of myoclonic jerks may treatment is to first establish the physiology of
help to exclude psychogenic myoclonus. It is not myoclonus (cortical versus subcortical or
possible to voluntarily produce an EMG burst spinal), because different drugs will work in dif-
of less than 5075 ms and therefore bursts lasting ferent types of myoclonus.
less than this are strong evidence of organicity. In
contrast, recording of premovement One single agent can seldom completely control
EEG potentials (Bereitschaftspotentials) just myoclonus; therefore multiple drug trials and
prior to a jerk is suggestive of a psychogenic combination of drugs are necessary, often in
cause (Figure 6). large dosages. In general, antiepileptic drugs
such as valproate, levetiracetam and piracetam
Most of these electrophysiological investigations are effective in cortical myoclonus, but ineffective
are available only in specialized centres and do in other forms of myoclonus. Clonazepam may
not form a part of everyday clinical practice. be helpful in all types of myoclonus

Cortical myoclonus
Treatment of myoclonus Treatment of cortical myoclonus is aimed at
The treatment of myoclonus depends on the enhancing deficient GABAergic inhibitory neu-
underlying disorder. Reversible causes of myoc- rotransmission [Caviness and Brown, 2004].
lonus include some toxicmetabolic states, drug As a rule, cortical myoclonus is treated with

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Therapeutic Advances in Neurological Disorders 4 (1)

Figure 6. Psychogenic myoclonus. A slow rising wave called the Bereitschafts potential is seen in EEG back
averaging of the right triceps jerk (duration of the triceps jerk is 200 ms).

a combination of drugs. Sedation and ataxia are (32004800 mg tds, maximum up to 20 g/day),
the main side effects of polytherapy, but they may but levetiracetam is a more potent drug (maxi-
be overcome with the start low, go slow princi- mum 3000 mg daily). In cortical myoclonus, pir-
ple. Of the GABAergic drugs, sodium valproate acetam or levetiracetam can be combined with
is the most effective. It should be introduced sodium valproate and clonazepam. Primidone
slowly and titrated up to 12002000 mg daily. and phenobarbital are rarely effective, whereas
Benzodiazepines are also very useful, especially zonisamde has helped in some cases of PME
clonazepam in large doses (up to 15 mg a day). [Leppik, 1999; Kyllerman and Ben-Menachem,
Tolerance may develop after several months, 1998]. Phenytoin, carbamazepine, lamotrigine
while rapid reduction or withdrawal can produce and vigabatrin are best avoided in cortical myoc-
marked deterioration. Piracetam and levetirace- lonus, as they may paradoxically exacerbate
tam are two related drugs, proven to be very myoclonus. This is particularly the case with phe-
useful in myoclonus [Genton and Gelisse, nytoin in UnverrichtLundborg disease.
2000; Ikeda et al. 1996], although their exact Treatment of PME is very challenging, as drugs
mechanism of action is poorly understood. that help generalized seizures may worsen myoc-
Large doses of piracetam may be required lonus and vice versa.

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M Kojovic, C Cordivari et al.

Negative myoclonus Psychogenic myoclonus


ENM in children suffering from idiopathic par- Psychogenic myoclonus may improve as a result
tial epilepsy may respond to ethosuximide and of placebo or psychotherapy.
levetiracetam [Gelisse et al. 2003; Capovilla
et al. 1999]. ENM associated with symptomatic Conclusion
or cryptogenic epilepsies is usually less responsive Myoclonus is a clinical sign that may be found in
to common antiepileptic drugs and may be wor- a number of different diseases. To provide a
sened by carbamazepine, valproic acid, phenyt- framework to match a patients myoclonus to its
oin, lamotrigine and oxcarbazepine. In aetiology, it is necessary to take a good history
posthypoxic myoclonus, distal action and reflex and to perform a detailed neurological examina-
myoclonus of upper limbs respond to therapy tion, before deciding which additional tests are
much better than NM of proximal lower limbs, needed. It is important to establish the presumed
which causes gait disturbances and frequent falls. origin of myoclonus (cortical, subcortical, spinal
or peripheral) in order to choose the most effec-
Subcortical myoclonus tive treatment. Controlled evidence on the treat-
Antiepileptic drugs used in cortical myoclonus ment of myoclonus is insufficient and therapy is
are not effective in subcortical myoclonus mostly empirical.
[Caviness and Brown, 2004]. Clonazepam is
useful in hyperekplexia and partially in reticular Acknowledgments
reflex myoclonus. Myoclonus dystonia responds We would like to thank Dr Joao Massano and
partially to clonazepam, although the response Dr Marcello Esposito for their help in preparing
fails to match that from alcohol. In one report, the figures and the table.
alcohol-sensitive myoclonus dystonia was suc-
cessfully treated with 6.125 g/day of gamma- Funding
hydroxybutyric acid [Priori et al. 2000]. Severe This research received no specific grant from any
cases of myoclonic dystonia can be helped by funding agency in the public, commercial, or not-
bilateral pallidal [Magarinos-Ascone et al. 2005; for-profit sectors.
Cif et al. 2004] or thalamic deep brain stimula-
tion [Trottenberg et al. 2001]. Conflict of interest statement
The authors have no conflicts of interest to
declare.
Spinal myoclonus
In spinal myoclonus, pharmacological treatment
is unsatisfactory. Clonazepam is the drug of first
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