The terms clonus (or clonic), myoclonus (or myoclonic), and polymyoclonus have been used, perhaps indiscriminately, to designate rhythmic or arrhythmic series of brief, shock-like muscular contractions associated with disease of the central nervous system. Clonus refers to a series of rhythmic, monophasic (i.e., unidirectional) contractions and relaxations of a group of muscles, differing in this way from tremors, which are always diphasic or bidirectional. Myoclonus specifies the very rapid, shock-like contractions of a group of muscles, irregular in rhythm and amplitude, and, with few exceptions, asynchronous and asymmetrical in distribution. If such contractions occur singly or are repeated in a restricted group of muscles, such as those of an arm or leg, the phenomenon is termed segmental myoclonus, whereas widespread, lightning-like, arrhythmic repeated contractions are referred to as polymyoclonus. The discussion that follows makes evident that each of the three phenomena has a distinctive pathophysiology and clinical implications.
Reference has already been made in Chap. 3 to the clonus that appears in relation to spasticity and heightened tendon reflexes in diseases affecting the corticospinal tract. It is most easily elicited by forcefully dorsiflexing the ankle; a series of rhythmic jerks of small to moderate amplitude result.
A common and benign example of myoclonus, familiar to many persons, is the "sleep-start" that consists of a jerking of the body, particularly the torso, while falling asleep or occasionally, just prior to waking (see Chap. 18). This movement will be vigorous enough to cause tongue biting and be mistaken for a convulsion.
Epilepsia partialis continua is a special type of rhythmic epileptic activity in which one group of muscles—usually of the face, arm, or leg—is continuously (day and night) involved in a series of rhythmic monophasic contractions. These may continue for weeks, months, or years. In most cases there is a corresponding EEG abnormality. The disorder appears to be cerebral in origin, but in most cases its precise anatomic and physiologic basis cannot be determined (see Chap. 16 for further discussion).
Focal and Regional Myoclonus
Patients with idiopathic epilepsy may complain of a localized myoclonic jerk or a short burst of myoclonic jerks, occurring particularly on awakening and on the day or two preceding a major generalized seizure, after which these movements cease. One-sided or focal myoclonic jerks are the dominant feature of a particular form of childhood epilepsy—so-called benign epilepsy with rolandic spikes (Chap. 16). Diffuse myoclonic jerks are the main—or sometimes only—manifestation of a fairly common seizure disorder with distinctive EEG features called juvenile myoclonic epilepsy; this diagnosis is suggested by an onset of myoclonus or single seizures during adolescence and myoclonus or lapses in upright posture, usually occurring in the morning, that become prominent with sleep deprivation and several hours after alcohol consumption. Myoclonus may be associated with atypical petit mal and akinetic seizures in the Lennox-Gastaut syndrome (absence or petit mal variants); the patient often falls during the brief lapse of postural mechanisms that follows a single myoclonic contraction. Similarly, in the West syndrome of infantile spasms, the arms and trunk are suddenly flexed or extended in a single massive myoclonic jerk ("jackknife" or "salaam" seizures); mental regression occurs in 80 to 90 percent of these cases, even when the seizures are successfully treated with adrenocorticotropic hormone (ACTH). These types of special "myoclonic epilepsies" are discussed further below and in Chap. 16 in relation to epilepsy.
Focal simple myoclonus is also one of the notable features of degenerative neurologic conditions, particularly corticobasal ganglionic degeneration; it is generally seen in a limb that is made rigid by this process.
Diffuse Myoclonus (Polymyoclonus)
Under the title paramyoclonus multiplex, Friedreich, in 1881, described a sporadic instance of widespread muscle jerking in an adult. It was probably in the course of this description that the term myoclonus was used for the first time. Muscles were involved diffusely, particularly those of the lower face and proximal segments of the limbs, and the myoclonus persisted for many years, being absent only during sleep. No other neurologic abnormalities accompanied the movement abnormality. The nature and pathologic basis of this disorder were never determined.
Over the years, the term paramyoclonus multiplex, or polymyoclonus has been applied to all varieties of myoclonic disorder (and other motor phenomena as well), to the point where it has nearly lost its specific connotation. Polymyoclonus may occur in pure or "essential" form as a benign, often familial, nonprogressive disease or as part of a more complex progressive syndrome that may prove disabling and fatal. More importantly, there are several acquired forms that are associated with various neurologic diseases as discussed below.
Essential (Familial; Hereditary; Genetic) Myoclonus
Symptoms may begin at any period of life but usually appear first in childhood and are of unknown etiology. An autosomal dominant mode of inheritance is evident in some families. The myoclonus takes the form of irregular twitches of one or another part of the body, involving groups of muscles, single muscles, or even a portion of a muscle. As a result, an arm may suddenly flex, the head may jerk backward or forward, or the trunk may curve or straighten. The face, neck, jaw, tongue, ocular muscles, and diaphragm may twitch. According to Wilson, even fascicles of the platysma may twitch. Some muscle contractions cause no visible displacement of a limb. In this and other forms of myoclonus, the muscle contraction is brief (20 to 50 ms)—i.e., faster than that of chorea, with which it may be confused. The speed of the myoclonic contraction is the same whether it involves a part of a muscle, a whole muscle, or a group of muscles. Some of the patients register little complaint, accepting the constant intrusions of motor activity with stoicism; they generally lead relatively normal, active lives. Seizures, dementia, and other neurologic deficits are notably absent. Occasionally there is hint of a mild cerebellar ataxia and, in one family studied by R.D. Adams, essential tremor was present as well, both in family members with polymyoclonus and in those without. Both the tremor and myoclonus were dramatically suppressed by the ingestion of alcohol. Similar families have been observed by Marsden and colleagues. In a Mayo Clinic series reported by Aigner and Mulder, 19 of 94 cases of polymyoclonus were of this "essential" type.
Several of the sleep-related syndromes that involve repetitive leg movements include an element of myoclonus. In a few patients, mainly older ones with severe "restless legs syndrome," the myoclonus and dyskinesias may become troublesome in the daytime as well. These patients march in place and rock their bodies during sleep (Walters et al). These disorders are discussed in Chap. 19.
Myoclonic Epilepsy (See Also Myoclonic Seizures in Chap. 16)
Myoclonic epilepsy constitutes an important syndrome of multiple etiologies. A relatively benign idiopathic form, juvenile myoclonic epilepsy, has been mentioned and is discussed extensively in Chap. 16. A more serious type of myoclonic epilepsy, which in the beginning may be marked by polymyoclonus as an isolated phenomenon, is eventually associated with dementia and other signs of progressive neurologic disease (familial variety of Unverricht and Lundborg). An outstanding feature of the latter is a remarkable sensitivity of the myoclonus to stimuli of all sorts. If a limb is passively or actively displaced, the resulting myoclonic jerk may lead, through a series of progressively larger and more or less synchronous jerks, to a generalized convulsive seizure. In late childhood this type of stimulus-sensitive myoclonus is usually a manifestation of the juvenile form of lipid storage disease, which, in addition to myoclonus, is characterized by seizures, retinal degeneration, dementia, rigidity, pseudobulbar paralysis, and, in the late stages, by quadriplegia in flexion.
Another form of stimulus-sensitive (reflex) myoclonus, inherited as an autosomal recessive trait, begins in late childhood or adolescence and is associated with neuronal inclusions (Lafora bodies thus Lafora-body disease) in the cerebral and cerebellar cortex and in brainstem nuclei. In yet another familial type (described under the title of Baltic myoclonus by Eldridge and associates), autopsy has disclosed a loss of Purkinje cells but no inclusion bodies. Unlike Lafora-body disease, the Baltic variety of myoclonic epilepsy has a favorable prognosis, particularly if the seizures are treated with valproic acid.
Under the title of cherry-red-spot myoclonus syndrome, Rapin and associates have drawn attention to a familial (autosomal recessive) form of diffuse, incapacitating intention myoclonus associated with visual loss and ataxia. This disorder develops insidiously in adolescence. The earliest sign is a cherry-red spot in the macula that may fade in the chronic stages of the illness. The intellect is relatively unimpaired. The specific enzyme defect appears to be a deficiency of lysosomal alpha-neuroaminidase (sialidase), resulting in the excretion of large amounts of sialylated oligosaccharides in the urine. This has been referred to as type 1 sialidosis to distinguish it from a second type, in which patients are of short stature (as a result of chondrodystrophy) and often have a deficiency of beta-galactosidase in tissues and body fluids. In patients with sialidosis, a mucopolysaccharide-like material is stored in liver cells, but neurons show only a nonspecific accumulation of lipofuscin. A similar clinical syndrome of myoclonic epilepsy is seen in a variant form of neuroaxonal dystrophy and in the late childhood–early adult neuronopathic form of Gaucher disease, in which it is associated with supranuclear gaze palsies and cerebellar ataxia (Chap. 37).
Diffuse Myoclonus with Acquired Neurologic Disease
The clinical settings in which one observes widespread random myoclonic jerks as a transient or persistent phenomenon in adults include structural diseases such as viral encephalitis, Creutzfeldt-Jakob disease, general paresis, advanced Alzheimer and Lewy-body disease, and corticobasal ganglionic degeneration (the degenerative types are discussed in Chap. 39), occasionally in Wilson disease, and more often with acquired metabolic disorders (prototypically uremic and anoxic encephalopathy) and certain drug intoxications, notably with haloperidol, lithium, and amphetamines; Table 6-2 lists these and others. A subacute encephalopathy with diffuse myoclonus may occur in association with the autoantibodies that are characteristically a component of Hashimoto thyroiditis and also in Whipple disease (both are discussed in Chap. 40). An acute onset of polymyoclonus with confusion occurs with lithium intoxication; once ingestion is discontinued, there is improvement (slowly over days to weeks) and the myoclonus is replaced by diffuse action tremors, which later subside. Diffuse, severe myoclonus may be a prominent feature of early tetanus and strychnine poisoning.
Table 6–2 Causes of Generalized and Regional Myoclonus ||Download (.pdf)
Table 6–2 Causes of Generalized and Regional Myoclonus
Epileptic forms (myoclonic epilepsies)
Benign epilepsy with rolandic spikes
Juvenile myoclonic epilepsy
Infantile spasms (West syndrome)
Cherry-red-spot myoclonus (sialidase deficiency)
Myoclonus epilepsy with ragged red fibers (MERRF)
Ceroid lipofuscinosis (Kufs disease)
Epilepsia partialis continua
Essential and heredofamilial forms
Subacute sclerosing panencephalitis
Familial progressive poliodystrophy
Alzheimer, Lewy-body, and Wilson diseases (occasional in late stages)
Whipple disease of the central nervous system
Corticobasal ganglionic degeneration
Myoclonus with cerebellar disease (myoclonic ataxia)
Opsoclonus-myoclonus syndrome (paraneoplastic [anti-Ri], neuroblastoma, post- and parainfectious)
Postanoxic myoclonus (Lance Adams type)
Ramsay-Hunt dyssynergia cerebellaris myoclonica
Metabolic, immune, and toxic disorders
Cerebral hypoxia (acute and severe)
Haloperidol and sometimes phenothiazine intoxication
Hepatic encephalopathy (rare)
Nicotinic acid deficiency encephalopathy
Other drug toxicities
Focal and spinal forms of myoclonus
Herpes zoster myelitis
Other unspecified viral myelitis
Traumatic spinal cord injury
Arteriovenous malformation of spinal cord
Subacute myoclonic spinal neuronitis
Paraneoplastic spinal myoclonus
Polymyoclonus that occurs in the acute stages of anoxic encephalopathy should be distinguished from postanoxic action or intention myoclonus that emerges with recovery from cardiac arrest or asphyxiation (it is discussed below and in Chap. 40). The factor common to all these disorders is the presence of diffuse neuronal disease.
Myoclonus in association with signs of cerebellar incoordination, including opsoclonus (rapid, irregular, but predominantly conjugate movements of the eyes in all planes as described in Chap. 14) is another syndrome of both children and adults. Most cases run a chronic course, waxing and waning in severity. Many of the childhood cases are associated with occult neuroblastoma, and some have responded to the administration of corticosteroids. In adults, a similar syndrome has been described as a remote effect of carcinoma (mainly of lung, breast, and ovary as discussed at length in Chap. 31), but it also occurs at all ages as a self-limited manifestation of a benign postinfectious (possibly viral) illness as described by Baringer and colleagues.
As mentioned above, diffuse myoclonus is a prominent and often early feature of the prion transmissible illness Creutzfeldt-Jakob disease, characterized by rapidly progressive dementia, disturbances of gait and coordination, and all manner of mental and visual aberrations (see Chap. 33). Initially the jerks are random but late in the disease they may attain an almost rhythmic and symmetric character. In addition there is an exaggerated startle response, and violent myoclonus may be elicited by tactile, auditory, or visual stimuli in advanced stages of the disease. In this condition too, there is a progressive destruction of neurons, mainly but not exclusively in the cerebral and cerebellar cortices, and a striking degree of gliosis. In addition to parenchymal destruction, the cortical tissue shows a fine-meshed vacuolation, hence the designation subacute spongiform encephalopathy.
In yet another group of myoclonic dementias, the most prominent associated abnormality is a progressive deterioration of intellect. Like the myoclonic epilepsies, the myoclonic dementias may be sporadic or familial and may affect both children and adults. A rare childhood type is subacute sclerosing panencephalitis (SSPE), which is an acquired subacute or chronic (occasionally remitting) disease related to a latent infection with the measles virus (Chap. 33).
Intention or Action (Postanoxic) Myoclonus
This type of myoclonus was described by Lance and Adams in a group of patients who were recovering from hypoxic encephalopathy. When the patient is relaxed, the limb and other skeletal muscles are quiet (except in the most severe cases); only seldom does the myoclonus appear during slow, smooth (ramp) movements. Fast (ballistic) movements, however, especially when directed to a target, as in touching the examiner's finger, elicit a series of irregular myoclonic jerks that differ in speed and rhythmicity from intention tremor. For this reason it was called intention or action myoclonus. Only the limb that is moving is involved; hence it is a localized, stimulus-evoked myoclonus. Speech may be fragmented by the myoclonic jerks, and a syllable or word may be almost compulsively repeated, as in palilalia.
Action myoclonus is almost always associated with cerebellar ataxia. The pathologic anatomy has not been entirely ascertained. Lance and Adams found the irregular discharges to be transmitted via the corticospinal tracts, preceded in some cases by a discharge from the motor cortex. Chadwick and coworkers postulated a reticular loop reflex mechanism, while Hallett and colleagues (1977) found that a cortical reflex mechanism was operative in some cases and a reticular reflex mechanism in others. Whether these are two aspects of one mechanism could not be decided.
Barbiturates and valproic acid have been helpful in some cases. Several clinical trials and case reports have suggested that the antiepileptic levitiracetam may be useful (Krauss et al, 2001). The use of 5-hydroxytryptophan alone or in combination with tryptophan or other drugs had been recommended in the past (van Woert et al). A combination of several of these medications is usually required to make the patient functional.
Spinal or Segmental Myoclonus (See Also Subacute Spinal Neuronitis in Chap. 44)
The notion that monophasic-restricted myoclonus always emanates from the cerebral cortex, cerebellum, or brainstem cannot be sustained, as there are forms that are traceable to a purely spinal cause. The problem takes the form of an almost continuous arrhythmic jerking of a restricted group of muscles, often on one side of the body. Such a subacute spinal myoclonus of obscure origin was described many years ago by Campbell and Garland, and similar cases continue to be cited in the literature. We have seen several in which myoclonus was isolated to the musculature of the abdominal or thoracic wall on one side or to the legs; only rarely were we able to establish a cause, and the spinal fluid has been normal. This form has been referred to as "propriospinal" when it involves repetitive flexion or extension myoclonus of the torso that is aggravated by stretching or action.
Examples of myelitis with irregular and strictly segmental myoclonic jerks (either rhythmic or arrhythmic) have been reported in humans and have been induced in animals by the Newcastle virus. Many such myelitic cases involve the legs or a few muscles of one leg. In our experience, this type of myoclonus has occurred following zoster myelitis, postinfectious transverse myelitis, and rarely with multiple sclerosis, epidural cord compression, or after traumatic spinal injury. A paraneoplastic form has also been described, usually associated with breast cancer (Chap. 31). When highly ionic contrast media was in the past used for myelography, painful spasms and myoclonus sometimes occurred in segments where the dye was concentrated by a block to the flow of spinal fluid.
Treatment is difficult and one resorts to a combination of antiepileptic drugs and benzodiazepines, just as in cerebral myoclonus. The glycine inhibitor levetiracetam reportedly has been successful when other drugs have failed (Keswani et al).
Pathophysiology of Polymyoclonus
It seems logical to assume that myoclonus is caused by abnormal discharges of aggregates of motor neurons or interneurons because of the directly enhanced excitability of these cells or the removal of some inhibitory mechanism. Sensory relationships are a prominent feature of polymyoclonus, particularly those related to metabolic disorders, and will eventually shed some light on the mechanism. Flickering light, a loud sound, or an unexpected tactile stimulus to some part of the body initiates a jerk so quickly and consistently that it must utilize a direct sensorimotor pathway or the mechanism involved in the startle reaction. Repeated stimuli may recruit a series of incremental myoclonic jerks that culminate in a generalized convulsion, as often happens in the familial myoclonic syndrome of Unverricht-Lundborg. However, evidence implicating cortical hyperexcitability in myoclonus is only indirect, being based mainly on the finding that the cortical components of the somatosensory evoked potential are exceedingly large and that in some instances, the myoclonic jerks have a strict time relationship ("time-locked") to preceding spikes in the contralateral rolandic area (Marsden et al; Brown et al). Conversely, it is just as likely that these potentials originate from subcortical structures that project both to the descending motor pathways and upward to the cortex. In humans, the indication is that postanoxic action myoclonus has its basis in reflex hyperactivity of the reticular formation and that the only consistent damage is in the cerebellum rather than in the cerebral cortex (see above, under "Intention or Action Myoclonus"). As already noted, several types of myoclonus are closely coupled with cerebellar cortical degenerations.
Pathologic examinations have been of little help in determining the essential sites of this unstable neuronal discharge because in most cases, the neuronal disease is so diffuse. Nonetheless, the most restricted lesions associated with myoclonus are located in the cerebellar cortex, dentate nuclei, and pretectal region. A removal of the modulating influence of the cerebellum on the thalamocortical system of neurons has been postulated as a mechanism, but it is uncertain whether the disinhibited motor activity is then expressed through corticospinal or reticulospinal pathways. For example, pentylenetetrazol (Metrazol) injections evoke myoclonus in the limbs of animals, and the myoclonus persists after transection of corticospinal and other descending tracts until the lower brainstem (medullary reticular) structures are destroyed.