Pathophysiolo gy

a nd Treatment
of Myo clonus
John N. Caviness, MD

KEYWORDS
 Myoclonus  Motor Cortex  Electrophysiology
 Pathophysiology  Treatment

INTRODUCTION, CLINICAL CLASSIFICATION, AND EVALUATION

The pathophysiology of myoclonus is complex and can be conceptualized at many

levels. Myoclonus is defined as sudden, brief, shock-like, involuntary movements
caused by muscular contractions or inhibitions.1 The abrupt character of the move-
ment suggests that there is a sudden change in the firing of certain neuron populations
that affect motorneurons. Because the movement systems of the brain, spinal cord,
and peripheral nerves comprise numerous levels and feedback loops, it is no surprise
that there are multiple ways to suddenly alter motorneuron activity in a way that
causes myoclonus. Moreover, a wide variety of diseases and conditions may create
a type of neuronal dysfunction that causes myoclonus.2 When including all known
etiologies, myoclonus has an average annual incidence of 1.3 cases per 100,000.3

Clinical Classification
The major categories of myoclonus in the popular etiologic classification scheme of
Marsden and colleagues1 are as follows: physiologic, essential, epileptic, and symp-
tomatic (secondary) (Box 1). The individual disorders/conditions that are listed for
each major category have been upd ated over the years.2 Each of the major categories
is associated with different clinical presentations. Physiologic myoclonus occurs in
neurologically normal people. There is minimal or no associated disability, and phys-
ical examination reveals no relevant abnormality. Jerks during sleep are the most
familiar examples of physiologic myoclonus. Essential myoclonus refers to myoclonus
that is the primary or only clinical finding. Essential myoclonus is idiopathic, sporadic,
or hereditary and progresses slowly or not at all. Some families with hereditary essen-
tial myoclonus manifest a genetic mutation. Epileptic myoclonus refers to the pres-
ence of myoclonus in the setting of epilepsy—that is, a chronic seizure disorder.
Myoclonus can occur as one component of a seizure, the only seizure manifestation,

Department of Neurology, Mayo Clinic,13400 East Shea Blvd, Scottsdale, AZ 85259, USA
E-mail address: jcaviness@mayo.edu

Neurol Clin 27 (2009) 757–777

doi:10.1016/j.ncl.2009.04.002 neurologic.theclinics.com
0733-8619/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
758 Caviness

Box 1
Clinical classification of myoclonus

I. Physiologic myoclonus (healthy individuals)

A. Sleep jerks (eg, hypnic jerks)
B. Anxiety-induced
C. Exercise-induced
D. Hiccough (singultus)
E. Benign infantile myoclonus with feeding
II. Essential myoclonus (primary symptom, non-progressive history)
A. Hereditary (autosomal dominant)
B. Sporadic
III. Epileptic myoclonus (seizures dominate, part of chronic seizure disorder)
A. Fragments of epilepsy
Isolated epileptic myoclonic jerks
Epilepsia partialis continua
Idiopathic stimulus-sensitive myoclonus
Photosensitive myoclonus
Myoclonic absences in petit mal epilepsy

B. Childhood myoclonic epilepsy

Infantile spasms
Myoclonic astatic epilepsy (Lennox-Gastaut)
Cryptogenic myoclonus epilepsy (Aicardi)
Awakening myoclonus epilepsy of Janz (juvenile myoclonic epilepsy)

C. Progressive myoclonus epilepsy: Baltic myoclonus (Unverricht-Lundborg)

IV. Symptomatic myoclonus (secondary, progressive, or static encephalopathy dominates)
A. Storage disease
Lafora body disease
GM2 gangliosidosis (late infantile, juvenile)
Tay-Sachs disease
Gaucher disease (noninfantile neuronopathic form)
Krabbe leukodystrophy
Ceroid-lipofuscinosis (Batten)
Sialidosis (cherry-red spot) (types 1 and 2)

B. Spinocerebellar degenerations
Ramsay Hunt syndrome
Friedreich ataxia
Ataxia-telangiectasia
 Pathophysiology and Treatment of Myoclonus 759

C. Other spinocerebellar degenerations

Basal ganglia degenerations
Wilson disease
Torsion dystonia
Hallervorden-Spatz disease
Progressive supranuclear palsy
Huntington disease
Parkinson disease
Multisystem atrophy
Corticobasal degeneration
Dentatorubropallidoluysian atrophy

D. Dementias
Creutzfeldt-Jakob disease
Alzheimer disease
Dementia with Lewy bodies
Frontotemporal dementia
Rett syndrome

E. Infectious or postinfectious
Subacute sclerosing panencephalitis
Encephalitis lethargica
Arbovirus encephalitis
Herpes simplex encephalitis
Human T-lymphotropic virus I
HIV
Postinfectious encephalitis
Miscellaneous bacteria (streptococcus, clostridium, other)
Malaria
Syphilis
Cryptococcus
Lyme disease
Progressive multifocal leukoencephalopathy

F. Metabolic
Hyperthyroidism
Hepatic failure
Renal failure
Dialysis syndrome
Hyponatremia
Hypoglycemia
Nonketotic hyperglycemia
760 Caviness

Multiple carboxylase deficiency

Biotin deficiency
Mitochondrial dysfunction
Hypoxia
Metabolic alkalosis
Vitamin E deficiency

G. Toxic and drug-induced syndromes

H. Physical encephalopathies
Posthypoxia (Lance-Adams)
Posttraumatic
Heat stroke
Electric shock
Decompression injury

I. Focal nervous system damage

CNS
Poststroke
Postthalamotomy
Tumor
Trauma
Inflammation (eg, multiple sclerosis)
Möbius syndrome
Developmental
Idiopathic
Peripheral nervous system
Hematoma

J. Malabsorption
Celiac disease
Whipple disease
K. Eosinophilia-myalgia syndrome
L. Paraneoplastic encephalopathies
M. Opsoclonus-myoclonus syndrome
Idiopathic
Paraneoplastic
Infectious
Other

N. Exaggerated startle syndrome

Hereditary
Sporadic

O. Hashimoto encephalopathy
 Pathophysiology and Treatment of Myoclonus 761

P. Multiple system degenerations

Allgrove syndrome
DiGeorge syndrome
Membranous lipodystrophy

Q. Unknown
Familial
Sporadic

Data from Marsden CD, Hallett M, Fahn S. The nosology and pathophysiology of myoclonus. In:
Marsden CD, Fahn S, editors. Movement disorders. London: Butterworths; 1982. p. 196–248.

or one of multiple seizure types within an epileptic syndrome. The most common
example of this category is the juvenile myoclonic epilepsy of Janz, which falls under
the rubric of idiopathic generalized epilepsy. Symptomatic (secondary) myoclonus
manifests in the setting of an identifiable underlying disorder, neurologic or non-neuro-
logic. Mental status abnormalities and ataxia are common clinical associations in
symptomatic myoclonic syndromes. Symptomatic causes of myoclonus comprise
a widely diverse group of disease processes and include neurodegenerative diseases,
storage diseases, toxic metabolic states, diffuse brain injuries, infections, focal
nervous system damage, paraneoplastic syndromes, and other medical illnesses.1,2
Most clinically relevant cases of myoclonus are in the symptomatic category, followed
by the epileptic and essential categories.3

Evaluation
The properties of the myoclonus and other aspects of the clinical presentation deter-
mine what type of evaluation and testing should be performed.2 For example, if an
infectious or inflammatory syndrome is present, a cerebrospinal fluid examination is
necessary. Knowledge of the various disorders in a well-delineated differential diag-
nosis for a particular patient will facilitate the proper diagnostic confirmation. An
important first step is to derive from a history and physical examination the appropriate
clinical category among physiologic, essential, epileptic, and symptomatic. Special
attention should be given to the presence of concomitant medical conditions, family
history of similar problems, and exposure to toxins and drugs known to cause myoc-
lonus. Numerous drugs are known to cause or contribute to myoclonus, and examples
are given in Box 2. If a drug is suspected to cause a patient’s myoclonus, a cautious
decreaseg or discontinuation of the medication should be considered. The result of
the medication change may be therapeutic as well as diagnostic. When the cause
of the myoclonus is unexplained even after this initial evaluation, the following minimal
testing should be performed:

Electrolytes (including bismuth, Ca21, Mg21)and glucose

Renal function tests
Hepatic function tests
Drug and toxin screen
Electroencephalography
762 Caviness

Box 2
Drugs that are associated with myoclonus

Psychiatric medications
Cyclic antidepressants
Selective serotonin reuptake inhibitors
Monoamine oxidase inhibitors
Lithium
Tardive syndrome (antipsychotic use)
Anti-infectious agents
Narcotics
Anticonvulsants
Anesthetics
Contrast media
Cardiac medications
Calcium channel blockers
Antiarrhythmics
Drug withdrawal
Other medications
Data from Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet
Neurol 2004;3:598–607.

Brain imaging
Paraneoplastic testing

This testing mainly evaluates metabolic, toxic, and structural brain lesions; seizure
disorders; and cancer-related causes of myoclonus. If these tests do not reveal the
diagnosis, then more advanced testing should be considered. This testing may
include cerebrospinal fluid examination, enzyme activity, imaging for cancer, tissue
biopsy, and other tests.2 Body imaging for cancer should be considered even though
paraneoplastic testing is negative. In some cases, genetic testing may be considered.
Before genetic testing is done, the patient should be fully aware of the implications for
positive and negative results. If appropriate, genetic counseling is recommended.
In those instances where the cause of myoclonus is not known, detailed consider-
ation of the myoclonus pathophysiology is recommended. The pathophysiologic
mechanism of the myoclonus complements its placement within the etiologic classi-
fication scheme. Ascertainment of myoclonus pathophysiology in the clinic setting is
feasible, because the pathophysiology of myoclonus may be probed with noninvasive
clinical neurophysiology testing. Definition of the myoclonus pathophysiology has
strong implications for neurologic localization, diagnosis, and treatment.

PATHOPHYSIOLOGY OF MYOCLONUS

Etiologic classification provides an organizational scheme within which causes of

myoclonus with similar clinical presentation are grouped. However, classifying myoc-
lonus according to its neurophysiology provides insight with regard to its pathophys-
iology. The classification also gives localizing information for the myoclonus and thus
 Pathophysiology and Treatment of Myoclonus 763

can provide at least partial localization for diagnosis of the underlying process. Since
most myoclonus treatments are based on attempting to normalize the dysfunctional
physiology mechanisms, ascertaining the physiology of the myoclonus directs one
toward the most effective treatment.2

Clinical Neurophysiology Methods for Studying Myoclonus

The brevity of myoclonus and its dramatic clinical presentation has led naturally to the
idea that it is generated from a source that somehow transmits a hyperexcitable drive
to motorneurons, which causes the jerk movement in positive myoclonus. Clinical
examination can provide clues to the myoclonus source, but myoclonus research
has relied heavily on clinical neurophysiology methods to provide corroborative
evidence for pinpointing the source localization. These methods have great clinical
usefulness for myoclonus as well. The equipment for invoking these methods is
commonly available, but the clinician should use available resources for recognizing
and interpreting the pattern of findings for various myoclonus sources.4,5 The specific
electrophysiologic methods used in the clinical neurophysiologic study of myoclonus
usually include, but are not limited to, multichannel surface electromyography (EMG)
recording with testing for long latency EMG responses to mixed nerve stimulation,
electroencephalography (EEG), EEG-EMG polygraphy with back-averaging, and
evoked potentials (eg, median nerve stimulation somatosensory-evoked potential
[SEP]).4 Positive and negative findings from these methods are used to determine
the physiologic type of myoclonus.5 The different physiologic types of myoclonus
are organized into a classification scheme whose major categories represent the
source of myoclonus generation along the neuraxis. The main physiologic categories
for myoclonus classification are:
 Cortical
 Cortical-Subcortical
 Subcortical-Suprasegmental
 Segmental
 Peripheral

Further subdivision is based on detailed electrophysiologic and examination find-

ings. Multiple myoclonus physiology types can occur in the same patient. The discus-
sion on myoclonus pathophysiology will be organized by the physiologic classification
scheme.

Cortical
The cerebral cortex is the most common origin for myoclonus. The establishment of
a cortical origin for the myoclonus may have diagnostic implications. Such etiologies
that may demonstrate cortical myoclonus include posthypoxic syndrome, progressive
myoclonus epilepsy syndromes, drugs and toxins, neurodegenerative syndromes,
various dementias, focal lesions, and other entities of unknown cause, sporadic and
familial (Box 3). Cortical myoclonus predominately affects those body parts with the
biggest cortical representations, the limbs and head. The motor cortex in humans is
known to particularly control fine or fractionated movements rather than acting across
multiple muscle segments. As a result, the jerks are most often multifocal or focal, but
segmental and generalized myoclonus also occur. The authors know that motor areas
of the cerebral cortex are most involved in creating voluntary action, and accordingly,
the myoclonus is exacerbated by voluntary muscle activation. It is the action of myoc-
lonus that usually produces the most disability in these patients. At rest, myoclonus is
764 Caviness

Box 3
Etiologies for which cortical myoclonus has been described

Posthypoxic myoclonus
Progressive myoclonic epilepsy syndromes
- Unverricht-Lundborg disease
- Mitochondrial disease
- Ceroid lipofuscinosis
- Lafora body disease
- Sialidosis

Drugs and Toxins

- Tricyclic antidepressant medication
- Lithium
- Levodopa
- Methyl bromide

Neurodegenerative syndromes
- Alzheimer disease
- Parkinson disease
- Multiple system atrophy
- Spinocerebellar degeneration
- Huntington disease

Creutzfeldt-Jakob disease
Subacute sclerosing panencephalitis
Celiac disease
Rett syndrome
Down syndrome
Angelman syndrome
Focal lesions from numerous causes
Syphilis
Traumatic encephalopathy
Unknown—sporadic
Unknown—familial

Data from Caviness JN, Brown P. Myoclonus: current concepts and recent advances. Lancet Neu-
rol 2004;3:598–607.

usually less prominent, unless the major clinical manifestation is a focal motor seizure.
Myoclonus induced by reflex stimulation (by way of transcortical loop) occurs
commonly, and its characterization is important for physiologic classification. It is
the most common situation for a patient to have myoclonus with a combination of
action and reflex precipitants and a smaller presence at rest.
 Pathophysiology and Treatment of Myoclonus 765

Electrophysiologic properties from clinical neurophysiology methods

The important electrophysiologic characteristics for cortical myoclonus are:4
1. 25 to 100 ms-duration surface EMG discharges
2. Focal cortical EEG transient preceding myoclonus by less than 40 ms (arm)
3. Enhanced long-latency EMG responses to mixed nerve stimulation
4. Enlarged cortical P25-N33 somatosensory components
An example of the short-duration surface EMG discharges in cortical myoclonus is
given in Fig. 1. The myoclonus EMG discharges typically demonstrate an agonist-
antagonist co-contracting pattern that may extend across muscle segments. Often,
the myoclonus EMG discharges occur in high-frequency rhythmic bursts or trains.
However, the visual appearance of the myoclonus is usually irregular because the
rhythmic trains are intermittent, and there is marked variability between the amplitude
of the myoclonus EMG discharges within and between trains. When the trains are
small and almost continuous, the term ‘‘cortical tremor’’ is sometimes applied.6
The premyoclonus EEG transient can sometimes be observed grossly on the EEG,
but it is useful to perform EEG back-averaging for more sensitive detection and to
assess the time-locked nature of the EEG transient to the motion detection or myoc-
lonus EMG discharge. An example is shown in Fig. 2. The transient is localized over

Fig.1. Surface EMG tracing from right wrist extensors in a patient with right arm myoclonus.
The ‘‘Myoclonus 1’’ trigger marks are located at three myoclonus EMG discharges. The myoc-
lonus EMG discharges show a sudden, brief, synchronous event that corresponded with the
right wrist myoclonus.
766 Caviness

Fig. 2. Back-averaged premyoclonus EEG transient over left motor cortex contralateral to the
right wrist myoclonus from the patient whose myoclonus EMG discharges are in Fig. 1.

the contralateral sensorimotor cortex. The transient is a biphasic or triphasic spike

beginning with a positive deflection whose peak precedes the onset of the myoclonic
discharge by an average of 20 ms for arm (range 10–40 ms).
Many cortical myoclonus patients demonstrate myoclonus after stimulation (reflex
myoclonus). The reflex myoclonus may be clinically demonstrable by touch or muscle
stretch. In the case of upper extremity myoclonus, briskly abducting the thumb may
evoke a reflex myoclonic jerk. This can be confirmed with EEG-EMG polygraphy,
but it is usually easier to prove reflex myoclonus by testing for long-latency EMG
responses to electrical nerve stimulation. A reproducible gross EEG transient may
or may not precede the myoclonus EMG discharge with each stimulus. For the
hand, median nerve stimulation can show EMG discharges at 50 ms latency or greater
(range 40–60) from the stimulus artifact trigger mark.4 Repetitive discharges may be
seen, at intervals of 20 40 ms.7 At rest, in a normal individual, no response should
be present. Care must be taken that the arm muscles are relaxed so as to avoid a false
positive response. Enlargement of the cortical SEP P25-N33 parietal wave from
median nerve stimulation is important evidence for cortical reflex myoclonus physi-
ology. A key characteristic of the enlarged P25-N33 wave is the similar morphology
and topography to the averaged time-locked EEG transient that precedes the myoc-
lonus EMG discharge elicited by muscle action or at rest. Additionally, the interval
between the P25 peak and the onset of any long-latency EMG response, which is
simultaneously recorded, is usually similar to the latency from the back-averaged
EEG transient to the onset of the myoclonus EMG discharge.
When cortical myoclonus arises dramatically from rest in a paroxysmal manner, it is
more often thought of as partial epilepsy with motor symptomatology. Nevertheless,
the basic movement phenotype is usually of focal myoclonus, either occurring as
paroxysms of repetitive focal jerks, or as epilepsia partialis continua when occurring
 Pathophysiology and Treatment of Myoclonus 767

for extended periods of time. Focal or more widespread cerebral cortical processes
can cause focal motor seizures. There are a variety of ictal EEG changes that may
be seen in the appropriate contralateral motor area for the focal motor seizure mani-
festation. Repetitive focal spike, spike and wave, sharp wave, rhythmic theta or delta
activity, or desynchronization may occur. In many cases, no grossly observable EEG
activity is seen, and back-averaging may uncover a transient in some of those cases.
In the case of epilepsia partialis continua, the above-mentioned transients will be peri-
odic and may even occur with the pattern of periodic lateralizing epileptiform
discharges.
Most of the cortical myoclonus patients have one or more of the three major cortical
physiology subtypes:5 (1) cortical origin myoclonus without reflex activation, (2)
cortical reflex myoclonus, (3) focal motor seizures. All of these cortical origin subtypes
need electrophysiologic properties #1 and #2 mentioned above to suggest a cortical
source classification. It is the exaggerated reflex features of enhanced long-latency
EMG reflexes to nerve stimulation (#3) and/or enlarged cortical SEP components
(#4) that are typical of cortical reflex myoclonus. The paroxysmal occurrence from
rest of cortical myoclonus shows the focal motor seizure phenotype.

Studies of cortical myoclonus using research methods

Back-averaging EEG studies performed with routine EEG positions can localize pre-
myoclonus cortical transients to contralateral sensorimotor cortex. Exact localization
can be performed with advanced techniques used in research. Fig. 3 shows dipole
localization of the abnormal EEG transient in a patient with upper extremity action
myoclonus using EEG source localization software CURRY 6.0 (Compumedics Neuro-
scan, Charlotte, North Carolina). This shows that the physiologic abnormality that
produces the right wrist myoclonus is in a highly focal neocortical location. Fig. 4
shows that the same myoclonus cortical electrical activity also overlaps the Talairach
coordinates of the precentral gyrus (motor cortex) on MRI. These data provide
evidence that the primary motor cortex is the most likely generation site for cortical
myoclonus in this particular patient.

Fig. 3. The abnormal electrical discharge dipole (red) is shown localizing to a very focal area
near the left central sulcus for the patient whose right wrist myoclonus electrophysiology is
depicted in Figs. 1 and 2.
768 Caviness

Fig. 4. The abnormal electrical discharge dipole (red) mapped on an averaged MRI from the
patient whose electrophysiology is depicted in Figs.1^3. The dipole is demonstrated to be on
the Talairach coordinates of the precentral gyrus/motor cortex (shaded with blue).

Magnetoencephalography (MEG) has the ability to perform better localization and

amplitude sensitivity for horizontal dipoles when compared with EEG. Uesaka and
colleagues8 found that among 6 subjects with cortical myoclonus, one case localized
to precentral gyrus only, one localized to precentral and postcentral gyrus, and five
cases localized to the postcentral gyrus only. In this study, the initial cortical somato-
sensory-evoked magnetic fields localized to the postcentral gyrus. Uesaka and
colleagues suggested that patients with enlarged SEPs are likely to have myoclonus
arise from the postcentral gyrus. In contrast, Mima and colleagues9 found the MEG
cortical correlate for all six of their myoclonus subjects to localize to the precentral
gyrus. In another report, Mima and colleagues10 found that enlarged cortical somato-
sensory-evoked magnetic fields localized to the precentral gyrus in four subjects and
to the postcentral gyrus in one subject. These varied results suggest that either there
are true locus differences between cortical myoclonus cases or methodological differ-
ences account for different source localization results.
Coherence has been used to provide information about the relationship between
cortical EEG signals and muscle activity in myoclonus patients. Coherence is
a frequency domain measure of correlation between 2 signals. Brown and
colleagues11 have found changes in EEG-EMG and EMG-EMG coherence patterns
for subjects with myoclonus. They have suggested that myoclonus patients show
pathologic exaggerations of physiologic central rhythmicity relating to movement
and that the precise pattern of coherence has possible diagnostic value. In some
cases, elevated coherence is more sensitive than EEG-EMG back-averaging.
Caviness and colleagues12 have found elevated corticomuscular coherence in the
small distal myoclonus of Parkinson disease. This suggests that motor cortical rhythms
are pathologically coupled to motor neurons in some cases of Parkinson disease. They
also found that corticomuscular coherence is elevated even when myoclonus does not
occur and that it elevates further around the time of myoclonus. This suggests that
abnormal coupling between EEG motor rhythms generated in pyramidal dendrites
and spinal motorneurons is elevated and unstable in cortical myoclonus.

Cortical myoclonus summary: concepts of cortical myoclonus generation

Since the first half of the last century, authors have suggested that cortical myoclonus
generation was characterized by a lack of inhibition in neuronal circuits. Although this
must be correct at some level, this physiologic explanation of myoclonus is too
simplistic, and evidence for where and how this lack of inhibition arises has not
 Pathophysiology and Treatment of Myoclonus 769

been generated. Regarding localization of the cortical source, recent studies seem to
favor a role for the primary motor cortex over that of the primary sensory cortex. The
observation of increased corticomuscular coherence in myoclonus suggests a defect
in the gating of oscillatory networks in the motor cortex, but the precise defect in
neuronal circuitry responsible is not known. None of these concepts rule out involve-
ment of subcortical structures, and historically the cerebellar system has been sug-
gested to play a role in cortical myoclonus generation. It is possible that the
specifics of cortical myoclonus generation differ with etiology and patient.
Evidence from pathology, pharmacology, and animal model studies has yet to
pinpoint a specific neuronal circuit lesion as the cause of cortical myoclonus. The
most unifying theme for the diverse causes of cortical myoclonus is the diffuse nature
of the brain disorder. Pathologic studies show diffuse changes, and no single location
shows consistent involvement.13–15 In posthypoxic myoclonus, the decrease in sero-
tonin metabolites and response to the serotonin precursor 5-hydroxytryptophan has
suggested deficient serotonin activity in this cause of cortical myoclonus, but it is
unclear whether all causes of cortical myoclonus are based on decreased serotonin
activity.13,15 It is known that serotonin overactivity can cause myoclonus, and
numerous drugs that affect a variety of chemical systems can cause myoclonus.2
Thus, it is unlikely that serotonin or any other single system is the necessary and suffi-
cient lesion for cortical myoclonus to occur. Animal models for cortical myoclonus
have also used diffuse and various lesions, and analogy to the human cortical
myoclonus is uncertain.16
In summary, hard evidence would suggest that cortical myoclonus is precipitated by
a cortical transient that represents an abnormal sudden and synchronous discharge of
pyramidal neurons in the context of diffuse brain pathology. At this point, it is difficult
to have confidence in a more specific mechanistic explanation. As far as the intrinsic
cortical mechanism is concerned, the end result may be a ‘‘lack of inhibition of cortical
neurons.’’ However, it is not known whether this constitutes a lack of inhibitory inputs,
rebound excitation from excessive inhibition, alteration of intrinsic pyramidal neuron
firing properties, or some combination of these mechanisms to cause sensorimotor
pyramidal neurons to discharge too synchronously. It is critical to decipher which of
these possibilities is important and how its basic mechanism may be treated.

Cortical-Subcortical Myoclonus
There is strong evidence that some generalized seizure phenomena arise from parox-
ysmal, abnormal, and excessive oscillation in bidirectional connections between
cortical and subcortical sites.17–19 The term ‘‘cortical-subcortical’’ myoclonus refers
to myoclonus arising from this type of physiology and other similar phenomena. For
these entities, the abnormal influence of the subcortical input is critical. Despite the
subcortical involvement, the cortical discharge precedes and drives the myoclonus
event. This myoclonus usually occurs in paroxysms from rest and can be associated
with other seizure phenomena that may even be more clinically significant than the
myoclonus itself. The myoclonus is often generalized or bilaterally synchronous, but
focal or multifocal distributions occur as well. It is this myoclonus physiology that
exists within the primary generalized epileptic syndromes with myoclonus.
The hallmark of the physiology for cortical-subcortical myoclonus is the generalized
spike-and-wave EEG discharge. The myoclonus EMG discharge duration is less than
100 ms and is time-locked to the spike discharge. The generalized spike-and-wave
discharges may be associated with the myoclonus (ictal) or occur between the myoc-
lonus events (interictal). Different forms and frequencies distinguish the epileptic
syndromes that include myoclonus. The 4 Hz to 6 Hz spike or polyspike and wave
770 Caviness

generalized discharge is typical for juvenile myoclonic epilepsy. A 2.5 Hz (slow spike
and wave) interictal pattern is characteristic for the Lennox-Gastaut syndrome, which
at times is associated with myoclonic seizures, but the ictal myoclonus may be asso-
ciated with faster frequencies. The 3 Hz spike and wave occurs ictally in absence
seizures whether or not they are associated with myoclonus.
The type of abnormality that gives rise to such bidirectional overexcitation between
cortical and subcortical areas entails intrinsic electrical abnormalities at the neuron
level. Thus, it is no surprise that genetic mutations relating to ion channels and ion
buffering have been associated with various myoclonic epilepsy syndromes.20–22

Subcortical-Suprasegmental
The clinical and neurophysiologic characteristics of subcortical myoclonus are more
variable than for those in cortical or cortical-subcortical myoclonus. In this category,
there is no evidence for intrinsic abnormal cortical excitability (eg, EEG transient corre-
lation, enlarged cortical SEP waves, EMG reflex responses with cortical latency) that
can be tightly correlated to the myoclonus. The myoclonus EMG duration is highly
variable among entities in this group and ranges from 25 to 300 ms. The temporal rela-
tionship between agonists and antagonists muscle activation depends on the specific
type of subcortical-suprasegmental myoclonus. The source locations within this cate-
gory extend from the basal ganglia to the spinal cord. However, in all examples, the
source transmits its excitatory influence to muscle segments far beyond its location
(suprasegmental). Assignment of a case to the subcortical category can be problem-
atic if it is based largely on absence of evidence for abnormal cortical excitability or
circumstantial findings rather than direct evidence. There are two major groups of
subcortical-suprasegmental myoclonus: (1) hereditary essential myoclonus (myoc-
lonus-dystonia) and (2) myoclonus caused by simultaneous rostral and caudal recruit-
ment of muscle segments along the neuraxis from a localized source—includes
reticular reflex, propriospinal, and subcortical reflex myoclonus.
Hereditary essential myoclonus usually shows an autosomal dominant hereditary
pattern. Major features include upper extremity and trunk/neck involvement with
notable worsening with action, onset before age 20 years with a fairly benign course,
absence of other severe neurologic deficits, and normal EEG. Alcohol responsiveness
is common enough to be characteristic. There is dystonia of a similar distribution in
many cases for which hereditary essential myoclonus has been renamed as the myoc-
lonus-dystonia syndrome. Of the known gene mutations, 3-sarcoglycan is the most
common, but there are families in which the genetic locus is not known. Roze and
colleagues23 characterized the clinical-electrophysiologic characteristics of those
patients with mutations in the 3-sarcoglycan gene. Their cases showed an average
EMG duration of 95 ms with a range of 25 to 256 ms. They found no features of cortical
hyperexcitability including a lack of back-averaged cortical potentials time-locked to
the myoclonus. 3-Sarcoglycan seems to be most highly expressed in subcortical
regions, but its function is not known.24 3-Sarcoglycan knockout mice demonstrate
myoclonus and defects in subcortical monoaminergic neurotransmitter systems.25 It
is possible that such subcortical defects transmit an excitatory influence onto motor
cortical areas through the thalamus to produce the myoclonus and dystonia in this
syndrome.
The myoclonus caused by simultaneous rostral and caudal recruitment of muscle
segments along the neuraxis from a localized source elicits jerks that may be gener-
alized or bilateral and widespread. Often, this myoclonus is reflex sensitive. The EMG
duration may range from 25 to 300 ms, and muscles in the same segment show nearly
synchronous activation. However, the simultaneous rostral and caudal recruitment
 Pathophysiology and Treatment of Myoclonus 771

order is the characteristic finding of the surface EMG polygraphy. The rostral and
caudal spread occurs more slowly than what is observed in the corticospinal path-
ways seen in cortical myoclonus. If any EEG activity is observed, it is seen after the
first muscle is activated and is not time-locked in a meaningful way to the EMG acti-
vation. Reticular reflex myoclonus is the prime example.26 The myoclonus source is
the lower brainstem reticular formation. Brainstem motor systems are particularly
involved in axial and bilateral movements and are tightly linked to subcortical reflex
centers. Thus brainstem myoclonus is generalized, especially axial, and very stim-
ulus-sensitive. The exaggerated startle jerks of hyperekplexia have a related patho-
physiology, but no doubt arises from a different lower brainstem neuronal
circuitry.27 Gene mutations in the glycine and gamma-aminobutyric acid receptor
have been found to be causes of exaggerated startle syndrome. Propriospinal myoc-
lonus, described by Brown and colleagues,28 has a locus in the cervical or thoracic
spinal cord region. It is believed that rostral and caudal recruitment occurs by way
of propriospinal pathways from the source locus. The myoclonic jerks may be trunk
extension or flexion and are commonly reflex sensitive to touch. Spinal structural
lesions of various types have been associated with the locus for propriospinal myoc-
lonus. Subcortical reflex myoclonus has been described for which the exact locus is
unknown but is believed to be somewhere between the midpons and thalamus.29
This causes a descending order of recruitment.

Segmental
Segmental myoclonus has its generator at a particular segment or contiguous
segments of the brainstem and/or spinal cord. This segmental generator produces
movements at that particular segment or contiguous segments close to the source
locus. The most common type of segmental myoclonus is palatal myoclonus. A variety
of etiologies may cause segmental myoclonus but vascular, tumor, trauma, infectious,
and idiopathic and/or ‘‘essential’’ diagnoses account for most cases. There is usually
fairly persistent, rhythmic activation of muscles corresponding to the brainstem/spinal
segment(s) involved. This myoclonus is relatively unaffected by state of conscious-
ness, motor activity, or stimulus. However, exceptions do occur and in these
instances, oscillatory movements occur in trains or episodes and may be modulated
by voluntary movement and sensory stimulation.
The EMG usually shows synchronous activation of the affected muscles. The typical
frequency is in the range of 0.5 to 3 Hz, and the typical EMG discharge duration varies
widely between 50 to 500 ms. The EEG and somatosensory-evoked potential are
normal. Brainstem auditory-evoked potentials (BAEP) have had abnormal findings in
some individuals with palatal myoclonus.30 These inconsistent BAEP abnormalities
probably represent the same lesion type, but not the same location as that responsible
for the palatal myoclonus pathophysiology. In spinal segmental myoclonus, mixed
nerve stimulation can evoke EMG discharges in the affected muscles at latencies
longer than 40 ms, but such findings are variable, and the latency values vary from
case to case. These reflex discharges may reflect hyperexcitability of polysynaptic
pathways that contribute to the generation of the myoclonus.31,32 The type of neuronal
circuitry defect that creates these oscillatory movements in brainstem or spinal cord is
unknown. It is known that when a partial lesion or denervation of brainstem or spinal
gray matter occurs, abnormal firing of some remaining neurons occurs.33 The pattern
of abnormal firing is rhythmic or irregular bursting of action potentials. It has been
postulated that this abnormal excitation overflows to motorneuron pools, which in
turn causes the segmental myoclonus.34 In the example of palatal myoclonus,
772 Caviness

denervation of the inferior olive from dentate-inferior olive pathway lesions may play
a key role in producing the abnormal movement.
Palatal myoclonus is the most common type of segmental myoclonus. The move-
ment is rhythmic and usually bilateral with a rate between 1 to 4 Hz, with other rates
being less common. Because of its smooth oscillatory nature, some clinicians choose
the term ‘‘palatal tremor’’ over palatal myoclonus. A distinction is made between
‘‘essential palatal myoclonus’’ (EPM) and ‘‘symptomatic palatal myoclonus’’
(SPM).35 EPM is associated with activation of the levator veli palatini muscle and
with no identifiable MRI lesion, and it is unlikely to involve other muscles. SPM is asso-
ciated with activation of the tensor veli palatini, an identifiable MRI brainstem lesion in
the dentate-inferior olive pathway, involvement of other muscles, cerebellar dysfunc-
tion, and an older age of onset. EPM patients are more likely to state that their ear click
is the chief complaint, whereas SPM patients are more concerned with the other asso-
ciated neurologic problems rather than the palatal movements per se. Important
differences in electrophysiologic testing have also been found.36 EPM shows
a complete suppression with sleep, but sleep only produces mild variations in rate
with SPM. The palatal movement cycle only exerts remote effects on tonic EMG
activity of extremity muscles in SPM. As shown by studies of blink reflex activity,
jaw jerk, and masseteric silent period, EPM had only polysynaptic brainstem reflex
abnormalities, whereas SPM patients can have abnormalities of monosynaptic,
oligosynaptic, and polysynaptic brainstem reflexes.

Peripheral
Peripheral myoclonus refers to myoclonic jerks that are driven from a peripheral site.37
The best-documented example is hemifacial spasm as was pointed out by Jankovic
and Pardo.38 Such EMG discharges are characterized by marked duration variability
from discharge to discharge. The EMG discharges that are supplied by the same nerve
are synchronous. In peripheral myoclonus, the spectrum of EMG discharge duration
may merge continuously with those EMG discharges that are responsible for move-
ments that are longer lasting. It should be recognized that the literature contains other
uses of the term ‘‘peripheral myoclonus.’’ For example, some studies report myoc-
lonus associated with peripheral nervous system lesions, but posit that the myoclonus
itself is centrally generated and results from ‘‘central reorganization.’’

TREATMENT

The first consideration is given to reversing any underlying etiology of the myoclonus.
The most straightforward example is that of drug-induced myoclonus, and discontin-
uation of the drug usually eliminates the myoclonus. Other potentially reversible
causes of myoclonus are an acquired abnormal metabolic state, removable toxin,
or an excisable lesion. However, in the majority of myoclonus cases, treatment of
the underlying disorder usually is neither possible nor effective, and symptomatic
treatment is justified if the myoclonus is disabling enough.
The best strategy for symptomatic treatment is derived from using the physiologic
classification as a surrogate for the myoclonus pathophysiology. A drug treatment
used for one physiologic classification may not work well in another or may even
worsen the condition. If the myoclonus physiology classification cannot be deter-
mined, then presuming the myoclonus physiology that usually occurs in that particular
diagnosis is a reasonable way to proceed cautiously. If the diagnosis and myoclonus
physiology are unknown, there is little to guide an approach to treatment. In this
instance, the drugs that work in cortical myoclonus may be tried first because cortical
 Pathophysiology and Treatment of Myoclonus 773

myoclonus physiology is the most common. However, the clinician should be

prepared for poor results until the reason for the myoclonus is better understood.
There is sparse controlled evidence on the treatment of myoclonus. Side effects are
commonly dose-limiting. The following discussion about treatment is outlined under
the physiologic classification of the myoclonus.

Cortical Myoclonus Treatment

Drug treatment presumably attempts to normalize inhibitory processes within the
sensorimotor cortex. Levetiracetam, piracetam, sodium valproate, and clonazepam
are the four most effective agents. Multiple drug combinations may be necessary,
but there may be increased side effects. Amelioration of the myoclonus is rare.
However, important improvement may be attained with decreased disability.
Levetiracetam and Piracetam—These are related drugs and have had limited
controlled study.39–44 Their mechanism of action remains unknown, but their binding
to the synaptic vesicle protein 2A may be important for moderating neurotransmitter
release. Both are well tolerated and generally nonsedating. Because of their relatively
favorable side effect profile, these drugs are used initially or as an add-on treatment.
There are anecdotal reports for levetiracetam responsiveness in many of the specific
etiologies of cortical myoclonus listed in Box 3. Daily dosages of levetiracetam range
from 1000 to 3000 mg and dosages of piracetam range from 2.4 to 21.6 g. An abrupt
withdrawal may precipitate a severe worsening of myoclonus, and in the case of pira-
cetam, seizures may occur.
Sodium valproate—many patients need doses of 1200 to 2000 mg/d for myoclonus
treatment.45 Transient gastrointestinal upset may occur during initial treatment,
usually with nausea and vomiting, but sometimes with abdominal pain and diarrhea.
Hair loss, tremor, hepatotoxicity, and drowsiness may also occur.
Clonazepam—Large doses of clonazepam are often necessary (as much as 6 mg/d
or more) but should be introduced slowly.45 Undue drowsiness and ataxia are the
only major adverse effects and can sometimes be overcome by gradually increasing
the dosage. Abrupt reductions and withdrawals can result in a marked deterioration in
myoclonus and withdrawal seizures. Unfortunately, tolerance to this drug is common
and may develop over a period of several months.
Other agents—Primidone and phenobarbital are useful at times, but generally are
limited to add-on therapy or when seizures coexist with the myoclonus.45 Zonisamide
may help as an add-on therapy.46 Phenytoin and carbamazepine are helpful in only
a minority of patients. In others, phenytoin may exacerbate myoclonus. Vigabatrin
may also lead to a paradoxic increase in myoclonus in some patients. These examples
serve as a useful reminder that antiseizure medications, old and new, have the poten-
tial to worsen myoclonus in certain patients. Sodium oxybate, the sodium salt of g-hy-
droxybutyric acid, has been reported to decrease cortical myoclonus in a few
patients.47

Cortical-Subcortical Myoclonus Treatment

The myoclonus in primary generalized epilepsies falls under this physiologic classifi-
cation. As such, conventional antiseizure medications for generalized epilepsy are
used. Valproic acid is the major drug of choice for these disorders. The favorable
controlled evidence for efficacy is mostly for juvenile myoclonic epilepsy.48 Less
impressive results are seen in other childhood myoclonic epilepsy syndromes. Lamo-
trigine may be used alone or as an adjunct to valproic acid but has the potential to
worsen the myoclonic seizures.49 Ethosuximide, zonisamide, and clonazepam are
mainly used as adjuncts. Polypharmacy may be useful but is limited by side effects.
774 Caviness

Paradoxically, antiseizure medications, including phenytoin, carbamazepine, and la-

motrigine, which are often used for partial seizures, sometimes increase seizures or
myoclonus in these syndromes. Intravenous valproic acid can be useful in myoclonic
seizure status.50

Subcortical-Suprasegmental Myoclonus Treatment

Standard antiepileptic treatments are usually not helpful in subcortical myoclonus. In
essential myoclonus (including myoclonus-dystonia), treatments such as clonazepam
and benzhexol (anticholinergic) are the most useful. Sodium oxybate, the sodium salt
of g-hydroxybutyric acid, has been reported to decrease myoclonus in a few cases of
myoclonus-dystonia.47 Deep brain stimulation of the thalamus or globus pallidus has
had success in case reports and awaits confirmation in a larger number of patients.51
Reticular reflex myoclonus and opsoclonus-myoclonus respond partially to clona-
zepam.52 The opsoclonus-myoclonus syndrome has recently been reported to be
responsive to intravenous immunoglobulin therapy, but this may be treating the under-
lying autoimmune disorder rather than the myoclonus per se.53 In childhood, the
opsoclonus-myoclonus syndrome may occur with a neuroblastoma, and treatment
considerations differ from the adult form. Clonazepam is the first line of therapy for
propriospinal myoclonus and in exaggerated startle syndromes such as
hyperekplexia.

Segmental Myoclonus Treatment

Palatal myoclonus can be challenging to treat. The list of drugs with anecdotal
success in palatal myoclonus includes but is not limited to clonazepam, carbamaze-
pine, baclofen (Lioresal), anticholinergics, tetrabenazine, valproic acid, phenytoin, la-
motrigine, sumatriptan, and piracetam.38 Because 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 variable success.54
Botulinum toxin injections have worked in some cases, but these injections may be diffi-
cult to perform, and spread of the toxin can produce significant side effects.55
Clonazepam, in dosages up to 6 mg/d, is the drug of first choice in spinal segmental
myoclonus but usually leads to only partial improvement at most. Diazepam, carba-
mazepine, tetrabenazine, and levetiracetam may prove useful. Botulinum toxin injec-
tions for the pain and movements of spinal segmental myoclonus are sometimes
successful.56

Peripheral Myoclonus Treatment

For the quick movements in hemifacial spasm, botulinum toxin injection is the estab-
lished first line therapy.37 Other causes of peripheral myoclonus have also responded
to botulinum toxin injections.57 Drugs for peripheral myoclonus are almost always
unsatisfactory, but carbamazepine shows improvement in a few cases.

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