Clinical manifestations

Presentation and course

Major clinical categories of myoclonus are distinguished by presentation and course:

Myoclonic jerks can exhibit a broad spectrum of characteristics, varying from mild muscular contractions with small amplitude movements to pronounced jerks that affect the entire body (26). These movements may manifest in diverse distributions, either symmetric or asymmetric. The consequential disability stems from the loss of muscle control during these sudden jerking episodes. In cases where myoclonus affects the lower extremities, patients may experience abnormal balance and gait disturbances, contributing to functional impairment.

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. Focal myoclonus is characterized by the involvement of a specific group of muscles. This form of myoclonus can manifest differently depending on its origin and location within the nervous system.

Cortical myoclonus. One notable subtype of focal myoclonus is cortical myoclonus, which exhibits distinct features:

It is important to note that cortical myoclonus often exhibits multifocality, affecting multiple brain areas rather than remaining strictly focal. Additionally, some forms of focal myoclonus, such as palatal myoclonus, are typically rhythmic in nature.

Palatal myoclonus. Palatal myoclonus represents a distinctive subtype of myoclonus characterized by continuous and rhythmic movements of the palate. These movements may resemble tremors in some patients, although a jerky component is typically present, justifying use of the term "myoclonus" (segmental myoclonus). Key features of palatal myoclonus include:

Types of myoclonus

The physiological classification of myoclonus in clinical neurophysiology is based on identifying its neuroanatomic source. Physiological classification further categorizes myoclonus according to the clinical syndrome it presents and the specific disease causing it. This approach aids in diagnosis and treatment by providing insights about the origin and nature of myoclonus (Table 1).

Table 1. Physiological Classification of Myoclonus

Myoclonus can take on various forms, each exhibiting distinct characteristics and underlying mechanisms. It is crucial to understand these differences for accurate diagnosis and effective management. Here, we discuss different types of myoclonus.

Multifocal myoclonus. Multifocal myoclonus involves individual jerks affecting different parts of the body, often occurring unpredictably. Cortical myoclonus frequently exhibits multifocality as well (72).

Generalized myoclonus. In generalized myoclonus, each jerk simultaneously affects a large area or the entire body. This type of myoclonus can be sensitive to external stimuli and may worsen during voluntary actions. It can originate from cortical-subcortical pathways, as seen in juvenile myoclonic epilepsy, or from subcortical-nonsegmental sources, as observed in reticular reflex myoclonus (72).

Asterixis typically occurs alongside multifocal myoclonus in the context of metabolic encephalopathy and is generally generalized. However, focal asterixis may be observed in lesions affecting the thalamus, putamen, or parietal lobe.

Reticular reflex myoclonus. Reticular reflex myoclonus typically originates in the brainstem. It primarily affects proximal muscles, with a preference for flexor muscle involvement (72).

Minipolymyoclonus. Minipolymyoclonus is characterized by small jerks occurring in various locations. This term has also been used to describe small-amplitude jerks in patients with spinal muscular atrophy. Distinguishing the origin may require considering associated signs like denervation in spinal muscular atrophy (141).

Cortical tremor. Cortical tremor manifests as fine, shivering finger twitching, primarily provoked by action and posture. It may resemble essential tremor phenomenologically and can exhibit familial patterns (77; 56).

Orthostatic myoclonus. Orthostatic myoclonus presents as leg shaking when standing, similar to orthostatic tremor. Unlike orthostatic tremor, it impairs gait and is often associated with more significant neurologic problems (74). Electromyographically, orthostatic myoclonus shows greater variability in discharge duration, with many brief discharges (shorter than 100 ms) (74).

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, two major groups exist: (1) progressive myoclonic epilepsies and (2) 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 problem.

Startle syndromes and related disorders. Startle syndromes are characterized by an exaggerated startle response to a surprising stimulus. In a typical startle response, there is a blink and activation of craniocervical muscles, with an EMG activity latency of 30 to 40 milliseconds (142). This response habituates quickly in normal individuals.

One specific condition related to startle syndromes is hyperekplexia, which is a familial condition typically beginning in infancy. It is characterized by an enhanced startle response to various stimuli, often leading to generalized stiffening and falling to the ground. In hyperekplexia, the EMG latency is shorter than in the normal startle response, and the burst duration is brief (48). Some cases may exhibit EEG correlates, and enhanced somatosensory evoked potentials have been reported (91).

Certain startle disorders have been categorized as "culture-specific" startle syndromes, although the relationship between these conditions and myoclonus is poorly understood. For instance, "latah," primarily observed in Indonesia and Malaysia, is characterized by exaggerated startle responses accompanied by vocalizations, echolalia, and echopraxia. Latah displays two phases in the startle response: a short latency motor startle reflex initiated in the lower brainstem (less than 100/120 ms) and a later second phase influenced more by psychological factors (the "orienting reflex") occurring 100/120 to 1000 ms after the stimulus (13). It has been suggested that latah should be considered a "neuropsychiatric startle syndrome." Other culture-specific syndromes include the "jumping Frenchman of Maine" and "myriachit" in Siberia. These syndromes share common features of a nonfatigable startle response followed by bizarre and stereotyped behaviors, often linked to cultural factors. Besides echolalia and echopraxia in latah, reports include forced obedience, coprolalia, and strange motor actions (55). Reliable treatment options for these syndromes are largely unknown.

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 5 years of age, she began experiencing jerking of the head from right to left in the horizontal plane. By 10 years of age, 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 categorized into clinical presentation categories, including physiological, essential, epileptic, and symptomatic causes. Notably, most myoclonus cases fall into the symptomatic category (30).

Clinical neurophysiological tests play a crucial role in pinpointing the anatomical origin of myoclonic jerks. Recognition of reversible forms of myoclonus is essential to initiate prompt treatment. Next-generation sequencing techniques allow for a rapid diagnosis, particularly in cases where myoclonus has a genetic basis.

An innovative eight-step algorithm has been proposed to guide clinicians in detecting myoclonus, assessing its anatomical subtype, and diagnosing its underlying cause. This algorithm is a valuable tool for clinical decision-making (147).

Several types of symptomatic myoclonus warrant discussion, including psychogenic jerks or spasms seen in patients with a conversion disorder or malingering. These psychogenic presentations exhibit distinctive features, such as inconsistency in character (amplitude, frequency, distribution), accompanying psychopathological symptoms, distractibility, suggestibility, acute onset, spontaneous remissions, and a tendency to show improvement with placebo interventions (101).

Each of these myoclonus categories is elaborated below, including insights into common etiologies within each category.

Physiological myoclonus

Physiological myoclonus refers to muscle jerks occurring in specific circumstances in normal individuals. Examples include hypnic jerks and hiccups (singultus). Research indicates that hypnic jerks originate from the brainstem (37). Some forms of myoclonus during sleep have been quantified (59). Fragmentary myoclonus during sleep is observed in all healthy individuals, with neck myoclonus occurring in 35%. Interestingly, some individuals exhibit movements that are considered "excessive" based on established criteria. It is crucial to emphasize that in all cases of myoclonus during sleep, the clinical implications of the movements, rather than just their amplitude or frequency, are of paramount importance.

Essential myoclonus

Essential myoclonus is characterized by myoclonus as the primary symptom, and it typically follows a nonprogressive course. Onset usually occurs at a young age, and the condition tends to have a chronic course. The term "essential" is used because of the condition's monosymptomatic focus on myoclonus and its chronic nature. The associated disability is generally minimal, and patients maintain functional abilities. Essential myoclonus can be further divided into hereditary and sporadic forms. Sporadic myoclonus cases are challenging to characterize because they appear clinically heterogeneous, possibly indicating undiscovered static lesions or genetic abnormalities. In contrast, hereditary forms of essential myoclonus exhibit greater uniformity, with most described as the myoclonus-dystonia syndrome, which has a genetic basis.

Myoclonus-dystonia

Familial myoclonus-dystonia is characterized by brief, "lightning-like" myoclonic jerks, primarily affecting the neck and upper limbs. Diagnostic criteria for myoclonus-dystonia (DYT 11) include (1) onset of myoclonus in the first or second decade of life with mild dystonic features, (2) equal prevalence in males and females, (3) a benign course compatible with a normal lifespan, (4) autosomal dominant mode of inheritance with incomplete penetrance, (5) absence of other neurologic deficits, and (6) normal EEG and neuroimaging (62). Mild dystonia often presents as cervical dystonia or task-specific focal dystonia (42). The myoclonus can exhibit rhythmic or arrhythmic patterns, be provoked by actions, or respond to alcohol.

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 (42; 115).

Epileptic myoclonus

Epileptic myoclonus is a category of myoclonus that occurs in the context of a seizure disorder and is frequently accompanied by EEG abnormalities, such as generalized spike and wave discharges (26). In children, myoclonus is commonly associated with epilepsy, and major syndromes within this category include infantile spasms and Lennox-Gastaut syndrome (18; 60). It is crucial to differentiate between infantile spasms and benign myoclonus of infancy, where EEG findings are normal, and the condition follows a nonprogressive course (54). Juvenile myoclonic epilepsy represents a classic idiopathic epileptic disorder in which myoclonus can manifest alongside various seizure types, including myoclonic, absence, and generalized seizures. For the diagnosis of juvenile myoclonic epilepsy, obtaining a comprehensive medical history that includes inquiring about early morning jerks is critical because most juvenile myoclonic epilepsy cases initially present with generalized tonic-clonic seizures (61).

Symptomatic myoclonus

Progressive myoclonus epilepsy-ataxia (including genetic metabolic disorders). Progressive myoclonic epilepsy is characterized by cortical myoclonus, myoclonic seizures, tonic-clonic seizures, and neurologic deterioration, which often includes dementia. Myoclonus in this context is typically multifocal, action-induced, and triggered by external stimuli like touch, sound, or light (15).

Several conditions fall under the category of progressive myoclonic epilepsy:

Progressive myoclonic ataxia (Ramsay Hunt syndrome). Known causes of progressive myoclonic ataxia include mitochondrial encephalomyopathy (14), celiac disease, late-onset neuronal ceroid lipofuscinosis, biotin-responsive encephalopathy (19), adult Gaucher disease (104), action myoclonus renal failure syndrome, May-White syndrome, and Ekbom syndrome (93). Neurodegenerative diseases, such as spinocerebellar degeneration (110) or dentatorubral-pallidoluysian atrophy (95), may also manifest as progressive myoclonic ataxia. Some disorders may present with both progressive myoclonic epilepsy and ataxia, and in such cases, the syndromic classification may not be straightforward. Various genetic mutations, including MRE11, GOSR2, and SCARB2, have been described in progressive myoclonic ataxia syndromes (99; 109; 136).

Neurodegenerative and other dementia syndromes. Dementia and myoclonus frequently coexist in neurodegenerative syndromes such as Creutzfeldt-Jakob disease, Alzheimer disease, and Lewy body disease (29; 75). In some cases of Creutzfeldt-Jakob disease, patients present with myoclonus and dementia that progress rapidly (117). In a series of 150 patients with variant Creutzfeldt-Jakob disease, myoclonus and chorea were the most common movement disorders (75). Among the elderly, myoclonus associated with clinical parkinsonism, originating from a cortical source due to various disorders, is prevalent (82). On rare occasions, 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 one 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 (26).

Infectious syndromes. Infectious syndromes, including viral and postviral conditions, can lead to the development of myoclonus. One notable example is Whipple disease, a rare yet treatable bacterial infection affecting multiple body systems. Systemic symptoms like gastrointestinal issues, fever, weight loss, joint problems, and CNS involvement characterize this condition. The presence of dementia, ophthalmoplegia (especially supranuclear gaze palsy), characteristic oculomasticatory myorhythmia, and myoclonus strongly suggests Whipple disease. Diagnosis relies on PCR-based detection of Tropheryma whipplei in cerebrospinal fluid or duodenal biopsy samples.

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 (145). It usually occurs in conjunction with metabolic derangements, such as hepatic encephalopathy. Myoclonus can also be associated with malabsorption syndromes. Multiple malabsorption disorders have been identified as potential causes of myoclonus (26).

Drug-induced and toxic syndromes. Drug-induced myoclonus typically manifests suddenly on starting a medication or, in some cases, after prolonged use, especially when concurrent illnesses are present. Importantly, discontinuing the causative drug often leads to a rapid resolution of drug-induced myoclonus. Some medications and substances known to induce myoclonus include serotonin reuptake inhibitors, antiepileptic drugs, narcotics, levodopa, lithium, selegiline, amantadine, and others (58; 90; 25; 78; 02; 43; 138; 52).

Toxic encephalopathies causing myoclonus can occur after exposure to substances like bismuth, methyl bromide, and toxic cooking oil (105).

Clinicians must understand the potential for drug-induced and toxic myoclonus when evaluating patients presenting with myoclonic symptoms. Discontinuing the causative medication or addressing the underlying toxic exposure can often lead to symptom improvement or resolution.

Static encephalopathies secondary to diffuse brain injuries. Static encephalopathies secondary to diffuse brain injuries can result in myoclonus-related syndromes. Lance-Adams syndrome, described by Lance and Adams in 1963, is characterized by action myoclonus following hypoxic brain injury, often accompanied by asterixis, seizures, and gait problems (87).

Recent studies have emphasized the distinction between acute post-hypoxic myoclonus and chronic post-hypoxic myoclonus (68). Acute post-hypoxic myoclonus typically emerges immediately or within a day after hypoxic insult, often within 24 to 48 hours. It is generalized, occurs in the context of coma, and may manifest at rest or in response to stimuli. In contrast, chronic post-hypoxic myoclonus, commonly referred to as Lance-Adams syndrome, appears after some neurologic recovery, tends to be multifocal, and is predominantly triggered by muscle activation (action myoclonus).

Acute post-hypoxic myoclonus is associated with a less favorable prognosis, irrespective of whether hypothermia treatment is administered (131). Recent evidence suggests that acute post-hypoxic myoclonus originates in the brainstem as reticular reflex myoclonus (106). This distinction is crucial for guiding treatment decisions between acute and chronic post-hypoxic myoclonus.

Paraneoplastic, other autoimmune, and idiopathic inflammatory syndromes.

(A) Opsoclonus-myoclonus syndrome is characterized by involuntary, arrhythmic, chaotic, multidirectional, fast eye movements in combination with brainstem myoclonus involving the axial muscles and limbs (33). Opsoclonus-myoclonus syndrome is usually a manifestation of a paraneoplastic syndrome and is associated with breast cancer or small-cell lung carcinoma in adults (80) and neuroblastoma in children (06). Other causes of opsoclonus-myoclonus include viral infections such as West Nile virus (01), drugs, toxins, nonketotic hyperglycemia, and celiac disease (143; 50). Notably, the antibodies associated with opsoclonus-myoclonus syndrome have been found to attack dendritic neuronal surface antigens, with significant pathophysiological implications (108). Idiopathic opsoclonus-myoclonus occurs in younger patients, and its clinical course is generally more benign (07).

(B) A growing number of paraneoplastic and autoimmune disorders are associated with myoclonus and various antibodies (11; 10). One such disorder is anti-N-methyl-D-aspartate receptor encephalitis, which can affect both children and adults and is linked to a range of psychiatric symptoms as well as movement disorders, including chorea, stereotypies, dystonia, myoclonus, and myorhythmia (12). Both GABA-A and glycine receptor antibodies can produce myoclonus or stiff-person syndrome in patients (51; 144). Patients with antibodies to voltage-gated potassium channels have also been identified in myoclonus cases (127). Although this syndrome may resemble Creutzfeld-Jakob disease, its diagnosis is crucial because a positive response to therapy may be observed. The immunology of this antibody has become more complex as it has been suggested that other antigens may be causing the clinical syndromes associated with voltage-gated potassium channels (11). Other rare antibody-associated myoclonus syndromes have been linked to thyroid-stimulating hormone antibodies (24) and Ophelia syndrome (86). A comprehensive search for possible antibodies and cancer presence is warranted in such disorders.

Regarding anti-NMDAR encephalitis, this condition is characterized by a combination of psychiatric symptoms, seizures, movement disorders, and encephalopathy (11). EEG typically reveals abnormal activity or a distinctive extreme delta-brush pattern. In cerebrospinal fluid, elevated cell counts with CSF-specific oligoclonal bands and the presence of NMDAR antibodies are indicative. Notably, individuals with anti-NMDAR encephalitis should be meticulously screened for solid tumors, particularly ovarian teratoma, which is identified in more than half of adult female patients with this condition (11). The likelihood of underlying tumors is lower in younger patients (under 18 years) (45).

Pathophysiology

Electrophysiology. Myoclonus arises due to excessive neuronal discharge, which can originate in various locations within the nervous system. This electrical discharge can spread rapidly through pathways, as observed in cortical myoclonus (73), or through slower pathways, as seen in propriospinal myoclonus (20). The pattern and timing of muscle activation resulting from this discharge can offer insights into the source of the abnormal activity, which has diagnostic and treatment implications. However, the rapidity of discharge propagation often necessitates neurophysiological studies for a detailed assessment.

Neurophysiological studies for myoclonus typically include methods such as multichannel surface EMG recording, testing for long latency EMG responses to mixed nerve stimulation, EEG, EEG-EMG polygraphy with back averaging, and evoked potentials (eg, median nerve stimulation somatosensory evoked potential). Positive and negative findings from these methods contribute to determining the physiological type of myoclonus (25). For instance, the presence of a back-averaged focal cortical EEG transient, enlarged cortical somatosensory evoked potential, and enhanced long EMG responses suggests cortical origin myoclonus (122). Myoclonus is categorized into various physiological types, including cortical, cortical-subcortical, subcortical-nonsegmental, segmental, and peripheral.

Cortical myoclonus, originating from the cerebral cortex, is the most common form and can be associated with various neurodegenerative diseases, toxic-metabolic conditions, and other disorders. Typically, it manifests as brief, stimulus-sensitive muscle jerks, often involving antagonist muscle pairs. Cortical myoclonus can result from a range of conditions, including tumors, angiomas, and encephalitis (132; 34). It may also present as epilepsia partialis continua, occurring in focal encephalitis, stroke, tumors, and, infrequently, multiple sclerosis (76). Other conditions like Rett syndrome and Angelman syndrome have also been associated with cortical myoclonus (67; 66).

Cortical-subcortical myoclonus corresponds to myoclonus observed in myoclonic and absence seizures, often involving interactions between cortical and subcortical centers, such as the thalamus (26). These jerks are typically bilaterally synchronous or generalized.

Subcortical-nonsegmental myoclonus, seen in conditions like essential myoclonus and reticular reflex myoclonus, originates below the cortical level and can spread beyond the source to multiple segmental levels. Reticular reflex myoclonus, for instance, is characterized by generalized jerks, sometimes stimulus-sensitive (72). It is thought to originate in the caudal brainstem and spreads both rostrally and caudally. Essential myoclonus, characterized by an EMG burst length of 50 to 150 msec, may also have a subcortical origin (89; 113).

Two major forms of spinal myoclonus are recognized: segmental myoclonus, originating from segmental brainstem or spinal generators, and propriospinal myoclonus, causing generalized axial movements (39). Propriospinal myoclonus is considered subcortical-nonsegmental myoclonus as it can spread both rostrally and caudally within the spinal cord (114).

Segmental myoclonus arises from segmental brainstem (palatal) or spinal generators (27). Symptomatic palatal myoclonus, for example, arises from lesions within the Guillain-Mollaret triangle, a neural pathway connecting various brainstem nuclei. On the other hand, spinal segmental myoclonus typically affects muscles innervated by adjacent spinal segments and may persist during sleep (27).

Peripheral myoclonus, except for hemifacial spasm, is relatively rare and may occur in conditions affecting peripheral nerves, plexuses, or roots or through a proposed mechanism called "ephaptic" transmission of peripheral ectopically generated potentials (94).

Biochemistry. The biochemical basis of myoclonus appears to be heterogeneous and may involve various mechanisms. In some forms of myoclonus, such as posthypoxic myoclonus, there is a characteristic reduction in 5-hydroxyindoleacetic acid levels in the cerebrospinal fluid (137). This specific biochemical profile may respond to treatment with 5-hydroxytryptophan and carbidopa.

Animal studies have shown that myoclonus can be induced by pp-dichlorodiphenyltrichloroethane (a chemical compound) and improved by agonists of 5-hydroxytryptophan while worsening with antagonists of 5-hydroxytryptophan (137). However, it's worth noting that L-5-hydroxytryptophan can also produce myoclonus that is not stimulus-sensitive.

In the context of Parkinson disease, myoclonus induced by L-dopa treatment may potentially improve with the use of 5-hydroxytryptophan receptor blockers (83).

Furthermore, experiments involving the injection of GABA antagonists into the putamen have demonstrated the ability to produce myoclonus (44).

Genetics. Myoclonus is associated with various genetic conditions, shedding light on the underlying causes and mechanisms of this phenomenon.

The International Parkinson and Movement Disorder Society Task Force has proposed a new nomenclature for genetically determined myoclonus syndromes, aiming to provide clarity for clinicians in their daily practice. This classification categorizes these genetic disorders into three main groups based on their clinical presentation:

(1) Prominent myoclonus syndromes. Genetic disorders in this group primarily manifest with prominent myoclonus in the majority of cases.

(2) Combined myoclonus syndromes. Genetic disorders falling into this category present with prominent myoclonus as well as another prominent movement disorder, such as dystonia or ataxia, in most cases.

(3) Disorders that can manifest as prominent myoclonus syndromes. In this group, genetic disorders typically present with other clinical phenotypes but can occasionally exhibit prominent myoclonus as part of the disorder's phenotypic spectrum, although this occurs in a minority of cases (135).

This new classification system provides a more precise framework for understanding and diagnosing genetically determined myoclonus syndromes, enabling clinicians to better identify and manage these conditions in clinical practice.

Autosomal recessive disorders. Progressive myoclonic epilepsy, Lafora disease, neuronal ceroid lipofuscinosis, Unverricht-Lundborg disease, and sialidosis are all autosomal recessive conditions.

Maternally inherited disorder. Myoclonic epilepsy with ragged red fibers is inherited through maternal lineage. Myoclonic epilepsy with ragged red fibers may result from an adenosine-to-guanine substitution in the tRNA gene, MTTK, in mitochondrial DNA (120).

Genetic abnormalities in specific disorders.

Hereditary hyperekplexia. Hereditary hyperekplexia, transmitted as an autosomal dominant trait, is linked to chromosome 5q33-q35 and involves a point mutation in the alpha-1 subunit of the glycine receptor.

Familial adult myoclonic epilepsy. Familial adult myoclonic epilepsy, characterized by "cortical tremor" and myoclonus, has been linked to chromosome 8q24 (111). It can also show genetic heterogeneity and linkage to chromosome 2p11.1-q12.2 (49).

22q11.2 deletion syndrome (DiGeorge syndrome). Myoclonus has been reported in association with the 22q11.2 deletion syndrome, which may present with neuropsychiatric disorders, seizures, parkinsonism, and tremor (17).

Epidemiology

Little is known about the frequency and distribution in the general population. The only available study is from Olmstead County, Minnesota (30). 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

To distinguish an isolated myoclonic jerk from other movement disorders (myoclonus mimics), such as chorea, tic, dystonia, and tremor, it is important to consider the following characteristics.

Chorea. Chorea movements are dance-like and lack a rhythmic quality. They integrate with normal movements and appear as a continuous flow of irregular motions. There is variability in burst duration and muscle recruitment order. In advanced chorea, motor impersistence can occur, leading to difficulty maintaining specific postures or movements, such as keeping the tongue protruded or grip strength fluctuations (milkmaid's grip).

Motor tics. Tics are stereotypic or repetitive movements typically seen in childhood. They may coexist with other tics and are often characterized by premonitory sensations preceding the movements. Tics can be voluntarily suppressed, and relief is experienced after performing the movement. Burst duration in tics typically exceeds 100 ms, and pre-movement potentials on back-averaging may be present. Conditions like Tourette syndrome may involve multiple motor and vocal tics, along with coprolalia (involuntary swearing) and obsessive-compulsive symptoms.

Dystonic jerks. Dystonic jerks occur alongside dystonia, which involves sustained muscle contractions. Sensory tricks (geste antagoniste) can temporarily alleviate dystonic symptoms. Dystonia entails the co-contraction of agonist and antagonist muscles. Burst duration in dystonic jerks usually exceeds 100 ms, and overflow (unintentional muscle contractions accompanying primary dystonic movements) may occur.

Tremor. Tremor is characterized by sinusoidal and rhythmic movements involving alternating contractions of antagonistic muscles. Tremor maintains a steady frequency, measurable with accelerometry. Myoclonus and ataxia can occasionally coexist, as seen in progressive myoclonic ataxia. In such cases, it may be necessary to treat the myoclonus first to accurately assess the underlying ataxia's severity.

Functional (psychogenic) jerks. Functional jerks may exhibit inconsistent movements that lack a specific pattern. They are often reduced or altered by distraction or entrainment. Variability is observed in muscle involvement, recruitment order, burst duration, and amplitude. Pre-movement potentials on back-averaging may be present, indicating a psychogenic origin.

Diagnostic workup

It is imperative to systematically investigate the underlying causes of myoclonus (31; 28). The initial approach should be guided by the clinical context, treating myoclonus as a symptom rather than the primary condition. This approach is essential because most instances of myoclonus are secondary and arise from various underlying diseases and conditions. For example, if there are indications of an infectious or inflammatory syndrome, conducting a cerebrospinal fluid examination is crucial. Furthermore, recent advancements in next-generation sequencing techniques have introduced an innovative eight-step diagnostic framework for patients with myoclonus.

Confirming myoclonus. The first step involves confirming that the observed movements indeed represent myoclonus. This distinction is critical in ruling out other hyperkinetic movement disorders, such as tremor, motor tics, chorea, dystonic jerks, and functional (psychogenic) jerks. The differentiation relies on a combination of clinical assessment and electrophysiological features.

Defining the anatomical bases of myoclonus. Myoclonus can manifest in various anatomical regions of the nervous system, including the peripheral, spinal (segmental and propriospinal), subcortical, and cortical areas. Different types of myoclonus have distinct etiologies, necessitating tailored clinical approaches. Cortical and subcortical myoclonus can either be acquired or result from genetic disorders, necessitating genetic testing in addition to MRI and laboratory investigations. Conversely, spinal and peripheral myoclonus are typically acquired.

Identifying the underlying cause. In cases of spinal or peripheral myoclonus, precisely determining the source is paramount. This necessitates a comprehensive assessment for signs of muscle denervation and the presence of structural lesions, using suitable electrophysiological and imaging examinations. Potential origins encompass conditions such as brachial plexus or spinal root lesions, which can be elucidated through EMG and MRI. It is worth noting that peripheral myoclonus can also emerge following limb amputation.

Spinal myoclonus, although rare, is typically associated with lesions affecting the spinal cord. The presence of acute or subacute onset, rapid disease progression, symptoms like radiculopathy or polyradiculopathy, and systemic manifestations, such as fever, skin rashes, or joint issues, may suggest an infectious or autoimmune etiology. Confirmatory laboratory tests should be conducted in such cases.

It is important to acknowledge that most instances of propriospinal myoclonus are categorized as functional movement disorders. However, in exceptional circumstances, medication or infections can trigger spinal myoclonus. Therefore, a thorough evaluation remains essential for these cases.

Cortical and subcortical myoclonus encompass a broad spectrum of potential causative factors. An acute or subacute onset with rapid disease progression may indicate an acquired origin, whereas early-onset disease with a more gradual progression often suggests a genetic disorder. Additional clinical features frequently yield valuable insights for accurately diagnosing the underlying condition.

Evaluation for toxic or medication-induced causes. Numerous drugs are recognized for their potential to induce or exacerbate myoclonus, including medications like lithium, antidepressants, anti-infectious agents, and narcotics, among others. When there is suspicion that a medication is responsible for a patient's myoclonus, careful consideration should be given to the gradual reduction or discontinuation of the drug. This change in medication not only serves therapeutic purposes but also contributes to the diagnostic process.

Laboratory testing. Cortical or subcortical myoclonus can often be linked to disturbances in homeostasis, organ failure, or infections. Examples of common underlying conditions include acute or chronic renal failure, acute or chronic hepatic failure, chronic respiratory failure leading to hypercapnia, disruptions in glucose regulation, hyperthyroidism, and metabolic imbalances, such as alkalosis or acidosis.

A meticulous assessment for potential infectious or immune-mediated causes of myoclonus is imperative. This evaluation may involve the following:

These tests primarily focus on assessing metabolic, toxic, and structural brain abnormalities, as well as identifying seizure disorders and potential cancer-related triggers of myoclonus. Although routine surface EEG may reveal epileptiform discharges or other diagnostic indicators, it may not always detect spikes in cases of cortical reflex myoclonus and can sometimes be normal in epilepsia partialis continua. Notably, the presence of antibodies to voltage-gated potassium channels has been observed in patients with myoclonus, and this often responds positively to treatment (127).

If the results of these initial tests fail to provide a definitive diagnosis, the next step involves considering more advanced diagnostic procedures. The clinical information accumulated thus far plays a crucial role in guiding this comprehensive evaluation, which may encompass cerebrospinal fluid examination, enzyme activity assessments, imaging studies to investigate the possibility of cancer, tissue biopsy procedures, and other specialized tests.

Cerebrospinal fluid analysis is especially warranted when infection is suspected (119). In cases of generalized and multifocal myoclonus, the metabolic workup should involve tests related to liver and kidney functions, blood gases, and blood sugar levels. For patients with progressive myoclonic epilepsy and progressive myoclonic ataxia, the diagnostic workup should encompass visual evoked responses and electroretinography to identify potential neuronal ceroid lipofuscinosis. Elevated plasma and cerebrospinal fluid lactate levels can point to a mitochondrial encephalopathy. It is also essential to perform white cell or fibroblast lysosomal enzyme estimations and screen for urinary oligosaccharides and organic acids. Additional diagnostic tools should be considered, such as skin and conjunctival biopsy with electromicroscopy to detect inclusions in nerves (especially in eccrine sweat glands), muscle biopsy to identify ragged-red fibers and study mitochondrial metabolism, and jejunal biopsy to explore conditions like celiac disease and Whipple disease. Furthermore, the presence of anti-Ri antibodies may yield positive results in cases of opsoclonus-myoclonus syndrome.

Brain imaging. An imperative component of the diagnostic process involves brain imaging, with MRI being the preferred modality. This imaging study aims to identify focal lesions or other indicators of specific conditions, including neurodegeneration with brain iron accumulation disorders, leukodystrophy, or mitochondrial disorders.

In the context of cortical myoclonus, a SPECT activation study can be employed. This specialized study helps pinpoint hyperexcitable regions within the cortex (128).

For cases of palatal myoclonus, it is essential to conduct an MRI scan to explore potential lesions in the Guillain-Mollaret triangle. MRI findings may reveal signs of olivary hypertrophy and hyperintensity on T2 sequences. The type and location of the lesion, such as distinguishing between a stroke and multiple plaques, will guide the subsequent diagnostic workup.

In situations involving spinal myoclonus, appropriate imaging studies are of paramount importance. Depending on the clinical presentation, an examination of cerebrospinal fluid may also be indicated to rule out potential underlying causes.

Additionally, despite negative results from paraneoplastic testing, considering body imaging for cancer remains crucial.

It is noteworthy that late-onset neurodegenerative disorders often coincide with myoclonus. These disorders may encompass Alzheimer disease, Parkinson disease, multiple system atrophy, and, less frequently, dementia with Lewy bodies, Huntington disease, and corticobasal degeneration. In cases of myoclonus associated with Parkinson disease and multiple system atrophy, manifestations typically include irregular, small-amplitude myoclonic jerks in the fingers, often characterized by their sensitivity to external stimuli. This phenomenon is referred to as cortical polyminimyoclonus (29).

Genetic testing considerations. In select cases, the option of genetic testing should be contemplated as part of the diagnostic process. However, patients must be fully informed about the potential implications of both positive and negative test results. When appropriate, genetic counseling is highly recommended to provide patients with a comprehensive understanding of their genetic testing journey.

Incorporating genetic testing into the diagnostic framework is essential not only for nuclear gene mutations but also for mitochondrial disorders stemming from mutations in mitochondrial DNA. These mitochondrial disorders can manifest with myoclonus, among a range of other clinical features.

The implementation of next-generation sequencing techniques offers distinct advantages. Next-generation sequencing can detect mutations associated with atypical clinical presentations, recognizing that patients with myoclonus-related disorders may exhibit a spectrum of symptoms that deviate from classic phenotypes.

It is important to acknowledge that several limitations exist with current next-generation sequencing methodologies. These techniques may overlook certain genetic anomalies, including repeat expansions, extensive structural rearrangements, and mutations located in noncoding regions, such as deep intronic mutations and promoter regions. Additionally, mutations in mtDNA may elude detection.

Therefore, in cases where the diagnostic puzzle remains unsolved after exhaustive genetic evaluation, it becomes prudent to consider targeted mtDNA analysis as a potential avenue for uncovering the underlying genetic basis of myoclonus-related disorders. This comprehensive approach ensures that even elusive genetic factors are thoroughly explored in the pursuit of an accurate diagnosis.

Management

Treatment of myoclonus. The initial step in addressing myoclonus involves classifying its type and identifying the underlying disease process, which should be treated or reversed whenever possible. In cases where the etiology remains elusive or is irreversible, treatment strategies are best guided by neurophysiological classification, which categorizes myoclonus into various types based on the location of its origin (cortical, cortical-subcortical, subcortical-nonsegmental, segmental, or peripheral) (28).

It is important to note that the evidence for myoclonus treatments is limited, and multiple trials of different treatments may be necessary to achieve optimal symptom suppression. Often, a combination of medications is required for the best response, although this approach may pose challenges due to potential side effects. Consequently, close monitoring of both treatment response and side effects is strongly advised.

Treatment for cortical myoclonus. For cortical myoclonus, several medications have been explored for symptomatic relief. Levetiracetam has shown promise in alleviating cortical myoclonus, although other similar drugs like brivaracetam have not demonstrated confirmed efficacy. Clonazepam, sodium valproate, and piracetam have also been found to be effective for cortical myoclonus. Anesthetic agents may suppress generalized myoclonus immediately post-hypoxia, although the overall prognosis for such patients often remains poor. Some less effective drugs for cortical myoclonus include lisuride, acetazolamide, and carbamazepine. Combining several of these drugs may be necessary to achieve a response, but side effects can be a limiting factor, and the evaluation of polytherapy can be complex.

It is worth noting that phenytoin may exacerbate cortical myoclonus in progressive myoclonic epilepsy and other cortical myoclonus cases. Acetazolamide can be beneficial for myoclonus in Ramsay Hunt syndrome. Negative myoclonus often resolves when the underlying metabolic derangement is corrected, with ethosuximide being particularly useful for symptomatic treatment in some cases. Sodium oxybate has shown promise in improving post-hypoxic myoclonus of cortical origin, and intrathecal baclofen has been reported to be beneficial in selected cases of post-hypoxic myoclonus. Although deep brain stimulation is not a primary choice for cortical myoclonus therapy, there have been isolated case reports of success, such as with bilateral globus pallidus stimulation in Lance-Adams syndrome (08).

Treatment of cortical-subcortical myoclonus. Cortical-subcortical myoclonus, as seen in conditions like juvenile myoclonic epilepsy, often responds well to specific medications. Valproic acid is a commonly used drug and is considered a major treatment choice, supported by controlled evidence (140). Although the evidence is not definitive, valproic acid is also used for other myoclonic seizure disorders (22). Lamotrigine can be employed either alone or as an adjunct to valproic acid (21). Levetiracetam is another option, particularly as a second-line drug for cortical-subcortical myoclonus in primary generalized epilepsy. Brivaracetam, a medication similar in nature to levetiracetam but with potentially fewer side effects, has shown promise in this type of myoclonus physiology (126). However, caution should be exercised when treating with certain antiseizure medications, as some agents can worsen myoclonus or seizures in these disorders (98). Treating less common myoclonic epilepsy syndromes can be particularly challenging (118).

Treatment of subcortical-nonsegmental myoclonus. Essential myoclonus, a form of subcortical-nonsegmental myoclonus, may be effectively managed with medications such as clonazepam or anticholinergics (40). In cases where essential myoclonus is part of the myoclonus-dystonia syndrome, there is increasing evidence that deep brain stimulation surgery can provide significant therapeutic benefits. Although earlier attempts focused on the ventral intermediate thalamic nucleus, more recent reports have targeted the globus pallidus (84). Multiple studies on globus pallidus stimulation have shown greater than 50% improvement in myoclonus and dystonia in patients with myoclonus-dystonia syndrome (85). Some reports even include cases of myoclonus-dystonia without the epsilon-sarcoglycan gene mutation (65; 107). Although a few studies have compared globus pallidus stimulation to ventral intermediate thalamic nucleus stimulation, there appears to be a slight advantage for globus pallidus stimulation, including a more favorable side effect profile (65). Because myoclonus can have various etiologies and locations, the response to deep brain stimulation may vary. Some studies suggest that patients with the epsilon-sarcoglycan gene mutation tend to respond better to deep brain stimulation, although some gene-negative patients also show improvement (139; 123). There is evidence of long-term benefits from globus pallidus stimulation or ventral intermediate thalamic nucleus stimulation (116; 146).

Paraneoplastic opsoclonus-myoclonus syndrome treatment. Paraneoplastic causes of opsoclonus-myoclonus syndrome may exhibit a response to cancer treatment. Additionally, on a symptomatic basis, myoclonus may improve with clonazepam use, regardless of its underlying cause (33). In cases with paraneoplastic or idiopathic inflammatory origins, immunomodulation therapies can be beneficial and may lead to the amelioration of opsoclonus-myoclonus. Conventional management typically involves the use of ACTH or corticosteroids. However, some experts recommend concomitant treatment with plasmapheresis (121) or intravenous immunoglobulin (09). Rituximab, a monoclonal antibody that targets mature B cells for apoptosis, has also shown promise in improving opsoclonus-myoclonus, including in pediatric patients with neuroblastoma (125). It is important to note that there are variations in treatment strategies for children compared to adults (129).

Propriospinal myoclonus treatment. Propriospinal myoclonus is a rare disorder characterized by repetitive, typically flexor, arrhythmic brief jerks affecting the trunk, hips, and knees in a fixed pattern. It is believed to originate in the spinal cord, and its diagnosis relies on specific features observed during polymyography. However, there has been a recent shift in the understanding of propriospinal myoclonus, with reports suggesting that it is, in most cases, a functional (or psychogenic) movement disorder (134).

For symptomatic relief in propriospinal myoclonus, clonazepam is the most commonly prescribed treatment (31). Other medications, including zonisamide, lioresal, valproic acid, and carbamazepine, have also demonstrated effectiveness in some cases (114).

Segmental myoclonus treatment. Segmental myoclonus presents unique challenges in terms of treatment options, and the effectiveness of therapies can vary depending on the specific type and location of the myoclonus.

Palatal segmental myoclonus. Palatal segmental myoclonus, particularly when associated with ear clicking, has proven resistant to therapy. Various agents have been attempted, including clonazepam, anticholinergics, 5-hydroxytryptophan, and carbamazepine (28). In cases where ear clicking significantly impairs the patient's quality of life, surgical interventions such as tensor veli palatini tenotomy and eustachian tube occlusion have been performed with varying success rates (57). Botulinum toxin injections have shown promise in managing palatal myoclonus, with studies indicating their usefulness (124). The choice between injections into the tensor-veli-palatini or medial uvula (levator-veli-palatini) may depend on the specific symptoms, such as clicking tinnitus or perceived palatal movements.

Middle ear myoclonus. Treatment for middle ear myoclonus, which can cause troublesome tinnitus, has not been extensively studied. Therapeutic approaches have included both medical and surgical methods (16). Given the limited data available, treatment decisions should be made on a case-by-case basis, considering the severity of symptoms and the patient's response to different interventions.

Spinal myoclonus. The management of spinal myoclonus can be challenging, and treatment options depend on the underlying cause. Surgical removal may be attempted to alleviate symptoms in cases where a compressing lesion is identified (47). Complete spine imaging is crucial for identifying such lesions. If the lesion cannot be treated surgically, medications such as clonazepam, carbamazepine, lioresal, or tetrabenazine may be considered. Some cases of spinal segmental myoclonus have responded positively to botulinum toxin injections, particularly when used to manage associated pain (133). Intrathecal baclofen has also been reported as beneficial in certain instances of spinal myoclonus (38).

Peripheral myoclonus. Hemifacial spasm is a common form of peripheral myoclonus and is effectively treated with botulinum toxin injections to reduce quick movements and spasms. Botulinum toxin has also shown promise in managing other forms of peripheral myoclonus, potentially alleviating associated discomfort (23). Carbamazepine may be considered as a drug therapy option for peripheral myoclonus, although achieving a satisfactory response with this medication is uncommon.

Uncertain pathophysiology. If the pathophysiology of the myoclonus cannot be determined, medications for the most common source (cortical) are often employed. If the diagnosis is known, the common pathophysiology of the myoclonus for that condition may be known in the literature (25). Gabapentin was effective in myoclonus induced by chronic opiate medication in cancer patients with pain (97). Immunotherapy may help patients with myoclonus associated with voltage-gated potassium channel antibodies (05).