Clinical manifestations

Presentation and course

The presentation of myoclonus varies with etiology. There may be an acute presentation in hypoxia, vascular, or drug side effects. A subacute presentation is characteristic for infectious, inflammatory, and metabolic causes. Chronic onset occurs with neurodegeneration, neoplasm, and inborn errors of metabolism due to genetic mutations.

Major clinical categories of myoclonus are distinguished by presentation and course. Physiologic myoclonus occurs in a benign setting without true neurologic dysfunction, such as jerking during sleep. Essential myoclonus etiologies are clinically stable with minimal disability and no widespread neurologic dysfunction. Epileptic myoclonus manifests from seizures within epileptic syndromes. Symptomatic myoclonus is secondary to a medical or neurologic disorder and as such, the myoclonus is usually just 1 of multiple significant clinical problems for the patient.

Myoclonic jerks can range from mild muscular contractions with small amplitude movement to gross jerks affecting the whole body (30). The movements may be in a variety of distributions and either symmetric or asymmetric. The disability from myoclonus arises from loss of muscle control during the jerking. In the lower extremities, abnormal balance and walking may result.

Myoclonus is often stimulus- and activity-sensitive.

Sudden and unexpected noise, bright lights, or muscle stretch can trigger a myoclonic jerk. The jerks may be present at rest or may be triggered or aggravated by attempts to perform fine movements. Myoclonus may be rhythmic, in which case, it is usually due to a focal lesion of the spinal cord or brainstem (segmental myoclonus). As a result of the rhythmicity, some refer to this as tremor instead of myoclonus.

Focal myoclonus involves a small group of muscles. In cortical myoclonus the jerks are usually more distal than proximal and more flexor than extensor. Cortical myoclonus is typically stimulus sensitive (except when of small amplitude) and may be precipitated by sudden loud noise or a visual stimulus. Epilepsia partialis continua refers to repetitive focal cortical myoclonus with some rhythmicity (84). Cortical myoclonus is frequently multifocal, rather than focal. Palatal myoclonus is usually rhythmic.

In some patients, the movements may resemble tremor; however, in most, they have a jerky component, justifying usage of the term “myoclonus” (segmental myoclonus). Palatal myoclonus is usually continuous, independent of rest, action, sleep, or distraction. It may occur unilaterally or bilaterally and results in 1.5 to 3 Hz movements that may also involve other muscles, including those of the eye, tongue, neck, and diaphragm (136). There may be an associated rhythmic clicking noise that is more likely to occur in cases of essential palatal myoclonus as compared to symptomatic palatal myoclonus (58).

Multifocal myoclonus is characterized by individual jerks affecting different parts of the body and usually occurring at random times. Cortical myoclonus is often multifocal. In generalized myoclonus, each jerk affects a large area or the entire body at the same instant. Either form can be stimulus sensitive. Generalized myoclonus is often of cortical-subcortical physiologic origin, such as in the jerks of juvenile myoclonic epilepsy. It can also be subcortical-nonsegmental, such as in reticular reflex myoclonus. Generalized myoclonus may be triggered by external stimuli and aggravated by action. In reticular reflex myoclonus, the origin of electrical discharge is usually in the brainstem. In this type of myoclonus, proximal muscles are more affected than distal ones and flexors are more active than extensors (85). Minipolymyoclonus is a form of multifocal myoclonus and is characterized by small jerks in different locations (169). This term has also been used to describe small amplitude jerks in patients with spinal muscular atrophy. The distinction can be made by the company these jerks keep (ie, evidence of denervation in spinal muscular atrophy). However, describing these jerks as small and multifocal is also adequate because such myoclonus may be cortical. Another type of cortical myoclonus is cortical tremor, which results in fine, shivering finger twitching provoked mainly by action and posture and may be phenomenologically similar to essential tremor (91). Cortical tremor may be familial (64). Orthostatic myoclonus manifests as leg shaking when standing, similar to orthostatic tremor. In contrast to orthostatic tremor, orthostatic myoclonus produces difficulties with gait and has a much higher prevalence of associated neurologic problems (88). Instead of the rhythmic 13 to 16 Hz surface EMG discharges that are seen with orthostatic tremor, orthostatic myoclonus shows much discharge duration variability with many brief discharges (< 100 ms).

Accompanying clinical features of myoclonus depend on its etiology. Progressive myoclonic epilepsies are a heterogeneous group of disorders associated with multifocal or generalized myoclonus and epileptic seizures. Under this category, 2 major groups exist: (1) the progressive myoclonic epilepsies and (2) the progressive myoclonic ataxias (04). Progressive myoclonic epilepsies refer to a combination of severe myoclonus, generalized tonic-clonic or other seizures and progressive neurologic decline, particularly dementia. Progressive myoclonic ataxia (also known as Ramsay Hunt syndrome) is distinguished from progressive myoclonic epilepsy as seizures are mild or absent, with ataxia as the major problems.

Startle syndromes are characterized by an exaggerated startle response to a surprise stimulus. The normal startle response consists of blink and activation of other craniocervical muscles with a latency between the stimulus and EMG activity of 30 to 40 milliseconds (170). Normal persons habituate quickly. Hyperekplexia refers to a familial condition in which symptoms start in infancy. Enhanced startle response occurs to any type of stimulus, with generalized stiffening and falling to the ground. The EMG latency is shorter than the normal startle response, and burst duration is brief (53). There may be an EEG correlate, and enhanced somatosensory evoked potentials have been described (111).

Certain startle disorders have been labelled “culture-specific”-startle syndromes in reviews of myoclonus even though the link between the conditions, if any, is not well understood. For example, "latah" seen primarily in Indonesia and Malaysia characterized clinically by exaggerated startle responses associated with vocalizations, echolalia, and echopraxia has been found to be have 2 phases for the startle response: a short latency motor startle reflex initiated in the lower brainstem (less than 100/120 ms) and a later, second phase more influenced by psychological factors (the "orienting reflex") 100/120 to 1000 ms after the stimulus) (14). The authors concluded that latah should be considered as a "neuropsychiatric startle syndrome." Other such syndromes include “jumping Frenchman of Maine” and “myriachit” in Siberia. Common to all these culture-specific startle syndromes are a non-fatigable startle response followed by bizarre and stereotyped behaviors believed to be related to the culture. Besides echolalia and echopraxia that occurs in latah, there are reports of forced obedience, coprolalia, and strange motor actions (61). Reliable treatment options are virtually unknown.

Asterixis usually occurs with multifocal myoclonus in the setting of a metabolic encephalopathy and is generalized. Focal asterixis may be seen in lesions of the thalamus, putamen, or parietal lobe.

Prognosis and complications

The prognosis depends on the underlying disorder causing myoclonus. No complications are related to isolated myoclonic jerks, but accompanying seizures may lead to hypoxia, injuries, and aspiration.

Clinical vignette

The patient, a 21-year-old, right-handed, female college student, presented with 16 years of involuntary movements. At the age of 5, she began experiencing jerking of the head from right to left in the horizontal plane. By the age of 10, the jerking involved her upper extremities and slowly spread to her lower extremities. The patient denied an urge to move and could not suppress the movements. Family history revealed jerky movements in her sister and brother along with slight torticollis. Examination revealed mild rotational torticollis and myoclonic jerks most prominent in the head and proximal upper extremities. The remainder of the neurologic examination, brain MRI, and EEG were normal.

Biological basis

Etiology and pathogenesis

Causes of myoclonus can be divided into the clinical presentation categories: physiological, essential, epileptic, and symptomatic. Most causes of myoclonus are symptomatic (34). Several types of symptomatic myoclonus are described in the following paragraphs. Psychogenic jerks or spasms occur in patients with a conversion disorder or malingering. Typical features include inconsistent character (amplitude, frequency, distribution), associated psychopathology, distractibility, suggestibility, acute onset, spontaneous remissions, and improvement with placebo (124). Each category is discussed below, including common etiologies from each category.

Physiological myoclonus. Physiological myoclonus refers to muscle jerks occurring in certain circumstances in normal subjects such as hypnic jerks and hiccough (singultus). There is evidence that the origin of hypnic jerks arises from the brainstem (41). Certain types of myoclonus during sleep have been quantified (67). Fragmentary myoclonus during sleep was present in all healthy individuals, whereas neck myoclonus was found in 35%. Some individuals (without complaints) had movements that were “excessive” by published criteria. For all cases of myoclonus during sleep, the clinical consequences of the movement in question, not just its amplitude or frequency, are paramount.

Essential myoclonus. Essential myoclonus presents with myoclonus as the primary symptom, with a nonprogressive course overall. Onset is usually young with a chronic course. The term “essential” is attached to this syndrome because of its monosymptomatic prominence of the myoclonus and the chronic course. The disability associated with the myoclonus is usually minimal and the patient has functional abilities. Essential myoclonus is divided into hereditary and sporadic forms. Sporadic myoclonus has been difficult to characterize because these cases seem heterogeneous in clinical appearance. It is suspected that these cases may represent yet undiscovered static lesions or genetic abnormalities. Hereditary forms of essential myoclonus are much more uniform than in sporadic myoclonus. The majority of hereditary essential myoclonus cases, with genetic basis, have been described clinically as the myoclonus-dystonia syndrome.

Myoclonus-dystonia. Familial myoclonus-dystonia presents with brief, “lightning-like” myoclonic jerks with predominance in the neck and upper limbs. Diagnostic criteria for myoclonus-dystonia (DYT 11) include (1) onset of myoclonic in first or second decade of life with mild dystonic features, (2) males and females equally affected, (3) a benign course compatible with normal life span, (4) autosomal dominant mode of inheritance with incomplete penetrance, (5) absence of other neurologic deficits, (6) normal EEG and neuroimaging (73). Mild dystonia often presents as cervical dystonia or task-specific focal dystonia (47). The myoclonus can be rhythmic or arrhythmic, action provoked, or alcohol-responsive.

Various combinations of myoclonus and dystonia in members of the same family have been seen.

Several investigators have reported an association with intellectual disability and psychiatric disturbances: obsessive-compulsive disorder, panic attacks, and alcoholism (47; 140).

Epileptic myoclonus. This category of myoclonus occurs in the setting of a seizure disorder and often is accompanied by EEG abnormalities, such as generalized spike and wave discharges (30). In children, myoclonus is usually associated with epilepsy. The major syndromes include infantile spasms and Lennox-Gastaut syndrome (20; 69). It is important to distinguish infantile spasms from benign myoclonus of infancy where EEG is normal and the course is nonprogressive (60). Juvenile myoclonic epilepsy (JME) is the classic idiopathic epileptic disorder in which myoclonus can present with various seizure types, including myoclonic, absence, and generalized. For JME, a history that asks about early morning jerks is critical because most JME cases present with generalized tonic-clonic seizures (72).

Symptomatic myoclonus. Progressive myoclonus epilepsy-ataxia (PME/PMA) (including genetic metabolic disorders).

Progressive myoclonic epilepsy. Progressive myoclonic epilepsy is characterized by cortical myoclonus, myoclonic seizures, tonic-clonic seizures, and neurologic deterioration that includes dementia. Myoclonus is typically multifocal, action-induced, and precipitated by external stimuli such as touch, sound, or light (16). The following conditions may cause progressive myoclonic epilepsy:

Neurodegenerative and other dementia syndromes. Dementia and myoclonus commonly coexist in neurodegenerative syndromes such as Creutzfeldt-Jakob disease, Alzheimer disease, and Lewy body disease (33; 89). Some cases of Creutzfeldt-Jakob disease present with myoclonus and dementia that progress rapidly (142). In a series of 150 patients with variant Creutzfeldt-Jakob disease, myoclonus and chorea were the most common movement disorders (89). In the elderly, myoclonus associated with clinical parkinsonism, originating from a cortical source due to a variety of disorders, is common (100). On rare occasion, myoclonus can occur in older individuals without other symptoms of neurodegenerative disease (03).

Myoclonus has also been described in patients with Parkinson disease, with or without dementia. It usually occurs distally and bilaterally, affecting the patient’s wrist and fingers. It is characteristically provoked during action, irregular, small amplitude, and multidirectional, with an average frequency of 1 jerk every 1 to 5 seconds. The myoclonus is smaller than that seen in dementia with Lewy bodies but still of cortical origin. No relation to levodopa or motor severity of parkinsonism exists (30).

Infectious syndromes. Viral and postviral syndromes may cause myoclonus.

Acquired metabolic syndromes. Multifocal myoclonus is frequently due to metabolic causes, including hepatic failure, uremia, hyponatremia, hypoglycemia, and nonketotic hyperglycemia. Asterixis results in lapses of maintained postures and is considered a form of negative myoclonus (173). It usually occurs in conjunction with metabolic derangements, such as hepatic encephalopathy.

Drug-induced and toxic syndromes. Drugs inducing myoclonus include anticonvulsants, narcotics, levodopa, lithium and other psychiatric medications, and selegiline. Lithium has been described to cause multifocal action myoclonus of cortical origin without epileptiform abnormalities on routine EEG at toxic and therapeutic doses (29). However, back averaging reveals evidence of a focal EEG transient in the contralateral sensorimotor area preceding the myoclonic jerk. Various anesthetic agents have been reported to cause transient myoclonus that requires no treatment. Mefloquine, used in chloroquine-resistant P falciparum malaria, caused multifocal myoclonus in 1 patient (93). Amantadine has been reported to cause cortical myoclonus (117). Tardive myoclonus has been described following exposure to long-term neuroleptics (107). Newer antiepileptic drugs such as lamotrigine (02), gabapentin (57), carvedilol (a beta-blocker) (66), flecainide (anti-arrhythmic) (165), and antibiotics such as gatifloxacin (110) have been reported to induce myoclonus. Pregabalin, with or without renal insufficiency, can cause myoclonus (48). Toxic encephalopathies causing myoclonus include bismuth, methyl bromide, and toxic cooking oil (128).

Static encephalopathies secondary to diffuse brain injuries. Lance-Adams syndrome refers to action myoclonus occurring after hypoxic brain injury with associated asterixis, seizures, and gait problems (106). Newer studies have emphasized the difference between acute posthypoxic myoclonus and chronic posthypoxic myoclonus (81). Acute posthypoxic myoclonus arises immediately to within a day after the hypoxia, usually less than 24 to 48 hours, is generalized in the setting of coma, and may arise from rest or be evoked by stimulus. Chronic posthypoxic myoclonus is the classically described “Lance-Adams syndrome”. It occurs after some neurologic recovery of mental status, is multifocal, and arises most commonly with muscle activation (action myoclonus). Acute posthypoxic myoclonus is associated with a poorer prognosis regardless of whether hypothermia is used (158). Chronic posthypoxic myoclonus has long been established to be of cortical origin. There is now more evidence that acute posthypoxic myoclonus arises from the brainstem as reticular reflex myoclonus (129). This is important as it provides a way to distinguish between acute and chronic posthypoxic myoclonus, which is critical for driving treatment decisions.

Malabsorption syndromes. Multiple malabsorption disorders may cause myoclonus (30).

Paraneoplastic, other autoimmune, and idiopathic inflammatory syndromes.

(A) Opsoclonus-myoclonus syndrome. Opsoclonus-myoclonus presents with progressive opsoclonus (irregular, rapid eye movements) and multifocal or generalized myoclonus (37). Opsoclonus-myoclonus in adults is idiopathic in about 50% of cases. The second most common cause is paraneoplastic, usually from ovarian cancer, malignant melanoma (95), renal cell carcinoma (167), and lymphoma. Opsoclonus has also been reported as a paraneoplastic syndrome secondary to a benign teratoma (98). The ANNA2 (Anti-Ri) antibody has been associated in this syndrome secondary to breast and ovarian cancer, and rarely ANNA1 (Anti-Hu) has been demonstrated in patients (132). Patients with GAD-abs may present with opsoclonus-myoclonus and should undergo a thorough search for underlying cancer (06). Idiopathic opsoclonus-myoclonus occurs in younger patients, and the clinical evolution is more benign (07). It has also been associated with viral infections such as West Nile virus (01). Neuroblastoma is a major consideration in children, mainly in tumors with diffuse and extensive lymphocytic infiltration. In children, an aggressive search for occult neuroblastoma is indicated. Interestingly, antibodies associated with opsoclonus-myoclonus syndrome have been found to attack dendritic neuronal surface antigens, a finding with pathophysiology implications (131). Other causes include drugs, toxins, nonketotic hyperglycemia and celiac disease (171; 55).

(B) There are a growing number of described paraneoplastic and autoimmune disorders associated with myoclonus and a variety of antibodies (12; 11). One such disorder is anti-N-methyl-D-aspartate receptor encephalitis, which can be seen in children and adults and is associated with a variety of psychiatric symptoms as well as movement disorders including chorea, stereotypies, dystonia, myoclonus, and myorhythmia (13). Both GABA-A and glycine receptor antibodies can produce myoclonus and/or stiff-person syndrome in patients (56; 172). Antibodies to voltage-gated potassium channels have been discovered in patients with myoclonus (154). This syndrome may present similar to Creutzfeld-Jakob disease, but is important to diagnose because response to therapy may be seen. The immunology of this antibody has become more complex because it has been suggested that other antigens are actually causing the voltage-gated potassium channel clinical syndromes (12). Other rare antibody-associated myoclonus syndromes have been associated with thyroid-stimulating hormone antibodies (28) and Ophelia syndrome (105). In such disorders, a comprehensive search for possible antibodies and cancer presence is needed.

Pathophysiology. Myoclonus occurs as a result of excessive discharge from a group of neurons. This electrical discharge then spreads up and down the neuraxis through rapidly conducting pathways as in cortical myoclonus (86) or slowly conducting pathways as in propriospinal myoclonus (22). The pattern and timing of activation of different muscles, as a result of this discharge, may give a clue to the site of origin of the abnormal discharge. Given that this information has implications for diagnosis and treatment, the clinician should be aware of these concepts. The spread of discharge is usually so fast that the details cannot be appreciated by the naked eye, necessitating neurophysiologic studies.

The specific methods used in the neurophysiological 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). Positive and negative findings from these methods can then be used to provide evidence for determining the physiological type of myoclonus (29). For example, a back averaged focal cortical EEG transient, enlarged cortical SEP, and enhanced long EMG responses suggest cortical origin myoclonus (147). The main physiological categories for myoclonus classification are cortical, cortical-subcortical, subcortical-nonsegmental, segmental, and peripheral.

Cortical myoclonus. The cortex is the most common source for myoclonus and has been reported for various neurodegenerative diseases, toxic-metabolic conditions, posthypoxic state (Lance-Adams syndrome), storage disorders, and other conditions. Cortical myoclonus is defined as involuntary brief muscle jerks originating from an abnormal discharge of the cerebral cortex. Typically stimulus-sensitive, these cortical discharges preceding the myoclonic jerk can be demonstrated in routine EEG or more consistently by back averaging (147). Patients with cortical myoclonus may display high amplitude (“giant”) somatosensory evoked potentials (P1-N2 component) indicating hyperexcitability. C-reflexes may be seen, EMG activity subsequent to the generation of a giant somatosensory potential (128). Any type of cortical lesion, including tumors, angiomas, and encephalitis, may be associated with focal cortical myoclonus. Huntington disease may cause cortical myoclonus (160; 38). Epilepsia partialis continua can occur in focal encephalitis as in Rasmussen syndrome (46), stroke, tumors, and, rarely, multiple sclerosis (90). Other disorders that may cause cortical myoclonus include Rett syndrome and Angelman syndrome (80; 79).

Cortical myoclonus results in focal or multifocal muscle jerks. The muscles are often activated in antagonist pairs. The duration of EMG bursts is usually short, in the range of 30 to 60 msec. The sequence of muscle activation is downward through the neuraxis so that the masseter muscle (fifth cranial nerve) is activated before the orbicularis oculi (seventh cranial nerve), which is followed by sternocleidomastoid (eleventh cranial nerve) (86).

The myoclonus seen in corticobasal degeneration differs from the typical cortical myoclonus in that the latency between the stimulus and the jerk is shorter. Additionally, somatosensory evoked responses are not enhanced, and abnormal cortical activity does not precede the jerk when using conventional EEG-EMG back averaging (161; 26).

Cortical-subcortical myoclonus. Cortical-subcortical myoclonus corresponds to the myoclonus in myoclonic and absence seizures. This physiology is believed to involve interactions of cortical and subcortical centers, such as the thalamus (30). These jerks are usually bilaterally synchronous or generalized.

Subcortical-nonsegmental myoclonus. Subcortical-nonsegmental myoclonus is seen in essential myoclonus and reticular reflex myoclonus, among others. The myoclonus arises from areas below the cortical level, and the resulting myoclonus distribution spreads distant to the source and multiple segmental levels.

Reticular reflex myoclonus is associated with generalized jerks that may occur spontaneously or be stimulus-sensitive (85). The pattern and timing of muscle activation suggests that the origin of the impulse is in the caudal brainstem from where it spreads both rostrally and caudally. The origin of the reticular formation implicated in certain forms of reticular reflex myoclonus is the nucleus reticularis gigantocellularis. When cranial nerves are involved, the pattern of muscle activation suggests upward transmission of impulse (ie, orbicularis oculi is activated before the masseter) (85). The cortical potential, if present, is not focal and does not precede the myoclonic jerk. Giant somatosensory evoked potentials are not found, suggesting a lack of cortical hyperexcitability.

Essential myoclonus is characterized by EMG burst-length of 50 to 150 msec. The myoclonus-dystonia syndrome caused by DYT11 mutations has electrophysiology characteristics that suggest a subcortical origin (Li et al 2008; 109; 137).

Two major forms of myoclonus are now recognized to arise from the spinal cord: (1) segmental myoclonus (see below), affecting a restricted body part, and (2) propriospinal myoclonus, producing generalized axial movements (43). Propriospinal myoclonus, because of its ability to spread rostrally and caudally, is considered to be subcortical-nonsegmental myoclonus.

In propriospinal myoclonus, the discharge originates in the lower thoracic segments and spreads up and down the spinal cord through slowly conducting pathways (139). Diffusion tensor imaging and fiber tracking abnormalities exist in propriospinal myoclonus (138).

Segmental myoclonus. This myoclonus arises from segmental brainstem (palatal) or spinal generators (31). Symptomatic palatal myoclonus arises from a lesion of Guillain-Mollaret triangle, a pathway connecting the red nucleus to the inferior olivary nucleus (central tegmental tract), the inferior olivary nucleus to the dentate nucleus (inferior cerebellar peduncle), and the dentate nucleus to the red nucleus (superior cerebellar peduncle). Within the anatomic triangle of Guillain-Mollaret, lesions of the rubo-dentate fibers and rubo-olivary fibers may cause symptomatic palatal myoclonus; however, this is not the case for lesions of the olivo-dentate fibers (83). A latent period usually precedes the onset of myoclonus. In symptomatic palatal myoclonus, the inferior olivary nucleus shows a hypertrophic degeneration at autopsy (58). Microscopically, the neurons are enlarged with cytoplasmic vacuolation, astrocytic proliferation and aggregates of argyrophilic fibers consisting of fibrous astrocytes, and interwoven neurites. To date, no pathological abnormality has been identified in essential palatal myoclonus (59). One unconfirmed study showed hypermetabolism of the inferior olive as shown by positron emission tomography scanning (62). Functional MRI reveals neuronal activation bilaterally in the putamen, but not structures of the Guillain-Mollaret triangle in essential palatal myoclonus (83). This discovery implies that disinhibition of the putamen may be an essential component of essential palatal myoclonus.

It has been proposed that the term “palatal tremor” supplant “palatal myoclonus” to reflect the characteristic rhythmic quality of this hyperkinetic movement disorder (174). In contrast to tremor, an oscillatory movement generated by alternating or synchronous contractions of antagonist muscles, the palatal movement is produced by rhythmic contractions of agonists only; hence, we prefer the term “palatal myoclonus.” Moreover, there are patients in whom the oscillations are irregular. Symptomatic palatal myoclonus usually persists during sleep, whereas essential palatal myoclonus, frequently associated with an ear-clicking sound, disappears with sleep. In essential palatal myoclonus, the muscle agonist is the tensor veli palatini, which opens the eustachian tube and is innervated by the trigeminal nerve. In symptomatic palatal myoclonus, the palatal movement is due to contractions of the levator veli palatini (innervated by the facial nucleus and nucleus ambiguous). When the tensor muscle contracts, as in essential palatal myoclonus, the entire soft palate moves, whereas only the edges of the soft palate move when the levator muscle contracts in symptomatic (but not essential) palatal myoclonus. Palatal myoclonus is often associated with hypertrophy of the inferior olive. Reported etiologies include stroke, trauma, encephalitis, tumors, demyelinating lesions, and neurodegenerative disorders (92). No known origin exists for essential palatal myoclonus, and brain imaging is normal (58).

Spinal segmental myoclonus is typically confined to muscles innervated by adjacent spinal segments, may be rhythmic, and often persists during sleep (31). Spinal myoclonus is associated with inflammatory causes, cervical spondylosis, tumors (70), trauma (22), ischemic myelopathy (52), syringomyelia (76), and a variety of other causes (92). Occasionally, there is no identifiable cause. The possible mechanisms in “primary” spinal myoclonus include loss of inhibitory function, abnormal hyperactivity of local dorsal horn interneurons, aberrant local axon re-excitation, and loss of inhibition from suprasegmental descending pathways (25).

Peripheral myoclonus. Except for hemifacial spasm, peripheral myoclonus is rare. This has been described in lesions of the peripheral nerve (74), plexus (162), and root (92; 162). The “ephaptic” transmission of peripheral ectopically generated potentials has been proposed as a mechanism (115).

Biochemistry. The biochemical basis of myoclonus is probably heterogeneous. Some forms of myoclonus, including posthypoxic myoclonus, are characterized by reduced 5-hydroxyindoleacetic acid in the cerebrospinal fluid and may respond to administration of 5-hydroxytryptophan and carbidopa (164). In animals, myoclonus may be induced by pp-dichlorodiphenyltrichloroethane; it is improved by 5-hydroxytryptophan agonists and worsened by 5-hydroxytryptophan antagonists (164). However, myoclonus that is not stimulus sensitive may be produced by L-5-hydroxytryptophan (164). Myoclonus induced by L-dopa in Parkinson patients may improve with 5-hydroxytryptophan receptor blockers (101). Injections of GABA antagonists into the putamen may produce myoclonus (49).

Genetics. Progressive myoclonic epilepsy, Lafora disease, neuronal ceroid lipofuscinosis, Unverricht-Lundborg disease, and sialidosis are all autosomal recessive, whereas myoclonic epilepsy with ragged red fibers is maternally inherited. Numerous other epileptic disorders have had a genetic basis described (121).

In Unverricht-Lundborg disease, the gene has now been localized to the long arm of chromosome 21q 22.3 in Finnish and Mediterranean families. The effected gene encodes cystatin B, a cysteine protease inhibitor (94). The major mutation worldwide is an unstable expansion of a dodecamer repeat (CCCCGCCCCGCG) in the promoter region of the Cystatin B gene. Mutant cystatin B promotes the initiation of apoptosis. The normal repeat size is 2 or 3 copies whereas those with disease phenotype have 30 or more copies (145). Unlike many trinucleotide repeat disorders, neither age of onset nor overall severity correlate with length of the dodecamer repeat.

At least 3 genes underlie Lafora disease, of which 2 have been characterized: EPM2A and NHLRC1. The gene product of EPM2A is a protein phosphatase named laforin whereas NHLRC1 encodes malin, an E2 ubiquitin ligase that promotes degradation of laforin (123). Up to 80% of patients with Lafora disease harbor EPM2A mutations and tend to have a more severe clinical course with shorter life expectancy compared to NHLRC1 mutations.

The most common genetic defect present 90% of the time in myoclonic epilepsy with ragged red fibers involves an adenosine to guanine substitution in the tRNA gene, MTTK, in mitochondrial DNA (145). Another less common molecular defect is a tyrosine to cytosine substitution in the same gene.

Each form of neuronal ceroid lipofuscinosis is genetically distinct with an autosomal recessive inheritance pattern with the exception of the adult form, which may be autosomal dominant. The classic late infantile form may arise from various mutations in the tripeptidyl peptidase 1 gene. The genes implicated in the other 4 types of neuronal ceroid lipofuscinosis have been mapped to various chromosomes, but the function of the translated proteins remain unknown (145).

KCNC1 encodes potassium ion channel subunits that are involved in high frequency neuronal firing. A mutation in this gene, associated with loss of function, is a cause of progressive myoclonus epilepsy (125).

A new type of genetic abnormality in progressive myoclonus epilepsy has been found. A mutation in the nuclear lamin gene LMNB2 is associated with progressive myoclonus epilepsy with early ataxia (50). This mutation causes disruption of the organization of the nuclear lamina in neuron. This now includes defects in nuclear lamin proteins within the progressive myoclonus epilepsy phenotype.

Angelman syndrome is associated with developmental delay, epilepsy, ataxia, and myoclonus. Multiple genetic mechanisms for this syndrome include: (1) deletions within a critical region of 15q11.2-q13 on the maternal chromosome; (2) paternal uniparental disomy; (3) imprinting defects in maternal DNA methylation; and (4) mutations within the ubiquitin protein ligase E3A gene (75). Episodic tremors may actually be repetitive rhythmic cortical myoclonus (75).

Spinocerebellar ataxias (SCA) with defined genetic abnormalities may be associated with myoclonus. SCA3, or Machado-Joseph disease, is a notable example. Myoclonus in Thai families with SCA17 was documented (45).

Dentatorubral-pallidoluysian atrophy is a rare autosomal dominant neurodegenerative disorder caused by unstable CAG repeat expansion. As with many CAG repeat disorders, an inverse correlation exists between age of onset and repeat size. The gene product is located at 12p13.31 and encodes atrophin 1 (97). Dentatorubral-pallidoluysian atrophy shows prominent "anticipation," with a mean acceleration of age at onset of 27 years in paternal transmission and 14 years in maternal transmission (145).

Myoclonus is only rarely seen in the ataxia with oculoapraxia type 2 syndrome. In these cases, the mutation may be different than in those cases without myoclonus. For the myoclonus cases, mutations in SETX (Senataxin) and AFG3L2 are associated (108).

Loss-of-function mutations in the epsilon-sarcoglycan gene are causative in the majority of familial myoclonus-dystonia (DYT 11) cases. However, investigators report 30% cases with the typical phenotype lack the epsilon-sarcoglycan mutation (157). Myoclonus-dystonia is inherited as an autosomal dominant trait with incomplete penetrance. The mutant allele undergoes genomic imprinting during maternal inheritance leading to reduced expression of clinical features when compared to paternal transmission (140). Patients with the epsilon-sarcoglycan mutation demonstrate a particular pattern of truncal myoclonus and axial dystonia when compared to familial myoclonus-dystonia without the epsilon-sarcoglycan mutation. A calcium channel CACNA1B mutation has been found in a family with myoclonus-dystonia syndrome (77). This calcium channel is involved in regulating neurotransmitter release. Another genetic form of myoclonus-dystonia, designated as DYT26, is an autosomal dominant form of dystonia associated with myoclonic jerks affecting predominantly the upper limbs, but also craniocervical regions, trunk, and lower limbs, beginning in the first or second decade of life, due to mutation in the KCTD17 gene on chromosome 22q12 (118). According to a new nomenclature of genetic movement disorders, recommendations by the International Parkinson and Movement Disorder Society Task Force, the following forms of genetic myoclonus have been identified: DYT-SGCE, HSP-KIF1C, SCA-PRKCG, SCA-ATXN2, SCA-ATN1, CHOR/DYT-ADCY5, and C9orf72 (112).

Hereditary hyperekplexia, transmitted as an autosomal dominant trait, has been linked to chromosome 5q33-q35, and the abnormal gene has now been identified to a point mutation in the alpha-1 subunit of the glycine receptor.

The gene for familial adult myoclonic epilepsy (an autosomal dominant adult-onset condition characterized by “cortical tremor,” various degrees of myoclonus in the limbs, and a benign course) has been localized to chromosome 8q24 (135). The cortical tremor is an action and postural finger tremor with electrophysiologic features of cortical reflex myoclonus. The same phenotype showed linkage to chromosome 2p11.1-q12.2, indicating that this is a genetically heterogeneous condition (54).

Myoclonus has been reported with the 22q11.2 deletion syndrome (19). This disorder has been called many names and does occur in adults. Neuropsychiatric disorders, sometimes severe, seizures, parkinsonism, and tremor are variably associated in addition. Side effects from drug treatment for this disorder may produce or exacerbate myoclonus.

Epidemiology

Little is known about the frequency and distribution in the general population. The only available study is from Olmstead County, Minnesota (34). The average annual incidence of pathologic and persistent myoclonus from 1976 to 1990 was 1.3 cases per 100,000 person-years. The lifetime prevalence of myoclonus was 8.6 cases per 100,000. Symptomatic myoclonus was the most common type, followed by epileptic and essential myoclonus. Dementing disorders most commonly caused symptomatic myoclonus. The rate increased with advancing age and was consistently higher in men. It should be kept in mind that whereas toxic-metabolic and drug-induced cases of myoclonus are common, they are also transient and, therefore, missed during epidemiological studies.

Prevention

Prevention is possible only in drug-induced and toxic myoclonus.

Differential diagnosis

The differential diagnosis of an isolated myoclonic jerk includes chorea and tic. Isolated choreic jerk may be indistinguishable from myoclonus; however, choreic jerk is not stimulus sensitive and tends to be not as rapid as myoclonus. In its fully developed form, chorea results in continuous random, flowing, quick, and arrhythmic movements. Further, motor impersistence occurs such as inability to keep the tongue protruded and waxing and waning of the grip strength (milkmaid's grip). Tic refers to a movement that may be simple or complex. In contrast to myoclonus, tics may be preceded by premonitory sensations, and their execution may be delayed or suppressed. The voluntary suppression results in a buildup of inner tension that is relieved by the execution of the movement. In Tourette syndrome, multiple motor and vocal tics may be associated with coprolalia and obsessive-compulsive symptoms. Dystonic movements can be rapid and may be confused with myoclonus. The term myoclonus-dystonia refers to a combination of myoclonus and dystonia in other muscles. Terminal kinetic tremor and cerebellar ataxia may be severe enough to be confused with myoclonus. The 2 may coexist as in progressive myoclonic ataxia, and only after the treatment of myoclonus can the true severity of the underlying ataxia be appreciated. Some patients with postural tremor may have changes in amplitude, giving the impression of myoclonus, but rarely do these 2 conditions coexist.

Diagnostic workup

It is important to conduct an organized search for myoclonus etiology (35; 32). The initial approach can be derived from the clinical circumstances associated with the myoclonus, just as if the myoclonus was not present. This is a valid approach as most myoclonus etiologies are symptomatic (secondary to a variety of diseases and conditions). For example, if an infectious or inflammatory syndrome is present, a cerebrospinal fluid exam is necessary. Numerous drugs are known to cause or contribute to myoclonus, such as lithium, antidepressants, anti-infectious agents, and narcotics, among others. If a drug is suspected to be causative for a patient’s myoclonus, consideration should be given to cautiously decreasing or discontinuing the medication. The result of the medication change may be therapeutic as well as diagnostic. In parallel, the first step to focusing on the myoclonus is to derive from a history and physical examination the appropriate clinical myoclonus category among physiological, 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 myoclonus. When the cause of the myoclonus is unexplained even after this initial evaluation, the following minimal testing should be performed as the second step of the myoclonus evaluation.

This testing mainly evaluates metabolic, toxic, and structural brain lesions, seizure disorders, and cancer-related causes of myoclonus. Routine surface EEG may uncover epileptiform discharges or other diagnostic features, but may fail to show spikes in cortical reflex myoclonus, and may be normal in epilepsia partialis continua. Antibodies to voltage-gated potassium channels have been discovered in patients with myoclonus, and this often responds to treatment (154). If these tests do not reveal the diagnosis, then the next step is to consider more advanced testing. The clinical information gathered so far is instrumental for guiding a more comprehensive evaluation. This testing may include cerebrospinal fluid examination, enzyme activity, imaging for cancer, tissue biopsy, and other tests.

Cerebrospinal fluid should be examined if infection is suspected (144). In generalized and multifocal myoclonus, the metabolic workup should include testing for liver and kidney functions, blood gases, and measurement of blood sugar. In patients with progressive myoclonic epilepsy and progressive myoclonic ataxia, the diagnostic workup should include visual evoked responses and ERG to look for neuronal ceroid lipofuscinosis. Elevated plasma and cerebrospinal fluid lactate point to a mitochondrial encephalopathy. White cell or fibroblast lysosomal enzyme estimations are necessary, as is screening for urinary oligosaccharides and organic acids. Skin and conjunctival biopsy and electromicroscopy (to look for inclusions in nerves especially in eccrine sweat glands, in neuronal ceroid lipofuscinosis, Lafora body disease, and neuroaxonal dystrophy), muscle biopsy (to look for ragged-red fibers and to study mitochondrial metabolism), and jejunal biopsy (to look for celiac disease and Whipple disease). Anti-Ri antibodies may be positive in the opsoclonus-myoclonus syndrome.

An imaging study, preferably an MRI, should be performed to look for focal lesions. A SPECT activation study can be employed to determine the hyperexcitable region in cortical myoclonus (155). Palatal myoclonus needs to be investigated by an MRI to look for lesions in the Guillain-Mollaret triangle. Olivary hypertrophy may be appreciable on MRI along with hyperintensity on T2 sequences. The type and location of the lesion (ie, stroke vs. multiple plaques) will guide further workup. In spinal myoclonus, appropriate imaging studies are most important; examination of cerebrospinal fluid may be indicated. 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 both positive and negative results. If appropriate, genetic counseling is recommended.

In instances in which the cause of myoclonus is not known, detailed consideration of the myoclonus pathophysiology is recommended. The pathophysiologic mechanism of the myoclonus compliments its placement within the etiologic classification scheme. Ascertainment of myoclonus pathophysiology in the clinic setting is feasible because the pathophysiology of myoclonus may be probed with noninvasive clinical neurophysiology testing (29). The goal of such evaluation is to classify the physiology of the myoclonus among cortical, cortical-subcortical, subcortical-nonsegmental, segmental, and peripheral. Definition of the myoclonus physiology has strong implications for neurologic localization, diagnosis, and treatment. This information can assess the diagnostic evaluation by incorporating it with the other evaluation results and clinical circumstances. Surface EMG polymyography involves recording the duration, distribution, and stimulus sensitivity of EMG activity in affected muscles to determine the sequence of contractions. Combined EEG-EMG digital recording may be used to correlate EEG changes with myoclonus EMG discharges, including the use of back averaging to elicit a discernible premyoclonus EEG transient. Other studies include measurement of C-reflexes to look for reflex production of myoclonus (147), and somatosensory evoked responses to look for giant somatosensory evoked potentials. Electrophysiological analysis of myoclonus can not only confirm its source but also provide subclassification or reclassify myoclonus in a significant number of instances (176).

Management

The most important initial step is to try to classify the type of myoclonus and to identify the underlying disease process. The underlying conditions should be treated or reversed if possible. If the myoclonus cause is unknown, or if the underlying etiology cannot be reversed, then a treatment approach is best formulated on the basis of neurophysiological classification (cortical, cortical-subcortical, subcortical-nonsegmental, segmental, peripheral) (32). For all myoclonus treatments, controlled evidence is limited, and multiple treatment trials are often necessary. In most instances, symptom suppression may require polypharmacy for optimal response but can also be problematic with regard to side effects. Follow-up of treatment response and side effects is advised.

Cortical myoclonus treatment. A number of different drugs have been used for the symptomatic control of cortical myoclonus. Levetiracetam has been reported to alleviate cortical myoclonus (71; 102; 99). Brivaracetam is similar in chemistry to levetiracetam and piracetam. However, brivaracetam’s efficacy for cortical myoclonus has not been confirmed (96). Other effective drugs for cortical myoclonus are clonazepam (4 to 10 mg per day), sodium valproate (250 to 4500 mg per day), and piracetam (10 to 24 g per day). For generalized myoclonus immediately posthypoxia, anesthetic agents may suppress the myoclonus, but the overall prognosis of the patient may remain poor (159). Somewhat less effective drugs include lisuride, acetazolamide, and carbamazepine. Several of these drugs can be used in combination to obtain a response, but side effects commonly limit this option. Moreover, polytherapy is difficult to evaluate. Phenytoin may worsen the cortical myoclonus of progressive myoclonic epilepsy as well as other instances of cortical myoclonus (63). Acetazolamide may be helpful in myoclonus of Ramsay Hunt syndrome. Negative myoclonus often resolves with the correction of the responsible metabolic derangement, and ethosuximide may be particularly useful in the symptomatic treatment (148). In uncontrolled studies, sodium oxybate improved posthypoxic myoclonus (cortical) (08). Intrathecal baclofen was reported to be beneficial in case reports of posthypoxic myoclonus (18). Deep brain stimulation is not a clear choice for cortical myoclonus therapy at this time (152). However, a case report showed success in Lance-Adams syndrome with bilateral globus pallidus stimulation (09).

Cortical-subcortical myoclonus treatment. Juvenile myoclonic epilepsy is the classic example of cortical-subcortical myoclonus. Controlled evidence favors valproic acid as the major drug of choice (168). Despite the lack of definitive evidence, valproic acid is used for other myoclonic seizure disorders (24). Lamotrigine can be used alone or used as an adjunct to valproic acid (23). Levetiracetam has also been used as a second line drug for cortical-subcortical myoclonus in primary generalized epilepsy. Brivaracetam has similar efficacy in this myoclonus physiology type, but because fewer side effects may occur with it compared to levetiracetam, a switch to brivaracetam may be advantageous (153). Caution needs to be used when treating with certain antiseizure medications because some agents can worsen the myoclonus or seizures in these disorders (120). The treatment of less common myoclonic epilepsy syndromes can be challenging (143).

Subcortical-nonsegmental myoclonus treatment. Essential myoclonus may be improved by clonazepam or anticholinergics (44). For those essential myoclonus examples that represent the myoclonus-dystonia syndrome, increasing reports are suggesting that deep brain stimulation surgery provides significant therapeutic benefit. Whereas earlier attempts targeted the ventral intermediate thalamic nucleus, more recent reports have targeted the globus pallidus (103). Multiple studies on globus pallidus stimulation have shown greater than 50% improvement in the myoclonus and dystonia of patients with myoclonus-dystonia syndrome (104). Such reports include a few cases of myoclonus-dystonia without the epsilon-sarcoglycan gene mutation (78; 130). Only a few studies have compared globus pallidus stimulation with that of the ventral intermediate thalamic nucleus (130). There may be a slight edge for globus pallidus stimulation in treating myoclonus-dystonia syndrome, including a more favorable side effect profile when compared to ventral intermediate thalamic nucleus stimulation (78). Because myoclonus may arise from different etiologies and locations, the response of myoclonus to deep brain stimulation can vary. One study suggests that patients with the epsilon-sarcoglycan gene mutation do better with deep brain stimulation than cases without this gene, but some gene negative patients do respond (166; 149). Evidence for long-term benefit using globus pallidus stimulation or ventral intermediate thalamic nucleus stimulation exists (141; 175).

Paraneoplastic causes of the opsoclonus-myoclonus syndrome may have a response to treatment of the cancer. On a symptomatic basis, the myoclonus may respond to clonazepam regardless of etiology (37). Paraneoplastic and idiopathic inflammatory causes may respond to immunomodulation and improve opsoclonus-myoclonus. Conventional management consists of ACTH or corticosteroids, though some investigators advocate concomitant treatment with plasmapheresis (146) or intravenous immunoglobulin (10). Rituximab, a monoclonal antibody directed to CD20, targets mature B cells for apoptosis and has been reported to improve opsoclonus-myoclonus, including in children with neuroblastoma (151). It is important to note that there are important differences in treatment strategies for children versus adults (156).

Propriospinal myoclonus may respond to treating a causative lesion (113). Clonazepam is the most commonly used symptomatic treatment (35). Zonisamide, lioresal, valproic acid, and carbamazepine have been reported to be effective in some cases (Fouillet et al 1995; 139).

Segmental myoclonus treatment. Palatal segmental myoclonus is usually resistant to therapy. Many agents have been used, including clonazepam, anticholinergics, 5-hydroxytryptophan, and carbamazepine (32). When ear clicking is disabling to the patient, surgical treatments such as tensor veli palatini tenotomy and occlusion of the eustachian tube have been performed. However, success has been variable (65). Botulinum toxin injections have been reported to be useful, and the literature on this treatment is increasing (150). A retrospective analysis suggested that injections into the tensor-veli-palatini were better for clicking tinnitus, whereas as injections into the medial uvula (levator-veli-palatini) worked for perceived palatal movements (150). Middle ear myoclonus can cause troublesome tinnitus. Treatment has not been studied rigorously and has included both medical and surgical methods (17).

Like palatal myoclonus, spinal myoclonus is challenging to treat. It may respond to removal of the compressing lesion (51). This makes complete spine imaging important. If the lesion cannot be seen or treated, clonazepam is often tried first. Carbamazepine or lioresal are sometimes effective. Some cases do respond to tetrabenazine (92). Botulinum toxin has been useful in cases of spinal segmental myoclonus (for pain) (162). Intrathecal baclofen was reported to be beneficial in case reports of spinal myoclonus (42).

Peripheral myoclonus treatment. The most common cause of peripheral myoclonus is hemifacial spasm. It is well known that botulinum toxin is efficacious for both the quick movements and spasms for this condition. Other causes of peripheral myoclonus have also responded to botulinum toxin injections, and this may improve any associated discomfort with the movements as well (27). Carbamazepine may be tried as drug therapy for peripheral myoclonus, but a satisfactory response is uncommon.

Uncertain pathophysiology. If the pathophysiology of the myoclonus cannot be determined, then medications for the most common source (cortical) are often employed. If the diagnosis is known, the pathophysiology of the myoclonus common for that condition may be known in the literature (29). Gabapentin was effective in myoclonus induced by chronic opiate medication in cancer patients with pain (119). Immunotherapy may help patients with myoclonus associated with voltage-gated potassium channel antibodies (05).