myoclonus with dementia

Review

Myoclonus and neurodegenerative disease—what’s in a name?

John N. Caviness*

Department of Neurology, Parkinson’s Disease and Movement Disorders Center, Mayo Clinic Scottsdale, 13400 East Shea Blvd, Scottsdale, AZ 85259, USA

Abstract

Myoclonus is a clinical symptom (or sign) defined as sudden, brief, shock-like, involuntary movements caused by muscular contractions or

inhibitions. It may be classified by examination findings, etiology, or physiological characteristics. The main physiological categories for

myocolonus are cortical, cortical–subcortical, subcortical, segmental, and peripheral. Neurodegenerative syndromes are potential causes of

symptomatic myoclonus. Such syndromes include multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy,

frontotemporal dementia and parkinsonism linked to chromosome 17, Huntington’s disease, dentato-rubro-pallido-luysian atrophy,

Alzheimer’s disease, and Parkinson’s disease, and other Lewy body disorders. Each neurodegenerative syndrome can have overlapping as

well as distinctive clinical neurophysiological properties. However, claims of differentiating between neurodegenerative disorders by using

the presence or absence of small amplitude distal action myclonus appear unwarranted. When the myoclonus is small and repetitive, it may

not be possible to distinguish it from tremor by phenotypic appearance alone. In this case, clinical neurophysiological offers an opportunity to

provide greater differentiation of the phenomenon. More study of the myoclonus in neurodegenerative disease will lead to a better

understanding of the processes that cause phenotypic variability among these disorders.

q 2003 Elsevier Science Ltd. All rights reserved.

Myoclonus is a clinical symptom (or sign) defined as

sudden, brief, shock-like, involuntary movements caused by

muscular contractions or inhibitions. Myoclonus has now

been recognized to have many possible etiologies, anatom-

ical sources, and pathophysiologic features [1]. When

including all known etiologies, myoclonus has an average

annual incidence of 1.3 cases per 100,000 [2]. The major

categories of myoclonus in the popular etiological classi-

fication scheme of Marsden et al. are as follows:

physiologic, essential, epileptic, and symptomatic (second-

ary) [3] (Table 1). Each of the major categories is associated

with different clinical circumstances. Physiologic myoclo-

nus occurs in neurologically normal people. There is

minimal or no associated disability and the physical exam

reveals no relevant abnormality. Jerks during sleep are the

most familiar examples of physiologic myoclonus. Essential

myoclonus refers to myoclonus that is the most prominent

or only clinical finding. Essential myoclonus is idiopathic

and either there is no or slow progress. Sporadic and

hereditary and sporadic forms exist, and some families

manifest a genetic mutation. Epileptic myoclonus refers to

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,

or one of multiple seizure types within an epileptic

syndrome. Symptomatic (secondary) myoclonus manifests

in the setting of an identifiable underlying disorder,

neurologic or non-neurologic. 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, physical processes, infections,

focal nervous system damage, and paraneoplastic syn-

dromes as well as other medical illnesses. Most cases of

myoclonus are in the symptomatic category, followed by the

epileptic and essential categories.

1. Physiological classification

Etiological classification provides a framework to match

a patient’s myoclonus to an etiology from a comprehensive

list of disorders. However, there are at least four advantages

of classifying the myoclonus with regard to its physiology.

First, physiology can provide localizing information for the

myoclonus and thus can provide at least partial localization

for diagnosis of the underlying process. Second, some

physiological myoclonus types are characteristic for certain

disorders, so identifying their presence can aid in

1353-8020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.

PII: S1 35 3 -8 02 0 (0 2) 00 0 54 -8

Parkinsonism and Related Disorders 9 (2003) 185–192

www.elsevier.com/locate/parkreldis

* Tel.: þ1-480-301-7989; fax: þ1-480-301-8451.

E-mail address: [email protected] (J.N. Caviness).

identifying the underlying diagnoses. Third, ascertaining the

physiology of the myoclonus directs the physician toward

the most effective treatment [1,4]. Finally, comparing and

contrasting the myoclonus physiology in various disorders

provides insights about the disease processes that create

them [4].

The specific methods used in the neurophysiological

study of myoclonus usually include but are not limited to

Table 1

Classification of myoclonus

I. Physiologic myoclonus (normal subjects) 3. Lewy body disease

A. Sleep jerks (hypnic jerks) 4. Frontotemporal dementia and parkinsonism linked to

chromosome 17

B. Anxiety induced E. Infections/post-infectious

C. Exercise induced 1. Subacute sclerosing panencephalitis

D. Hiccough (singultus) 2. Encephalitis lethargica

E. Benign infantile myoclonus with feeding 3. Arborvirus encephalitis

4. Herpes simplex encephalitis

II. Essential myoclonus (no known cause and no other gross neurologic deficit) 5. HTLV-I

A. Hereditary (autosomal dominant) 6. Human immunodeficiency virus (HIV)

B. Sporadic 7. Post-infectious encephalitis

8. Malaria

III. Epileptic myoclonus (seizures dominate and no encephalopathy, at least initially) 9. Syphilis

A. Fragments of epilepsy 10. Cryptococcus

1. Isolated epileptic myoclonic jerks F. Metabolic

2. Epilepsia partialis continua 1. Hyperthyroidism

3. Idiopathic stimulus-sensitive myoclonus 2. Hepatic failure

4. Photosensitive myoclonus 3. Renal failure

5. Myoclonic absences in petit mal epilepsy 4. Dialysis syndrome

B. Childhood myoclonic epilepsy 5. Hyponatremia

1. Infantile spasms 6. Hypoglycemia

2. Myoclonic astatic epilepsy (Lennox–Gastaut) 7. Non-ketotic hyperglycemia

3. Cryptogenic myoclonus epilepsy (Aicardi) 8. Multiple carboxylase deficiency

4. Awakening myoclonus epilepsy of Janz (Juvenile myoclonic epilepsy) 9. Biotin deficiency

C. Benign familial myoclonic epilepsy (Rabot) 10. Mitochondria dysfunction

D. Progressive myoclonus epilepsy: Baltic myoclonus (Unverricht–Lundborg) G. Toxic and drug-induced syndromes

H. Physical encephalopathies

VI. Symptomatic myoclonus (progressive or static encephalopathy dominates) 1. Post-hypoxia (Lance-Adams)

A. Storage disease 2. Post-traumatic

1. Lafora body disease 3. Heat stroke

2. GM2 gangliosidosis (late infantile, juvenile) 4. Electric shock

3. Tay-Sachs disease 5. Decompression injury

4. Gaucher’s disease (non-infantile neuronopathic form) I. Focal Nervous System Damage

5. Krabbe’s leukodystrophy 1. Central Nervous System

6. Ceroid-lipofuscinosis (Batten) (a) Post-stroke

7. Sialidosis (‘cherry-red spot’) (types 1 and 2) (b) Post-thalamotomy

B. Spinocerebellar degenerations (c) Tumor

1. Ramsay Hunt syndrome (d) Trauma

2. Friedreich’s ataxia (e) Inflammation (e.g. multiple sclerosis)

3. Ataxia telangiectasia 2. Peripheral nerve lesions

4. Other spinocerebellar degenerations J. Malabsorption

C. Basal ganglia degenerations 1. Coeliac disease

1. Wilson’s disease 2. Whipple’s disease

2. Torsion dystonia K. Eosinophilia-Myalgia syndrome

3. Hallervorden–Spatz disease L. Paraneoplastic encephalopathies

4. Progressive supranuclear palsy M. Opsoclonus-Myoclonus syndrome

5. Huntington’s disease 1. Idiopathic

6. Parkinson’s disease 2. Paraneoplastic

7. Multisystem atrophy 3. Infectious

8. Corticobasal degeneration 4. Other

9. Dentato-rubro-pallido-luysian atrophy N. Exaggerated Startle syndromes

D. Dementias 1. Hereditary

1. Creutzfeldt–Jakob disease 2. Sporadic

2. Alzheimer’s disease

From Marsden et al. [3], with modification.

J.N. Caviness / Parkinsonism and Related Disorders 9 (2003) 185–192186

multichannel surface electromyography (EMG) recording

with testing for long latency EMG responses to nerve

stimulation, electroencephalography (EEG), EEG–EMG

polygraphy with back-averaging, and evoked potentials

(e.g. median nerve stimulation somatosensory evoked

potential (SEP)). Positive and negative findings from these

methods can then be used to provide evidence for

determining the physiological type of myoclonus. For

example, a back-averaged focal cortical EEG transient,

enlarged cortical SEP, and enhanced long EMG responses

Fig. 1. Multichannel surface EMG recording in a PD subject during wrist extension demonstrates brief (,50 ms) myoclonus discharges. The arrow denotes the

beginning of a train of myoclonus EMG discharges showing cocontraction between agonist and antagonist (wrist flexors and wrist extensors).

Fig. 2. Back-averaging of myoclonus discharges occurring in right wrist extensors shows a triphasic positive–negative–positive focal EEG transient over the

contralateral sensorimotor region. The waveforms were produce by averaging 100 myoclonus EMG discharges similar to those seen in Fig. 1. The EEG

electrode scalp locations are shown on the head figure at the right lower corner. The averaged right wrist extensor EMG is shown at the left lower corner. Time

zero in all waveforms refers to the time at which the trigger mark was placed at the initiation of the myoclonus EMG discharge. For all waveforms, the x-axis is

given in milliseconds and the y-axis is given in microvolts.

J.N. Caviness / Parkinsonism and Related Disorders 9 (2003) 185–192 187

are variably seen in cortical origin myoclonus [4]. The

main physiological categories for myoclonus classification

are:

† Cortical: most common and has been reported for

various neurodegenerative diseases, toxic–metabolic

conditions, post-hypoxic state (Lance–Adams syn-

drome), storage disorders, and other conditions. An

example of cortical myoclonus physiology is shown in

Figs. 1 and 2.

† Cortical–subcortical: corresponds to the myoclonus in

myoclonic and absence seizures. This physiology is

believed to involve interactions of cortical and sub-

cortical centers such as the thalamus.

† Subcortical: seen in essential myoclonus and reticular

reflex myoclonus, among others.

† Segmental: arise from segmental brainstem (palatal) and/

or spinal generators.

† Peripheral: except for hemifacial spasm, peripheral

myoclonus is rare.

One should be aware that multiple myoclonus physi-

ology types could occur in the same patient.

2. Myoclonus in neurodegenerative disease

2.1. Multiple system atrophy

Two series of multiple system atrophy have reported an

upper extremity small amplitude ‘jerky postural tremor’ in

20 and 55% of cases, respectively [5,6]. It is believed that

this movement predominantly occurs in the parkinsonian

type of multiple system atrophy. In these same series,

stimulus sensitive myoclonus of the upper extremities was

found in 31 and 16.6% of cases. The literature is split as to

whether this stimulus sensitive myoclonus is more prevalent

in the parkinsonian or cerebellar type of multiple system

atrophy [5,7]. Clearly, the examiners in these case series

made a distinction between the jerky postural tremor and

myoclonus. Salazar et al. [7] argued both on clinical and

electrophysiological grounds that the jerky postural tremor

movements were best characterized as myoclonus rather

than tremor. They found such movements in 9/11 or 82% of

their parkinsonian type multiple system atrophy cases.

Salazar et al. suggested ‘minipolymyoclonus’ as the term of

choice for this movement.

In the cerebellar presentation of multiple system atrophy,

the electrophysiology of the somatosensory stimulus-

sensitive myoclonus has shown reflex EMG activation

consistent with a trancortical conduction time and enlarged

cortical components of the SEP [8]. Because of these

observations, the myoclonus origin was proposed to be

cortical. In addition, a photic cortical reflex myoclonus has

been described. In these cases, the occipital potentials have

normal amplitude and precede the bilateral frontal potentials

that are time-locked before the generalized myoclonus [9].

In their cases of minipolymyoclonus during postural

activation, Salazar et al. found EMG discharges with less

than 100 ms duration, enhanced long latency EMG

responses to cutaneous stimulation at 50–63 ms, and

normal SEP and EEG. Back-averaging of 50 samples of

the myoclonus demonstrated no back-averaged cortical

correlate. As a result, Salazar et al. [7] were uncertain with

regards to the origin of the myoclonus.

2.2. Corticobasal degeneration and progressive

supranuclear palsy

Myoclonus is an important feature of corticobasal

degeneration and occurs in 50% of cases. Its clinical

presentation parallels that of the overall syndrome with a

focal distribution in the arm (sometimes leg) associated with

other focal limb manifestations that can include apraxia,

rigidity, dystonia, and alien limb phenomenon. A ‘jerky

tremor’ has been stated to be part of the syndrome, and it has

been noted that the myoclonus is preceded by increased

tremor or jerky tremor [10,11]. The myoclonus in

corticobasal degeneration occurs in repetitive rhythmic

fashion when an attempt is made to activate the arm [12].

Reflex myoclonus to somatosensory stimulation is also very

common.

Multichannel surface EMG recordings in corticobasal

degeneration show rhythmic repetitive trains of 25–50 ms

discharges with simultaneous activation in agonist–antag-

onist pairs. The physiology in corticobasal degeneration

shows a sensitive response to digital nerve stimulation at

about 50 ms. The SEP is either unremarkable or can be

altered in morphology without enlargement. There has been

a cortical correlate back-averaged from magnetoencephalo-

graphy for this myoclonus, but no back-averaged activity

detected with EEG is characteristic [12]. This myoclonus is

believed to have a cortical origin and may represent a

distinct type of cortical reflex myoclonus [13]. Corticobasal

degeneration is known as a sporadic tau disorder. The tau

pathology has a strong presence in frontoparietal areas and

this could serve as a substrate for the myoclonus generation.

Progressive supranuclear palsy (PSP) is another sporadic

tau disorder, but in contrast to corticobasal degeneration,

myoclonus has only been rarely mentioned in the context of

PSP [14–16]. In one case of autopsy-confirmed PSP, action

myoclonus with seizures showed myoclonus EMG dis-

charges of ,50 ms duration [15]. The myoclonus EMG

discharges grossly correlated with EEG epileptiform

activity, but a time-locked analysis was not done. The

pathology, indicative of PSP, was present in the cerebral

cortex in addition to the more typical subcortical distri-

bution. Palatal myoclonus has also been reported in a case of

PSP [16]. More examples of myoclonus in autopsy-

confirmed PSP need to be characterized before any

generalization can be formulated.


2.3. Frontotemporal dementia and parkinsonism linked to

chromosome 17 (FTDP-17)

Although not initially thought to be a prominent feature,

myoclonus has now been described in some FTDP-17

syndromes. These syndromes, associated with tau gene

mutations, manifest cognitive, psychiatric, and parkinsonian

symptoms. Myoclonus is rarely seen in FTDP-17 kindreds

but has been reported with the N279K, P301S, and V337M

tau mutations, and a different family with the P301S

mutation has been reported to have seizures [17]. We have

described two types of myoclonus physiology in pallido-

ponto-nigral degeneration (PPND) which has been associ-

ated with the N279K tau mutation. The absence of a back-

averaged EEG transient characterized the myoclonus

physiology associated with disease progression, whereas a

pre-myoclonus EEG transient was present in the myoclonus

that occurred in one of the individuals with Stage 0 (pre-

symptomatic, gene positive) PPND [17]. FTDP-17 syn-

dromes commonly have cortical and subcortical pathology

[18]. The precise mechanism of the myoclonus types seen

in FTDP-17 syndromes is unclear, but it has been

suggested that pathology in the fronto-parietal area is

more pre-disposed to myoclonus degeneration than fronto-

temporal pathology [18].

2.4. Huntington’s disease

The occurrence of myoclonus is unusual in Huntington’s

disease, but when present, can be clinically impressive. The

myoclonus is usually restricted to individuals with a young

age of onset and higher CAG repeat mutation values.

Seizures may be present. The physiology of the myoclonus

is consistent with cortical reflex myoclonus, although the

cortical SEP waves are rarely enlarged [19]. Presumably, in

these rapidly progressive young-onset Huntington’s disease

cases, cortical pathology is much more significant when

compared to older cases with lower CAG repeat mutation

values and slower progression, thus enabling the myoclonus

to occur.

2.5. Dentato-rubro-pallido-luysian atrophy (DRPLA)

This neurodegenerative disorder is associated with a

CAG repeat expansion in a gene on chromosome 12.

DRPLA has protean neurologic manifestations that are

variable both within and between families, including

chorea, dystonia, parkinsonism, epilepsy, psychosis, and

dementia [20]. The myoclonus in dentato-rubro-pallido-

luysian-atrophy is uncommon, but is usually associated with

epilepsy. A cortical source seems likely for the myoclonus

because of associated epileptiform activity on the EEG, but

detailed electrophysiological examination of the myoclonus

has not been reported [12].

2.6. Alzheimer’s disease

The myoclonus in Alzheimer’s disease has a varied

presentation profile. It is usually multifocal, although it can

be generalized. The appearance can be sporadic large

myoclonic jerks or repetitive small ones. The occurrence of

the jerks may be at rest, with action, or stimulus induced. It

is common for all the above-mentioned phenotypic

characteristics to occur in a single patient. The prevalence

of myoclonus increases steadily during disease progression,

and up to 50% of Alzheimer’s disease patients eventually

develop myoclonus. Although myoclonus often develops in

the later stages of the illness, an earlier age of Alzheimer’s

disease onset, faster progression, or familial causes of

Alzheimer’s disease are associated with myoclonus appear-

ing earlier and at a higher incidence. In a paper by Wilkins

et al., a few examples of myoclonus in Alzheimer’s disease

were described as minipolymyoclonus, i.e. small amplitude

repetitive myoclonus occurring distally in the upper

extremities [21]. In the same article, these authors acknowl-

edge the overlap with tremor [21].

Multiple different electrophysiological descriptions of

the myoclonus in Alzheimer’s disease have been reported.

The most commonly reported instance is myoclonus EMG

discharges ,100 ms duration, and a focal contralateral

central EEG negativity, with onset 20–40 ms pre-myoclo-

nus and duration 40–80 ms [22]. Longer duration and

latencies from EEG transient to the myoclonic jerk, as well

as more widespread EEG transient distributions have been

reported [23]. There can also be periodic sharp waves with

similarity to Creutzfeldt–Jacob disease or no EEG correlate

whatsoever. The SEP and long latency EMG reflexes are

variably abnormal.

2.7. Parkinson’s disease and other Lewy body disorders

We have described cortical action myoclonus in non-

demented Parkinson’s disease (PD) individuals, one of which

was pathologically verified as PD [24]. Most cases showed

sporadic small and infrequent myoclonic jerks. However, in

few cases, frequent (.6 Hz) repetitive rhythmic trains of

EMG discharges coincided with a movement that could

overlap with a tremor phenotype. In our study, multichannel

surface EMG during muscle activation showed multifocal

brief (50 ms) myoclonus EMG discharges in distal upper

extremities (Fig. 1). Back-averaging consistently showed a

focal, short latency, EEG transient prior to the myoclonus

EMG discharge (Fig. 2) [24]. Cortical SEP waves were not

enlarged and long latency EMG responses at rest were not

present. The mechanism of this cortical myoclonus in PD and

other Lewy body disorders has differences from the more

common ‘cortical reflex myoclonus’ physiology, which is

associated with enlarged cortical SEP waves and enhanced

long latency EMG reflexes. Among our cases, advanced

parkinsonism was not a requirement to manifest this type of

myoclonus [24]. Although these cases were not demented,


we have observed the subsequent development of dementia

in a PD patient who was found to have this cortical

myoclonus 3 years before became manifest. At autopsy,

Lewy bodies were found in the limbic system and neocortex

as well as in the substantia nigra. Thus, it is possible that the

cortical dysfunction that produces myoclonus has an

association with the cortical dysfunction that produces

dementia. In individuals who have dementia with Lewy

bodies (DLB) by consensus criteria, similar myoclonus

properties also occur. However, the myoclonus amplitude in

DLB is clinically more impressive and more common,

occurring in about 15% of cases [25]. In our experience,

patients who experience PD with dementia also demonstrate

the same myoclonus physiology regardless of when the

myoclonus develops. We have also described myoclonus

with similar physiology in a family with hereditary

parkinsonism-dementia with Lewy body pathology [26].

The fact that cortical myoclonus occurs with similar

physiological properties across a spectrum of Lewy body

disorders suggests that a unifying mechanism is responsible

for the myoclonus. It would be of interest to ascertain if the

abnormal basal ganglia output to the cortex via thalamus,

which plays a role in the parkinsonism of voluntary

movements, in some way facilitates cortical myoclonus in

PD. This seems unlikely with the available evidence. Many

of our PD cases demonstrated only a relatively low Hoehn

and Yahr stage of 1.5–2.5 [24]. In other conditions where

parkinsonism and multifocal cortical action myoclonus

coexist such as in DLB and multiple system atrophy, no

correlation with parkinsonism severity has been obvious or

reported. Indeed, a study by Louis et al. [27] found that

myoclonus was much more likely to occur in DLB whereas

a perceived need to treat the patient’s parkinsonism was

more likely to occur in PD. Although basal ganglia

dysfunction is thought to be pre-eminent in Lewy body

disorder motor symptom pathophysiology, the existence of

cortical myoclonus presents a significant possibility that in

certain cases, cortical pathology may have some influence

on the motor system as well. The neuropathological

examination of our previously reported case showed rare

Lewy bodies in the pre- and post-central gyri as well as

occasional Lewy bodies in the parietal area, cingulate gyrus,

temporal area, and entorhinal cortex [24]. One possible

mechanism for the cortical myoclonus in our cases would be

the lack of inhibitory influences and/or excessive excitation

of sensorimotor cortex produced by the neurodegeneration

occurring locally around the sensorimotor cortical region.

Despite the presence of Alzheimer’s disease pathology in

Lewy body disorders, it may not contribute to the

mechanism of myoclonus production. As mentioned earlier,

Alzheimer’s disease patients can develop cortical myoclo-

nus, although sometimes with different electrophysiological

characteristics than what we have described for Lewy body

disorders. However, Dickson [28] has pointed out that

several studies support that Lewy body pathology in PD

brains can become widespread in the cerebrum, but the

Alzheimer-type pathology is not greater than would be

expected for the age of the individual. Marui et al. [29] have

reported that among DLB patients, Lewy body pathology in

the cerebral cortex progresses first in layers V-VI,

subsequently in layer III and finally in layer II. Although

the cerebral pathology first progresses in the amygdala, it is

known to subsequently spread to the limbic cortex and

finally in the neocortex [29]. Such pathology, if it reaches

motor areas of the neocortex, could be responsible for

cortical myoclonus generation. However, with these diffuse

changes, neurochemical abnormalities and/or abnormal

remote input from other areas (cortical and/or subcortical)

possibly may be playing a significant role.

3. Small amplitude repetitive movements in

neurodegenerative disorders—myoclonus versus tremor

When the myoclonus is moderately large and has obvious

irregular timing, the phenomenology is clear. This is typical

in Creutzfeldt–Jakob disease, post-hypoxic myoclonus,

progressive myoclonus epilepsy, toxic–metabolic con-

ditions, and in many other disorders, including some cases

of Alzheimer’s disease and DLB. Stimulus sensitive

myoclonus is usually easily discerned. However, when the

myoclonus is small and action induced, it is only a minor

determinant of disability at most and may be difficult or

impossible to differentiate from tremor. Besides the

examples mentioned above concerning neurodegenerative

disease, other investigators have examined rhythmic

phenomena in myoclonus. Peter Brown and others [30,31]

have recently emphasized physiological evidence of rhyth-

mic EEG and EMG discharges with significant EEG–EMG

coherence. The term, ‘cortical tremor’ was first coined by

Ikeda et al. [32]. The movement in their patients was

described as ‘shivering-like tremor’ and ‘fine shivering-like

twitchings.’ In that paper, the ‘tremor’ discharges were found

to have classic characteristics of cortical reflex myoclonus,

including the finding of a back-averaged cortical spike

discharge. Other articles about cortical tremor have since

been published, including Toro et al. who asserted that such a

phenomenon was a common manifestation of cortical

myoclonus [33–35]. The consensus statement of the Move-

ment Disorder Society on tremor implies that the term,

cortical tremor, is misleading. The statement comments that

cortical tremor is not a tremor but a specific form of rhythmic

myoclonus consisting of (1) high-frequency, irregular

tremor-like postural and kinetic myoclonus almost indis-

tinguishable from high-frequency postural tremor and (2)

synchronous, short, high-frequency jerks (7–18 Hz) on

EMG [36].

Chronic progression and insidious onset characterize

neurodegenerative diseases. In such cases that produce

hyperkinetic movement disorders, the abnormal physiology

of movement control gradually evolves over time. Before

the repetitive action myoclonus of neurodegenerative


disease is easily identified as myoclonus, it would be

conceivable that the abnormal physiology may pass through

a stage when the EMG discharges produce a movement

elicited by action that appears as a small amplitude tremor.

This has already been alluded to in the instance of

corticobasal degeneration as mentioned earlier. Before,

during, and after the ‘transition’ between tremor and

myoclonus, the discharges themselves and their associated

physiology may be different. The abnormal physiology may

never progress to reveal a clear distinctive phenomenology

between tremor and myoclonus. Thus, it is unrealistic to

suggest that there are definitive criteria to decide where

regularity stops and irregularity begins or that the dividing

line between myoclonus and tremor is always clear.

Furthermore, the consensus statement terms, ‘tremor-like,’

and ‘almost indistinguishable’ lack precision. It may be

most prudent to accept the inexact nature of phenomenology

and the inability of a clinical exam to discern tremor from

‘myoclonus’ in all of these cases. Indeed, reasonable

persons (even experts) will disagree on whether a certain

example of repetitive brief movements is tremor, myoclo-

nus, or something else. Description of electrophysiologic

features, as the consensus statement on tremor points out,

should be performed to allow greater specificity on the

classification of signs and symptoms [36]. However,

especially in neurodegenerative disease, phenomenological

boundaries will continue to be debated.

4. Summary: myoclonus in neurodegenerative disease

and its significance

Most myoclonus in neurodegenerative disease is classi-

fied as cortical. This is easy to accept in disorders such as

Alzheimer’s disease and corticobasal degeneration, in which

the cortical pathology is fairly consistent and well known. In

PD, most noted for its subcortical pathology, the finding of

small amplitude myoclonus with an EEG correlate on

clinical neurophysiology testing documents cortical dys-

function and probably primary cortical pathology. In our

experience, this can sometimes herald the onset of dementia

in PD. Thus, in this instance, even if the cortical myoclonus is

small, it may have important meaning. Cortical myoclonus

can respond to treatment, but the disability from small

amplitude myoclonus may not justify treatment side effects

[1]. An important exception to the cortical origin of

myoclonus in neurodegenerative disease may be multiple

system atrophy, where the source of the small amplitude

distal action myoclonus is unknown [7]. It is also important to

realize that even when a myoclonus cortical correlate is

present, subcortical influences may still exist. Nevertheless,

small amplitude distal action myoclonus seems to be a

possible manifestation of many different neurodegenerative

disorders and maybe more common in individual disorders

than what is generally appreciated. Thus, claims of

differentiating between neurodegenerative disorders by

using the presence or absence of small amplitude distal

action myoclonus appear unwarranted. The use of clinical

neurophysiology helps in defining the nature of the EMG

discharges in such disorders, but the current ability of these

electrophysiology techniques to provide desired specificity is

lacking. However, this situation should improve with further

study of myoclonus physiology in the various neurodegen-

erative disorders. Finally, determining with certainty

whether a given repetitive high frequency small amplitude

distal movement should be named myoclonus or tremor may

be not possible in some cases and may be arbitrary. This

should not discourage the study of such movements. Rather,

it should make us wonder more about why they come to exist

in the various neurodegenerative disorders.

References

[1] Cavinesss JN. Myoclonus: a clinical review. Mayo Clinic Proc 1996;

71:679–88.

[2] Caviness JN, Alving LI, Maraganore DM, Black R, McDonnell SK,

Rocca WA. The incidence and prevalence of Myoclonus in Olmsted

County. Mayo Clinic Proc 1999;74:565–9.

[3] 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.

[4] Shibasaki H. Electrophysiological studies of myoclonus. AAEM

Minimonograph #30. Muscle Nerve 2000;23:321–35.

[5] Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP.

Clinical features and natural history of multiple system atrophy. Brain

1994;117:835–45.

[6] Gouider-Khouja N, Vidaihet M, Bonnet A-M, Pichon J, Agid Y. Pure

striatonigral degeneration and Parkinson’s disease: a comparative

clinical study. Mov Disord 1995;10:288–94.

[7] Salazar G, Valls-Sole J, Marti MJ, Chang H, Tolosa ES. Postural and

action myoclonus in patients with Parkinsonian type multiple system

atrophy. Mov Disord 2000;15:77–83.

[8] Rodriguez ME, Artieda J, Zubieta JL, Obeso JA. Reflex myoclonus in

olivopontocerebellar atrophy. J Neurol Neurosurg Psychiatry 1994;

57:316–9.

[9] Artieda J, Obeso JA. The pathophysiology and pharmacology of

photic cortical reflex myoclonus. Ann Neurol 1993;34:175–84.

[10] Brunt ERP, van Weerden TW, Pruim J, Lakke WPFJ. Unique

Myoclonic pattern in corticobasal degeneration. Mov Disord 1995;10:

132–42.

[11] Lang AE, Riley DE, Bergeron C. Cortical-basal ganglionic degener-

ation. In: Calne DB, editor. Neurodegenerative diseases. Philadelphia:

WB Saunders; 1994. p. 877–94.

[12] Thompson PD, Shibasaki H. Myoclonus in corticobasal degeneration

and other neurodegenerations. In: Litvan I, Goetz CG, Lang AE,

editors. Corticobasal degeneration, advances in neurology, vol. 82.

Philadelphia: Lippincott/Williams & Wilkins; 2000. p. 69–81.

[13] Thompson PD, Day BL, Rothwell JC, Brown P, Britton TC, Marsden

CD. The myoclonus in corticobasal degeneration. Brain 1994;117:

1197–207.

[14] Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC,

Goetz CG, Golve LI, Grafman J, Growdon JH, Hallett M, Jankovic J,

Quinn NP, Tolosa E, Zee DS. Clinical research criteria for the

diagnosis of progressive supranuclear palsy (Steele–Richardson–

Olszewski syndrome): report of the NINDS-SPSP international

workshop. Neurology 1996;47:1–9.

[15] Kurihara T, Landau WM, Torack RM. Progressive supranuclear palsy

with action myoclonus, seizures. Neurology 1974;24:219–23.


[16] Suyama N, Kobayashi S, Isino H, Iijima M, Imaoka K. Progressive

supranuclear palsy with palatal myoclonus. Acta Neuropathol 1997;

94:290–3.

[17] Caviness JN, Wzsolek ZK. Myoclonus in ponto-pallidal-nigral-

degeneration (PPND). In: Fahn S, Frucht SJ, Hallett M, Truong DD,

editors. Myoclonus and paroxysmal dyskinesias. Advances in

Neurology, vol. 89. New York, NY: Lippincott/Williams & Wilkins;

2002. p. 35–9.

[18] Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton

M, et al. Frontotemporal dementia and corticobasal degeneration in a

family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999;

58(6):667–77.

[19] Caviness JN, Kurth M. Cortical myoclonus in Huntington’s disease

associated with an enlarged somatosensory evoked potential. Mov

Disord 1997;12(6):1046–51.

[20] Warner TT, Williams LD, Walker WH, Flinter F, Robb SA, Bundey

SE, Honavar M, Harding AE. A clinical and molecular genetic study

of dentatorubropallidoluysian atrophy in four european families. Ann

Neurol 1995;37:452–9.

[21] Wilkins DE, Hallett M, Erba G. Primary generalised epileptic

myoclonus: a frequent manifestation of minipolymyoclonus of

cortical origin. J Neurol Neurosurg Psychiatry 1985;48:506–16.

[22] Wilkins DE, Hallett M, Berardelli A, Walshe T, Alvarez N.

Physiologic analysis of the myoclonus of Alzheimer’s disease.

Neurology 1984;34:898–903.

[23] Ugawa Y, Kohara N, Hirasawa H, Kuzuhara S, Iwata M, Mannen T.

Myoclonus in Alzheimer’s disease. J Neurol 1987;235:90–4.

[24] Caviness JN, Adler CH, Newman S, Caselli RJ, Muenter MD. Cortical

myoclonus in Levodopa-responsive parkinsonism. Mov Disord 1998;

13:540–4.

[25] Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, de la Monte

S, Norenberg MD, Schneck SA. Diffuse Lewy body disease and

progressive dementia. Neurology 1988;38:1520–8.

[26] Caviness JN, Gwinn-Hardy KA, Adler CH, Muenter MD. Electro-

physiological observations in hereditary parkinsonism-dementia with

Lewy body pathology. Mov Disord 2000;15:140–5.

[27] Louis ED, Klatka LA, Liu Y, Fahn S. Comparison of extrapyramidal

features in 31 pathologically confirmed cases of diffuse Lewy body

disease and 34 pathologically confirmed cases of Parkinson’s disease.

Neurology 1997;48:376–80.

[28] Dickson DW. Alpha-synuclein and the Lewy body disorders. Curr

Opin Neurol 2001;14:423–32.

[29] Marui W, Iseki E, Nakai T, Miura S, Kato M, Ueda K, Kosaka K.

Progression and staging of Lewy pathology in brains from patients

with dementia with Lewy bodies. J Neurol Sci 2002;195:153–9.

[30] Brown P, Marsden CD. Rhythmic cortical and muscle discharge in

cortical myoclonus. Brain 1996;119:1307–16.

[31] Brown P, Farmer SF, Halliday DM, Marsden J, Rosenberg JR.

Coherent cortical and muscle discharge in cortical myoclonus. Brain

1999;122:461–72.

[32] Ikeda A, Kakigi R, Funai N, Neshige R, Kuroda Y, Shibasaki H.

Cortical tremor: a variant of cortical reflex myoclonus. Neurology

1990;40:1561–5.

[33] Toro C, Pascul-Leone A, Deuschl G, Tate E, Pranzatelli MR, Hallett

M. Cortical tremor—a common manifestation of cortical myoclonus.

Neurology 1993;43:2346–53.

[34] Oguni E, Hayashi A, Ishii A, Mizusawa H, Shoji S. A case of cortical

tremor as a variant of cortical reflex myoclonus. Eur Neurol 1995;35:

63–4.

[35] Terada K, Ikeda A, Mima T, Kimura K, Nagahama Y, Kamioka Y,

Murone I, Kimura J, Shibasaki H. Familial cortical myoclonic tremor

as a unique form of cortical reflex myoclonus. Mov Disord 1997;12:

370–7.

[36] Deuschl G, Bain P, Brin M, et al. Consensus statement of the

movement disorder society on tremor. Mov Disord 1998;13:2–23.


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