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Myoclonus is defined as sudden, brief, shocklike, involuntary movements caused by muscular contractions or inhibitions. Myoclonic movements have now been recognized to have many possible variants and pathophysiologic features. Myoclonus may arise from several sites within the neuraxis, of which the cortex and brain stem reticular formation are the most common. An etiologic classification scheme and electro-diagnostic tests are useful for clinical purposes. Therapy is limited and usually involves symptomatic treatment with valproic acid or clonazepam. Careful attention to the basic characteristics of the movement appearance, the clinical circumstances in which the myoclonus occurs, and the results of the electro-diagnostic assessment techniques provide a basis for identifying the syndrome in which the myoclonus occurs.
He described them as quick multifocal muscle jerks involving the patient's entire body, which seemingly occurred independent of each other. Friedreich posited that these abnormal movements should be distinguished from epilepsy, inasmuch as it occurred in different clinical circumstances. Today, the use of the abbreviated term “myoclonus” is more generic than Friedreich intended, and it is used in many disorders, even in epilepsy.
A currently favored definition of myoclonus is sudden, brief, shocklike, involuntary movements caused by muscular contractions (positive myoclonus) or inhibitions (negative myoclonus).
Although some definitions state that myoclonus arises from the central nervous system (CNS), this aspect of the definition is best omitted because myoclonus has been described with peripheral lesions.
“Myoclonus” is a term that is meant to be primarily descriptive. It is not a diagnosis and is nonspecific relative to the cause of the disorder in which it occurs as well as to its neuroanatomic source and pathogenesis.
Despite its nonspecific nature, myoclonus is a useful sign for physicians who understand its clinical significance. The presence of myoclonus often has strong implications for the diagnosis, prognosis, and treatment of the underlying disorder. Therefore, the purpose of this article is to present an approach in which current knowledge of myoclonus and its variants can be used to enhance clinical practice.
Physiologic Characteristics and Clinical Identification of Myoclonus
Identifying the myoclonic jerk is the initial clinical goal. The appearance of the abnormal movement patterns of myoclonus can be appreciated by examining the electromyographic (EMG) discharge patterns. An EMG burst from the wrist flexor muscle group in a normal subject is shown in Figure I A; EMG was performed as quickly and briefly as possible. An EMG burst from the wrist flexor muscle group during myoclonus of the wrist in a patient is shown in Figure 1B. This myoclonic burst was brief (less than 100 ms) and was produced by an abnormal hypersynchronous recruitment of multiple motor units. The normal burst (Fig. 1 A) has a longer duration and a more gradual crescendo and decrescendo pattern of motor unit activity in comparison with the abnormal burst (Fig. 1 B). The excessively rapid recruitment of motor unit activity, the brief duration, and, to a lesser extent, the amplitude of the EMG discharge make myoclonus appear abnormally quick. The spatial and temporal patterns of the agonist-antagonist muscle relationships also influence the appearance of movements. EMG discharge durations up to 200 ms and occasionally longer can produce the appearance of a “shocklike” involuntary myoclonic movement, and no clear boundary exists between myoclonus and slightly slower movements that appear as a muscle jerk but are not quick enough to be myoclonus. In borderline cases, movement disorder experts often disagree on whether the term “myoclonus” is being properly applied.
Fig. 1Electromyographic bursts from wrist flexor muscle group. A, In normal subject, electromyography was performed as quickly and briefly as possible. B, In patient, during myoclonus of wrist.
Examples of other abnormal movements that are quick enough to be occasionally confused with myoclonus are tics, startle reflexes, chorea, dystonia, tremor, and fasciculations. Simple motor tics are brief jerks involving a single group of muscles, which can be virtually indistinguishable from myoclonus on the basis of appearance only. The relief of the inner urge to perform tics and their relative suppressibility distinguish them from myoclonus. Complex tics involve sequences of movements that persist far too long to be confused with myoclonus. An exaggerated startle response is a quick jerk involving the face, head, neck, and, sometimes, the proximal limbs. Although myoclonus may occasionally be triggered by startle, usually it is elicited by other stimuli or is spontaneous. Chorea is defined as unsustained and nonstereotyped movements of variably changing speed that seemingly flow from one muscle group to another. In contrast, myoclonic movements are stereotyped in both direction and speed. Dystonia is a syndrome of excessive muscle contractions, which frequently cause twisting and repetitive movements, or abnormal postures. Quick movements can occur in dystonia, but their association with slower movements or postures distinguishes them from myoclonus. The movements of tremor appear as a rhythmic and sinusoidal oscillation of one body part in relationship to another. Myoclonus can be rhythmic, but the movement form resembles the appearance of a “square wave” temporal pattern, with a distinguishable interval between each movement.
Fasciculations appear as muscle twitches and result from spontaneous firing of motor units or bundles of muscle fibers, usually in the setting of peripheral nerve disease. These small movements do not result in the movement of a whole muscle as does myoclonus.
Clinical Diagnostic Approach to Myoclonus
The best strategy for using the symptom of myoclonus in the diagnosis of its underlying is to view it within the context of the total clinical picture. Information obtained from the history and physical examination is no more important than the characterization of the associated clinical features. Aspects of the patient's history that aid in the diagnosis include history of drug or toxin exposure, history of seizures, past or current medical problems, and family history. Besides delineating the muscle groups involved, the examination should reveal the distribution of the myoclonus as focal, multifocal, segmental, or generalized. The temporal pattern may be sporadic or repetitive, with irregular or rhythmic timing. The activation of the myoclonus may be at rest (spontaneous), induced by stimuli (reflex myoclonus), or induced by voluntary movement (action myoclonus) (or some combination of these factors).
Any combination of general somatic afferent, visual, auditory, or startle stimuli may elicit myoclonus. A thorough evaluation of other neurologic findings, including cognitive dysfunction, ataxia, and parkinsonism, as well as other examination findings is crucial for determining the underlying disorder.
Because myoclonus is a nonspecific finding, an organized framework for the diagnosis of the underlying disorder is necessary. Marsden and associates
The major categories of myoclonus are as follows: physiologic, essential, epileptic, and symptomatic (secondary). Each of the major categories is associated with different clinical circumstances. The initial task is to determine which major category reflects the circumstances of the patient.
Physiologic myoclonus occurs in normal people. This has minimal or no associated disability, and a physical examination shows normal findings and no additional pathologic conditions. Thus, the key to identifying physiologic myoclonus is to recognize that the jerk, based on clinical history, is a normal phenomenon. Essential myoclonus is clinically significant and usually easily elicited on examination, but otherwise it has minimal or no other important pathologic features. Thus, the myoclonus is an isolated or “essential” phenomenon, but the patient usually experiences some disability. Essential myoclonus is idiopathic and progresses slowly or not at all. 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. Seizures usually dominate the clinical picture in epileptic myoclonus, and the disorder is generally idiopathic. The presence of associated seizure manifestations such as lapses in consciousness and epileptiform abnormalities on an electroencephalogram (EEG) can help to clarify the underlying epileptic syndrome. The myoclonus in epileptic syndromes is presumed to be of cortical origin. Symptomatic myoclonus manifests in the setting of an identifiable underlying disorder, neurologic or nonneurologic. These symptomatic syndromes are the most common cause of myoclonus. Often, clinical or pathologic evidence indicates diffuse nervous system involvement. The other clinical manifestations are important and often are more prominent than the symptom of myoclonus. Chronic clinical progression suggests symptomatic myoclonus. Although seizures with characteristics other than myoclonus may be present, they are not the only prominent clinical manifestation. Mental status abnormalities and ataxia are common clinical associations in symptomatic myoclonic syndromes,
and the cortex is the most commonly proven source of the myoclonic jerks.
After the major category of the disorder has been determined by using the aforementioned outlined characteristics of physiologic, essential, epileptic, and symptomatic syndromes, the more specific qualities of the disorder should be ascertained for further definition. Essential myoclonic syndromes are classified as either hereditary or sporadic. Epileptic syndromes are categorized into those that have myoclonus as a “fragment” of epilepsy and those that have myoclonus occurring as a myoclonic seizure. Symptomatic myoclonic syndromes are subcategorized by the major associated clinical manifestation (for example, ataxia), known causes (for example, storage disorders), or insult (for example, focal nervous system damage). The neurodegenerative syndromes of the ataxic, basal ganglia, and dementia subcategories are the most common causes of symptomatic myoclonus. Hence, the dominant presence of ataxia, parkinsonism, or dementia in the clinical picture helps to place the underlying disorder in one of these subcategories. The characteristics of common myoclonic disorders are briefly discussed in the subsequent sections.
Physiologic Myoclonus
The ability to identify the jerks associated with physiologic myoclonus based on the history enables the clinician to reassure all involved persons, and no treatment is necessary. Jerks during sleep are often noted by the spouse who complains of being kicked in bed. Types of sudden movement that occur during sleep or sleep transitions are “partial myoclonic jerks,” “massive myoclonic jerks” (hypnic jerks), and nocturnal myoclonus.
Partial myoclonic jerks are usually multifocal and occur in distal muscles. Massive myoclonic jerks are generalized and affect trunk and proximal muscles; they often occur as the person is falling asleep. Nocturnal myoclonus consists of stereotyped repetitive dorsiflexions of the toes and foot, and, occasionally, flexion of the knee and hip.
Hereditary essential myoclonus has been characterized by onset before age 20 years, dominant inheritance with variable severity, a benign course compatible with an active life and normal life span, absence of other neurologic deficits, and normal findings on EEG.
Sporadic essential myoclonus is more clinically heterogeneous than is hereditary essential myoclonus. This “entity” has the nonspecific inclusion criteria of any idiopathic case that does not correspond with any other myoclonic category. Thus, the term “sporadic essential myoclonus” is a miscellaneous list more than anything else. In a large series, the age of onset ranged from 2 to 64 years, and the distribution, region affected, and activation features showed little uniformity.
This term likely represents various heterogeneous yet undiscovered causes and false-negative findings on family histories.
Epileptic Myoclonus
A generalized tonic-clonic seizure can be preceded by generalized myoclonic jerks, and the clonic phase is typified by a series of myoclonic jerks that usually signal the end of the seizure.
Epilepsia partialis continua usually resembles spontaneous myoclonus; it occurs irregularly or regularly at intervals no longer than 10 seconds, is confined to one part of the body, and continues for a period of hours, days, or weeks.
Most investigators believe that it has a cerebral cortical origin, and the EEG usually, but not always, shows a focal abnormality appropriate for the affected region.
Commission on Classification and Terminology of the International League Against Epilepsy Proposal for revised clinical and electroencephalographic classification of epileptic seizures.
in: Niedermeyer E Lopes da Silva F Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 2nd ed. Urban & Schwarzenberg,
Baltimore1987: 209-227
Myoc lonus can accompany absence seizures as movements of the eyelid, head, or more extensive body jerks, and the generalized ictal EEG pattern has a frequency of approximately 3 Hz, which is typical for absence syndromes.
Myoclonic seizures are epileptic seizures in which the motor manifestation is myoclonus. The myoclonus is generalized without local onset and is usually accompanied by a generalized ictal epileptiform EEG discharge.” Infantile spasms and Lennox-Gastaut are well-known childhood epileptic syndromes that exhibit myoclonic seizures and are associated with other severe neurologic dysfunction. Interictal EEG abnormalities help define these syndromes.
Juvenile myoclonic epilepsy (awakening myoclonus of Janz) is the classic idiopathic syndrome in which myoclonic seizures may occur in conjunction with generalized tonicclonic or absence seizures (or both). It is characterized by onset during adolescence or young adulthood and generalized myoclonus exacerbated by sudden awakening, sleep deprivation, or photic stimulation (or some combination of these entities).
The ictal EEG shows a 4- to 6-Hz polyspike-and-wave pattern, and the interictal EEG may demonstrate the same pattern or normal findings. Valproic acid is highly effective in controlling all seizure types associated with this syndrome.
Various storage diseases have been designated to be part of the clinical syndrome of progressive myoclonic epilepsy (PME). PME is characterized by myoclonic seizures, tonic-clonic seizures, and progressive neurologic dysfunction, particularly ataxia and dementia.
Characteristic electrophysiologic features of PME include abnormal background EEG rhythms, interictal and ictal epileptiform discharges, and enlarged somatosensory evoked potentials.
Several clinical differences exist between individual storage diseases relative to age of onset, rate of progression, details of clinical expression, and pattern of stimulus sensitivity.
Neurodegenerative syndromes have widely distributed pathologic features with variable involvement of cerebellar pathways, basal ganglia, and cerebral cortex. Action myoclonus is often characteristic in cerebellar myoclonic syndromes.
Myoclonus as a finding in Parkinson's disease is best known as a consequence of levodopa therapy, although its occurrence without medication has been rarely reported.
Multisystem atrophy predominantly manifests as varying degrees of parkinsonism, ataxia, and autonomic dysfunction, but a stimulus-sensitive distal limb myoclonus was found in 31% of patients.
The distribution of the myoclonus in corticobasal degeneration is either asymmetric or focal and is similar to the other clinicopathologic manifestations of the disease. The myoclonus in Creutzfeldt-Jakob disease is a clinical hallmark of the disorder, and it can occur at rest or be exacerbated by action or a stimulus.
In metabolic conditions, myoclonus often occurs in the hospital setting, frequently with mental status changes. The myoclonus may be multifocal and subtle or generalized and almost constant, as in the entity “myoclonic status epilepticus.”
Prognosis in such cases depends on the severity and reversibility of the underlying process. Asterixis, which is now termed “negative myoclonus,” is a well-known accompaniment to metabolic encephalopathies.
The toxic and drug-induced causes of myoclonus are numerous (Table 2). Most of the agents that cause myoclonus can also produce mental status changes and tremor. The effects are reversed when use of the agent is discontinued.
Table 2Toxins and Drugs That Are Associated With Myoclonus
described myoclonus in patients after recovery from severe hypoxic episodes. One study showed that all patients experience hypoxic coma for several hours to days and that spontaneous myoclonus and seizures may or may not occur during the coma.
reported that such cases of posthypoxic (Lance-Adams) myoclonus responded to oral administration of 5-hydroxytryptophan (5-HTP), a precursor of the neurotransmitter serotonin. Cerebrospinal fluid serotonin metabolites have been found to be decreased in patients with this syndrome, and this finding has led to the hypothesis that suppression of serotonin system activity is important.
Investigators believe that 5-HTP is effective because of conversion to serotonin in the CNS and thus increased serotonergic activity, which somehow suppresses the myoclonus.
Brain-stem lesions involving the dentato-olivary pathway are believed to be important in the generation of palatal myoclonus. This movement is rhythmic and usually bilateral, with a rate of 2 to 3 Hz.
Because of the rate, rhythmicity, and relative slowness of the palatal movement in comparison with other examples of myoclonus, many clinicians believe that it resembles a tremor phenotype more than myoclonus. Palatal myoclonus may be associated with similar movements in other body segments, and in many cases, no brain-stem lesion is found.
The myoclonus originating from the spinal cord is usually rhythmic, is slow (less than 4 Hz), and involves only the musculature from a few spinal levels. A newly described type of myoclonus arising from the spinal cord termed “axial propriospinal myoclonus” consists of axial jerks that seem to start from a single spinal level and spread both rostrally and caudally. These jerks are reflex sensitive and can also involve limb muscles. Investigators believe that the neuronal hyperactivity spreads through propriospinal pathways.
Peripheral nervous system lesions have been reported to be associated with myoclonus; however, whether the pathophysiologic features are wholly peripheral is unclear.
Possibly, in these peripheral cases, the peripheral lesion affects CNS excitability, which in turn causes myoclonus.
Evaluation
Diagnostic testing should be considered an extension of the clinical examination. Such testing is usually necessary unless the diagnosis seems straightforward after elicitation of the history and performance of the physical examination. Basic tests (Table 3) should be done in most patients. If, after such testing, the diagnosis is still unknown, advanced testing (Table 3) should be considered. Expert referral may be useful if such detailed testing is indicated. Other testing may include screening for a malabsorption syndrome, imaging the body for an occult cancer, or examining the cerebrospinal fluid for infectious or inflammatory processes.
In general, findings will be normal in patients with physiologic and essential myoclonus, but various abnormalities will be evident in those with epileptic and symptomatic syndromes.
in: Niedermeyer E Lopes da Silva F Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 2nd ed. Urban & Schwarzenberg,
Baltimore1987: 259-273
in: Niedermeyer E Lopes da Silva F Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 2nd ed. Urban & Schwarzenberg,
Baltimore1987: 259-273
Polygraphic EEG-EMG monitoring is useful because EMG discharge duration, agonist -antagonist relationships, order of muscle activation, and the correlation of EMG signals with the time of EEG changes are variable in different types of myoclonus.
This technique increases the signal-to-noise ratio and records preceding EEG waveforms that are time-locked to the myoclonus. An example of this back-averaging technique establishing a cortical origin for symptomatic limb myoclonus is demonstrated in Figure 2. It shows a diphasic averaged scalp potential over the left sensorimotor cortex preceding the averaged EMG discharge from the right first dorsal interosseous muscle (Fig. 2). The manner in which electrodiagnostic techniques can distinguish among the three most common neuroanatomic origins of myoclonus is shown in Table 4.
Fig. 2Results from back-averaging myoclonic discharge from right first dorsal interosseous muscle, which produces diphasic averaged scalp potential over left sensorimotor cortex, preceding right first dorsal interosseous muscle averaged EMG discharge. FC = fronto-central region; R = right.
Classifying the myoclonus and identifying its underlying disorder are especially critical goals relative to treatment considerations. Some causes of myoclonus are easily reversible, such as an acquired abnormal metabolic state, an excisable lesion, or a side effect of a medication. Physiologic myoclonus needs no management other than reassurance. If the myoclonus arises as part of an epileptic syndrome, standard anticonvulsant therapy is used and often includes valproic acid or clonazepam (or both). Successful treatment decreases the incidence of myoclonus, as well as the other seizure types or manifestations (or both). Symptomatic treatment of myoclonus is currently less than satisfactory. Valproic acid and clonazepam are the two most useful drugs for symptomatic treatment of myoclonus;
however, they are ineffective in many cases. The mechanism of valproic acid relative to its antiepileptic activity and its antimyoclonic activity has been a subject of controversy. Initially, investigators thought that valproic acid inhibited γ-aminobutyric acid (GABA) transaminase, which in turn increased brain levels of the inhibitory neurotransmitter GABA, which led to inhibiting the myoclonus. We now know that, even though GABA levels are increased, the effects of valproic acid may have little to do with GABA transaminase inhibition.
Several other agents are reported to be particularly useful for certain myoclonic syndromes. 5-HTP is available only for experimental protocol, but it has been used successfully in the treatment of posthypoxic (Lance-Adams) myoclonus; however, many patients do not respond.
Drugs that can act to block the reuptake of serotonin at nerve terminals can be used to lower the required dosage of 5-HTP and carbidopa and to decrease side effects.
5-HTP has also been used to treat other types of myoclonus, although the beneficial effect has not been as substantial.
Piracetam, which is not available in the United States, has been reported to have antimyoclonic myoclonic activity, particularly in combination with other agents.
Piracetam is a member of a group of substances known as nootropic drugs, which are believed to stimulate mental activity. The reasons for the antimyoclonic property are unclear. Piracetam has only mild effects on GABA and monoaminergic activity. It increases adenosine metabolism, modulates acetylcholine levels, affects energy metabolism, and has other miscellaneous effects.
The anticonvulsants phenytoin, phenobarbital, and carbamazepine are used in cases of rhythmic myoclonus; success varies. Benzodiazepines can be helpful in attempts to treat acute myoclonic seizures after a severe hypoxic insult.
Tetrabenazine is another drug that is considered experimental, but it has been used successfully in cases of rhythmic myoclonus such as palatal myoclonus and spinal myoclonus.
Myoclonus consists of sudden, brief, shocklike, involuntary movements caused by muscular contractions or inhibitions. The cortex and brain stem are the most common origins. The term “myoclonus,” used by itself, is becoming increasingly nonspecific as the different variants are further defined by clinical, genetic, biochemical, and electrophysiologic means. Thus, the clinician must appreciate the differences among the types of myoclonus. A clinical approach based on the four etiologic categories—physiologic, epileptic, essential, and symptomatic—in conjunction with the appropriate electrodiagnostic methods is currently the best strategy to evaluate and classify myoclonus. The hope is that further research into the basic pathophysiologic features and the experimental therapeutics for myoclonus will yield better treatments for this disabling, abnormal movement.
References
Friedreich N
Neuropathologische Beobachtung beim paramyoklonus multiplex.
in: Niedermeyer E Lopes da Silva F Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 2nd ed. Urban & Schwarzenberg,
Baltimore1987: 209-227
in: Niedermeyer E Lopes da Silva F Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 2nd ed. Urban & Schwarzenberg,
Baltimore1987: 259-273
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