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Symptomatic (secondary) myoclonus

Symptomatic (secondary) myoclonus
Author:
John N Caviness, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Aug 2022. | This topic last updated: May 09, 2022.

INTRODUCTION — Myoclonus is a clinical sign that is characterized by brief, shock-like, involuntary movements caused by muscular contractions or inhibitions [1]. Muscular contractions produce positive myoclonus, whereas muscular inhibitions produce negative myoclonus (ie, asterixis). Patients will usually describe myoclonus as consisting of "jerks," "shakes," or "spasms."

Myoclonic movements have many possible etiologies, anatomic sources, and pathophysiologic features [2]. Myoclonus may be classified by clinical presentation, examination findings, clinical neurophysiology testing, and etiology. The first iteration of genetic nomenclature for myoclonus syndromes now exists and will likely evolve further [3].

This topic will discuss disorders associated with symptomatic (secondary) myoclonus. Other aspects of myoclonus are reviewed separately. (See "Classification and evaluation of myoclonus" and "Treatment of myoclonus".)

TERMINOLOGY AND EPIDEMIOLOGY — The classification scheme of Marsden and colleagues uses four major categories to organize the numerous etiologies of myoclonus (table 1) [1]:

Physiologic

Essential

Epileptic

Symptomatic (secondary)

Myoclonus that occurs secondary to a neurologic or systemic disorder has been traditionally termed "symptomatic myoclonus." Symptomatic myoclonus can occur in association with conditions that span the entire spectrum of neurologic disease (table 1). Often there is clinical or pathologic evidence of diffuse nervous system involvement.

Symptomatic myoclonus is the most common type of myoclonus, accounting for 72 percent of cases in one large epidemiologic study [4]. Posthypoxic state, neurodegenerative disease, and epilepsy syndromes are the most common causes. Toxic-metabolic and drug-induced etiologies are particularly common in the hospital setting.

Most patients with symptomatic myoclonus have additional clinical manifestations, such as cognitive abnormalities, ataxia, or other movement disorders. These features can be more prominent than the myoclonus. While seizures may occur in many of these entities, encephalopathy (ie, a confusional state secondary to a diffuse brain disorder, sometimes called delirium) predominates, and the causative syndrome is not considered a primary epileptic disorder.

Many conditions with symptomatic myoclonus are further characterized by chronic or subacute clinical progression. The cortex is the most common origin of the myoclonic jerks.

PROGRESSIVE MYOCLONIC EPILEPSY AND PROGRESSIVE MYOCLONIC ATAXIA — Symptomatic myoclonus is a major feature of the rare, genetically heterogeneous syndromes known as progressive myoclonic epilepsy (PME) and progressive myoclonic ataxia (PMA). The latter is also known as dyssynergia cerebellaris myoclonica or the Ramsay Hunt cerebellar syndrome (to be distinguished from the Ramsay Hunt zoster syndrome of the facial nerve).

PME and PMA share overlapping phenotypes and causes. The myoclonus physiology demonstrated in these disorders is cortical action and/or cortical reflex myoclonus. (See "Classification and evaluation of myoclonus", section on 'Anatomic and physiologic classification'.)

Progressive myoclonic epilepsy – The main features of PME are seizures, myoclonus, ataxia, and dementia, usually leading to severe mental impairment and death. PME can be differentiated from the more benign epileptic syndromes and from PMA by its progressive nature and the greater severity of the seizures and cognitive decline. The myoclonus associated with PME is typically multifocal and induced by action or by somatosensory stimulation, including touch, sound, or light [5].

The most common causes of PME are Lafora disease, myoclonic epilepsy with ragged red fibers (MERRF), neuronal ceroid lipofuscinosis, dentatorubral pallidoluysian atrophy (DRPLA), and Gaucher disease [5].

Rare causes of PME include the action myoclonus-renal failure syndrome, juvenile Huntington disease, familial encephalopathy with neuroserpin inclusion bodies, noninfantile neuronopathic Gaucher disease, atypical inclusion body disease, neuroaxonal dystrophy, celiac disease, juvenile GM2 gangliosidosis, pantothenate kinase-associated neurodegeneration (formerly known as Hallervorden-Spatz disease), C9ORF72 repeat expansion, and early-onset Alzheimer disease (AD) [5,6].

Progressive myoclonic ataxia – In the syndrome of PMA, cerebellar ataxia and myoclonus are the more prominent or sole components [7]. Clinical progression is slower than in PME. The most frequent causes of PMA are Unverricht-Lundborg disease (ULD), sialidosis, celiac disease, mitochondrial disorders, certain spinocerebellar degenerations, and some late-onset metabolic disorders [8].

ULD is an autosomal recessive disorder. Symptoms usually begin between ages 6 and 15 years with stimulus-sensitive myoclonus. Affected patients develop dysarthria, ataxia, intention tremor, and mild intellectual decline. While progressive, the clinical course is variable. Some patients are bedridden within five years after onset of symptoms, while others are able to live independently. (See "Hyperkinetic movement disorders in children", section on 'Unverricht-Lundborg disease'.)

STORAGE DISEASES — Several genetic metabolic disorders can be associated with symptomatic (secondary) myoclonus:

Lafora disease

Gaucher disease (noninfantile neuronopathic form)

GM2 gangliosidoses:

Hexosaminidase A deficiency including infantile (Tay-Sachs disease), late infantile, and juvenile onset

Hexosaminidase A and B deficiency (Sandhoff disease)

Krabbe leukodystrophy

Neuronal ceroid lipofuscinosis

Sialidosis types 1 and 2

The conditions may manifest with features of the progressive myoclonic epilepsy (PME) and/or progressive myoclonic ataxia (PMA) syndromes. (See 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' above.)

Lafora disease, GM2 gangliosidoses, Gaucher disease, and Krabbe leukodystrophy almost always present as PME. (See "Hyperkinetic movement disorders in children", section on 'Lafora body disease' and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Krabbe disease".)

Neuronal ceroid lipofuscinosis typically causes PME, but the late-onset subtype can cause PMA. Sialidosis can cause either type but is more often PMA. Unverricht-Lundborg disease (ULD) almost always presents as PMA. (See "Overview of the hereditary ataxias", section on 'Sialidosis' and "Hyperkinetic movement disorders in children", section on 'Unverricht-Lundborg disease'.)

NEURODEGENERATIVE DISEASES — Myoclonus can be a manifestation of many progressive neurodegenerative diseases, including the following:

Spinocerebellar degenerations:

Progressive myoclonus ataxia (Ramsay-Hunt syndrome) (see 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' above)

Friedreich ataxia (see "Friedreich ataxia")

Ataxia-telangiectasia (see "Ataxia-telangiectasia")

Other spinocerebellar degenerations (see "The spinocerebellar ataxias")

Basal ganglia degenerations:

Wilson disease (see "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Neurologic manifestations')

Early-onset isolated dystonia (see "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Early-onset isolated dystonia')

Pantothenate kinase-associated neurodegeneration (formerly known as Hallervorden-Spatz disease) (see "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation')

Progressive supranuclear palsy (PSP) (see 'Progressive supranuclear palsy' below)

Huntington disease (see 'Huntington disease' below)

Parkinson disease (PD) (see 'Parkinson disease and dementia with Lewy bodies' below)

Multiple system atrophy (see 'Multiple system atrophy' below)

Corticobasal degeneration (see 'Corticobasal degeneration' below)

Dentatorubral pallidoluysian atrophy (DRPLA) (see 'Dentatorubral pallidoluysian atrophy' below)

Dementias:

Creutzfeldt-Jakob disease (CJD) (see 'Creutzfeldt-Jakob disease' below)

Alzheimer disease (AD) (see 'Alzheimer disease' below)

Dementia with Lewy bodies (DLB) (see 'Parkinson disease and dementia with Lewy bodies' below)

Frontotemporal dementia (see 'Frontotemporal dementia and parkinsonism linked to chromosome 17' below)

Rett syndrome (see "Rett syndrome: Genetics, clinical features, and diagnosis")

Most of these neurodegenerative disorders progress to involve multiple brain areas in the basal ganglia and cortex. Myoclonus may be absent or mild early in the course of these conditions, but eventually appears and/or increases in significance during the middle and late stages of disease.

Myoclonus has a variable expression in neurodegenerative disorders. It is usually multifocal, although it can be generalized.

Multifocal jerks occur in a widespread distribution as separate distinct nonsimultaneous jerks, such as a jerk in the right thigh, then the left shoulder, then the right forearm, and so on

A generalized jerk occurs simultaneously in many muscles in a widespread distribution

The myoclonus physiology demonstrated in these disorders is mostly cortical action and/or cortical reflex myoclonus. (See "Classification and evaluation of myoclonus", section on 'Anatomic and physiologic classification'.)

The association of myoclonus with some of these neurodegenerative disorders is discussed in greater detail in the following sections.

Creutzfeldt-Jakob disease — CJD is a prion disorder characterized by a rapidly progressive dementia leading to death within weeks or months [9]. Myoclonus is a common but not universal feature of CJD. It tends to be generalized and can be provoked by loud noise (startle). Periodic sharp waves on electroencephalography (EEG) are a common finding with CJD, but are not specific for the diagnosis. (See "Creutzfeldt-Jakob disease".)

Alzheimer disease — Myoclonus in AD is variable. It is usually multifocal, although it can be generalized. The appearance can be sporadic large myoclonic jerks or repetitive small ones. The jerks may occur at rest, with action, or with stimulation. It is common for all these various phenotypic characteristics to occur in a single patient. (See "Clinical features and diagnosis of Alzheimer disease".)

The prevalence of myoclonus increases steadily during disease progression, and up to 50 percent of patients with AD eventually develop myoclonus. An earlier age of AD onset, faster progression, or familial causes of AD are associated with myoclonus appearing earlier and more frequently.

Some patients with rapidly progressive AD can have very prominent myoclonus with periodic sharp waves on EEG and be misdiagnosed with CJD.

Parkinson disease and dementia with Lewy bodies — Myoclonus of cortical origin occurs across the spectrum of Lewy body disorders [10,11].

Small-amplitude cortical myoclonus in PD occurs during muscle activation and may appear repetitive and rhythmic enough to resemble action tremor. (See "Clinical manifestations of Parkinson disease".)

In DLB, cortical action myoclonus is more common (one-third of cases), has a larger amplitude, and is more likely to occur at rest compared with PD. (See "Clinical features and diagnosis of dementia with Lewy bodies".)

Cortical myoclonus has been found in one family with hereditary Lewy body disease due to an overexpression of alpha-synuclein [12].

The myoclonus in all of these Lewy body disorders shows identical physiologic properties [13]. Even though the parkinsonism in these conditions arises from a subcortical localization, the cortical action myoclonus physiology signifies that the sensorimotor cortex is not functioning properly. The fact that the dementia and myoclonus are more prominent in DLB than in PD suggests that cortical myoclonus is a marker for cortical dysfunction in Lewy body disorders and correlates with the presence or development of cognitive dysfunction.

Corticobasal degeneration — Myoclonus is an important feature of corticobasal degeneration and occurs in 50 percent of cases. The clinical presentation parallels that of the overall syndrome with a focal distribution in the arm, and less often in the leg. It is associated with other focal limb manifestations that can include apraxia, rigidity, dystonia, and alien limb phenomenon. A "jerky tremor" has been described as part of the syndrome, and the myoclonus is preceded by increased tremor [14].

The myoclonus in corticobasal degeneration occurs in repetitive rhythmic fashion when an attempt is made to activate the arm [15]. Reflex myoclonus to somatosensory stimulation is also very common. This myoclonus is believed to have a cortical origin and may represent a distinct type of cortical reflex myoclonus [16].

Corticobasal degeneration is a sporadic disorder of the microtubule-associated protein tau. The tau pathology has a strong presence in frontoparietal areas, and this could serve as a substrate for the generation of myoclonus. (See "Corticobasal degeneration".)

Progressive supranuclear palsy — PSP is another sporadic tau disorder, but in contrast to corticobasal degeneration, myoclonus has only been rarely observed in the context of PSP [17]. In one case of autopsy-confirmed PSP and action myoclonus, pathology indicative of PSP was present in the cerebral cortex in addition to the more typical subcortical distribution [17]. (See "Progressive supranuclear palsy (PSP): Clinical features and diagnosis".)

Multiple system atrophy — In two series of patients with multiple system atrophy, an upper extremity small-amplitude "jerky postural tremor" was reported in 20 and 55 percent of cases [18,19]. These reports focused on the action myoclonus of the parkinsonian type. Stimulus-sensitive myoclonus of the upper extremities and photic-induced myoclonus have also been reported [20,21]. (See "Multiple system atrophy: Clinical features and diagnosis".)

Frontotemporal dementia and parkinsonism linked to chromosome 17 — Frontotemporal dementia is a heterogeneous entity that is characterized by focal atrophy of the frontal and temporal lobes. (See "Frontotemporal dementia: Clinical features and diagnosis".)

The syndromes of frontotemporal dementia and parkinsonism are associated with tau gene mutations linked to chromosome 17 (FTDP-17). Patients manifest cognitive, psychiatric, and parkinsonian symptoms. Although not initially thought to be a prominent feature, myoclonus was subsequently described in patients with N279K, P301S, and V337M tau mutations [22].

FTDP-17 syndromes commonly have cortical and subcortical pathology [23]. The precise mechanism of myoclonus in FTDP-17 syndromes is unclear, but pathology in the frontoparietal area may be more predisposed to myoclonus than pathology in the frontotemporal area [23].

Huntington disease — Myoclonus is unusual in Huntington disease, but can be clinically impressive when present. The myoclonus is usually restricted to individuals with a young age of onset and higher number of overexpressed cytosine-adenine-guanine (CAG) trinucleotide repeats of the mutated huntingtin gene (HTT) on chromosome 4. Seizures may also be present. (See "Huntington disease: Clinical features and diagnosis".)

Rapidly progressive young-onset cases of Huntington disease are presumed to have more pronounced cortical pathology than older patients with lower CAG repeat mutation values, thus enabling the cortical myoclonus to occur.

The physiology is cortical action and/or cortical reflex myoclonus, although the cortical somatosensory evoked potential waves are rarely enlarged [24].

Dentatorubral pallidoluysian atrophy — DRPLA is an autosomal dominant neurodegenerative disorder that is relatively common in Japan, but rare in other countries. It is associated with a CAG repeat expansion in a gene on chromosome 12. DRPLA has protean neurologic manifestations that include ataxia, chorea, dystonia, parkinsonism, epilepsy, psychosis, and dementia [25]. (See "The spinocerebellar ataxias", section on 'Dentatorubral pallidoluysian atrophy'.)

Myoclonus is an uncommon feature of DRPLA. When present, it is usually associated with a progressive myoclonic epilepsy (PME) or progressive myoclonic ataxia (PMA) syndrome. (See 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' above.)

The physiology of the myoclonus with DRPLA is presumed to be cortical, but has received little study.

INFECTIOUS, POSTINFECTIOUS, AND AUTOIMMUNE INFLAMMATORY DISORDERS — Myoclonus may be associated with numerous diffuse infectious, postinfectious, and autoimmune inflammatory disorders, including the following:

Arbovirus encephalitis (see "Viral encephalitis in adults")

Coronavirus disease 2019 (COVID-19) [26] (see "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations')

Cryptococcal meningoencephalitis (see "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV")

Encephalitis lethargica

Hashimoto encephalopathy (see "Hashimoto encephalopathy")

Herpes simplex encephalitis (see "Herpes simplex virus type 1 encephalitis")

Human immunodeficiency virus (see "Approach to the patient with HIV and central nervous system lesions")

Human T-lymphotropic virus I (see "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment")

West Nile virus [27] (see "Clinical manifestations and diagnosis of West Nile virus infection")

Lyme disease (see "Clinical manifestations of Lyme disease in adults")

Malaria (see "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children")

Miscellaneous bacteria (Streptococcus, Clostridium, other)

Paraneoplastic syndromes (see "Overview of paraneoplastic syndromes of the nervous system")

Postinfectious encephalitis (see "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations')

Progressive multifocal leukoencephalopathy (see "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis")

Subacute sclerosing panencephalitis (see "Measles: Clinical manifestations, diagnosis, treatment, and prevention")

Syphilis (see "Neurosyphilis")

Voltage-gated potassium channel complex antibody syndromes (sometimes mimicking Creutzfeldt-Jakob disease [CJD]) [28] (see "Paraneoplastic and autoimmune encephalitis")

Occasionally, myoclonus is an early clue for diagnosis of these disorders. The acute or subacute onset of myoclonus in a previously healthy person should trigger the screening for these conditions, including specific infectious agents. Specific antibody-associated myoclonus disorders are becoming increasingly identified [29]. Many of these are treated with immunotherapy, so identification is crucial.

The physiology of myoclonus in this group of disorders is heterogeneous and depends on localization of the pathology in the central nervous system. In infectious encephalitis, the myoclonus is commonly accompanied by seizures and altered mental status. COVID-19 has been associated with myoclonus either at the time of initial symptoms or within 30 days [26]. The myoclonus can be acute, multifocal, or generalized and categorized as postinfectious or parainfectious. Many cases improve within weeks, and immunotherapy may help. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations'.)

Other notable causes of myoclonus under this category include opsoclonus-myoclonus syndrome (OMS) and malabsorption disorders.

Opsoclonus-myoclonus syndrome — Opsoclonus is a disorder of ocular motility characterized by involuntary, repetitive, rapid, and arrhythmic conjugate eye movements (ocular saccades) occurring in all directions of gaze without a saccadic interval.

Opsoclonus-myoclonus syndrome (OMS) is a rare disorder, more common in children than adults. The pathogenesis is thought to be immune mediated, but the precise mechanism remains unclear [30].

OMS can be a remote effect (paraneoplastic) of an underlying malignancy, usually a neuroblastoma in children, and lung or breast cancer in adults. (See "Opsoclonus-myoclonus syndrome".)

OMS can also occur in the context of infection, or without identifiable cause (idiopathic). Celiac disease has been rarely associated with OMS [31]. (See 'Malabsorption disorders' below.)

The myoclonus in OMS is usually multifocal and action related [32]. There is often a prodrome of systemic complaints, including nausea, vomiting, vertigo, oscillopsia (jerks in vision), or gait difficulty. The onset of myoclonus can be abrupt or gradual. Onset over days to a few weeks is common, with ataxia, opsoclonus, myoclonus, and other movement disorders occurring together. Less often, the onset is gradual over weeks to months, and mild ataxia occurs before the onset of opsoclonus and myoclonus.

The physiology of the myoclonus in both idiopathic and paraneoplastic OMS is subcortical-nonsegmental [33]. In some patients, isolated myoclonus occurs as a remote effect of cancer without opsoclonus, and such cases have a different myoclonus physiology.

Malabsorption disorders — Both celiac disease and Whipple's disease may cause myoclonus in the setting of malabsorption, but the myoclonus is generated from the disease process rather than the malabsorption per se.

The myoclonus of celiac disease most commonly presents as a progressive myoclonus ataxia (PMA) with cortical action and cortical reflex physiology [34]. Celiac disease has been associated more rarely with the OMS [31]. (See 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' above and 'Opsoclonus-myoclonus syndrome' above.)

Whipple's disease can cause various types and distributions of myoclonus [35,36]. The classic oculomasticatory myorhythmia resembles segmental myoclonus [37].

Myoclonus after transplantation — Myoclonus that develops in a patient after transplantation may have multiple possible etiologies. A major consideration is the net state of immunosuppression, which is a complex function determined by the interaction of several factors. These include the use of immunosuppressive therapy itself; underlying diseases or comorbid conditions; devitalized tissues or fluid collections in the transplanted organ; invasive devices such as vascular access or urinary catheters, surgical drains, and ventricular assist devices; other host factors affecting immune function including neutropenia, hypogammaglobulinemia, and metabolic problems (eg, protein-calorie malnutrition, diabetes); and concomitant infection with immunomodulating viruses including cytomegalovirus, Epstein-Barr virus, human herpesvirus (HHV) 6 and 7, hepatitis B virus, and hepatitis C virus. Thus, new-onset myoclonus following transplantation should trigger a thorough investigation for possible infection. (See "Infection in the solid organ transplant recipient".)

Other potential causes of myoclonus in the setting of transplantation are directly related to organ dysfunction, such as hepatic encephalopathy or uremia. In addition, organ dysfunction can change drug metabolism, such that a previously tolerated medication dose can lead to elevated drug levels associated with myoclonus.

METABOLIC DISORDERS — A long list of metabolic disorders is linked to myoclonus, including the following:

Hyperthyroidism

Hepatic failure

Renal failure

Dialysis syndrome

Hyponatremia

Hypocalcemia

Hypomagnesemia

Hypoglycemia

Nonketotic hyperglycemia

Multiple carboxylase deficiency

Biotin deficiency

Hypoxia

Metabolic alkalosis

Vitamin E deficiency

The onset of myoclonus secondary to acquired metabolic disorders, including organ and gland failure, is typically acute or subacute. The temporal relationship of the underlying metabolic disorder to the myoclonus may be offset by days, weeks, or longer. The distribution of myoclonus in these conditions is most often multifocal.

In liver and kidney failure, tremors and altered mental status are common accompaniments to the myoclonus. Asterixis (negative myoclonus) is particularly common in patients with renal or hepatic failure. In addition, liver and kidney failure may produce myoclonus by inhibiting the metabolism or clearance of drugs or other chemical agents that cause myoclonus [38,39].

DRUG-INDUCED AND TOXIC SYNDROMES — Several classes of medications and other agents that cross the blood-brain barrier may cause myoclonus, including the following [40]:

Levodopa, amantadine [41]

Psychiatric medications (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, lithium)

Antibiotics (eg, penicillins, cephalosporins, quinolones)

Narcotics (particularly meperidine and morphine)

Antiseizure medications [42]

Anesthetics

Contrast media

Cardiac medications (eg, calcium channel blockers, antiarrhythmic agents)

Drug withdrawal from certain agents (eg, sedatives)

Toxins associated with myoclonus include the following:

Bismuth

Heavy metals

Methyl bromide

Dichlorodiphenyltrichloroethane (DDT)

As more drugs and toxins are introduced, the number of such agents has steadily increased [43,44].

The mechanisms responsible for myoclonus induced by drugs or toxins are not well established [44]. Furthermore, it is not clear why myoclonus occurs in some exposed individuals but not others.

The time profile of exposure to the drug or toxin may be acute, subacute, or chronic [45,46]. Likewise, improvement in myoclonus after withdrawal may occur over an extended period. Polypharmacy can cause or worsen the drug-induced myoclonus of a single agent [47,48]. Some agents, such as lithium, can cause a dose-dependent spectrum of motor cortex hyperexcitability disorders, ranging from isolated cortical action myoclonus to generalized tonic-clonic seizures [49].

Myoclonus induced by drugs or toxins is potentially treatable, since the myoclonus typically resolves upon withdrawal of the offending agent(s). It is important to scrutinize all drugs, either in isolation or combination, when evaluating for a potential causative role in myoclonus.

ENCEPHALOPATHIES — Myoclonus can be a feature of a number of conditions associated with diffuse or multifocal cerebral dysfunction:

Hypoxia (acute and posthypoxic myoclonus)

Head trauma

Heat stroke

Electric shock

Decompression illness

Hypoxia is the most common diffuse cerebral insult that causes myoclonus. (See "Hypoxic-ischemic brain injury in adults: Evaluation and prognosis".)

Posthypoxic myoclonus — This myoclonus occurs in both acute and chronic types.

Acute posthypoxic myoclonus occurs immediately or within hours of the hypoxic episode with coma. The distribution is generalized. Spontaneous myoclonus and/or seizures may or may not be present during the coma. However, during the myoclonus, electroencephalography (EEG) changes are timed after the myoclonus itself. It has been suggested that this myoclonus arises from the brainstem [50].

Typically, chronic posthypoxic myoclonus (also known as Lance-Adams action myoclonus) occurs after severe acute hypoxic coma that lasts for several hours to days. With recovery from the severe hypoxic episode, the posthypoxic myoclonus is present or subsequently develops quickly [51].

Chronic posthypoxic myoclonus can produce marked disability [52]. Action and reflex myoclonus, subsiding at rest, are characteristic features. In addition, ataxia and mental status changes are frequent parts of the syndrome, and cerebrospinal fluid serotonin metabolites are often decreased. This finding has led to the hypothesis that depression of serotonin system activity is important in this and other myoclonic syndromes [53]. The physiology of chronic posthypoxic myoclonus is usually both cortical action and cortical reflex myoclonus.

The evaluation and management of posthypoxic seizures and myoclonus after cardiac arrest are reviewed separately. (See "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Seizures and myoclonic jerks'.)

FOCAL NERVOUS SYSTEM DAMAGE — Several types of pathology can cause a focal lesion of the central or peripheral nervous system that results in myoclonus.

Central nervous system:

Poststroke

Postthalamotomy

Olivodentate lesions (palatal myoclonus)

Spinal cord lesions (segmental/spinal myoclonus)

Tumor

Trauma

Infection

Inflammation (eg, multiple sclerosis)

Moebius syndrome

Developmental

Idiopathic

Peripheral nervous system, including root and plexus:

Trauma

Hematoma

Focal, multifocal, or generalized jerks may arise from damage to the cerebral cortex [54,55]. Brainstem damage can produce generalized jerks in the form of exaggerated startle syndromes (eg, hyperekplexia) or reticular reflex myoclonus that are spontaneous and stimulus sensitive (reflex myoclonus) [56]. Rhythmic myoclonus in a brainstem or spinal segmental distribution raises the concern for a focal lesion at or near that segment of the brainstem/spinal cord [57].

Propriospinal myoclonus — Lesions in the spinal cord may cause propriospinal myoclonus, which is characterized by rostral and caudal spread of the hyperactivity from the damaged area [58,59]. Propriospinal myoclonus takes the form of flexion or extension jerks of the trunk that can be spontaneous or stimulus sensitive (reflex myoclonus).

In a report on propriospinal myoclonus confirmed by clinical neurophysiology in 10 adults (8 men, 2 women) ranging in age from 17 to 70 years, the following observations were reported [60]:

All 10 patients had involuntary spontaneous repetitive jerks involving the abdominal wall muscles and legs. Lying down exacerbated the movements in eight patients, stimulus sensitivity occurred in four, and premonitory sensations (paresthesia, muscle tickling or tightening, cold sensation) were reported by six.

The myoclonic generator was located at the thoracic level in eight patients.

Magnetic resonance diffusion tensor imaging with fiber tracking revealed spinal tract disorganization in all 10 patients, and quantitative fiber thinning in nine. The abnormalities correlated with the level of the myoclonic generator in seven.

A definite cause was identified for two patients, one with lymphocytic meningitis and another with a thoracic disc herniation. A possible cause was present for three others, including back trauma in two and myelopathy associated with antithyroid antibodies in another.

Palatal myoclonus — Palatal myoclonus is also known as palatal tremor because the movements are typically slow and rhythmic and thus resemble tremor [61]. A rare disorder, it is usually symptomatic (secondary) to a brainstem and/or cerebellar lesion, such as a pontine infarct, within the triangle of Guillain and Mollaret [62]. This triangle describes the neuronal circuit comprised of the following pathways:

Dentate nucleus in the cerebellum to the contralateral red nucleus in the midbrain via the superior cerebellar peduncle

Red nucleus to the medullary inferior olivary nucleus via the central tegmental tract

Inferior olivary nucleus to the contralateral dentate nucleus via the inferior cerebellar peduncle

Symptomatic palatal myoclonus is usually characterized by contractions of the levator veli palatini, and middle ear myoclonus is characterized by contractions of the tensor tympani and/or stapedius muscles [63-66]. However, some patients have no apparent structural lesion and are considered to have essential palatal myoclonus. In such cases, the myoclonus is characterized by contractions of the tensor veli palatini. These conditions may cause tinnitus or ear clicking [67-69].

With palatal myoclonus (mainly the symptomatic type), the myoclonic jerks can also involve the larynx, tongue, and face.

Hemifacial spasm — Peripheral nervous system lesions can cause myoclonus [70]. The best-known example is hemifacial spasm, which is characterized by involuntary, irregular, tonic, and clonic movements of facial muscles innervated by the seventh cranial nerve. (See "Nonepileptic paroxysmal disorders in adolescents and adults", section on 'Hemifacial spasm, blepharospasm, and Meige syndrome'.)

Although most often idiopathic, hemifacial spasm can be caused by extra-axial brainstem pathology, including tumors, and vascular compression of the facial nerve.

DISORDERS AFFECTING MULTIPLE SYSTEMS — Myoclonus can be a feature of several heterogeneous conditions that affect multiple organ systems, including the following:

Action myoclonus-renal failure syndrome [71]

Mitochondrial disorders

Triple A syndrome (achalasia, alacrima, and adrenal insufficiency) [72]

DiGeorge syndrome [73]

Membranous lipodystrophy [74]

The action myoclonus-renal failure syndrome is a form of progressive myoclonic epilepsy (PME) associated with renal dysfunction [71]. It is inherited in an autosomal recessive manner. (See 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' above.)

Certain mitochondrial disorders can present with a PME (eg, myoclonic epilepsy with ragged red fibers [MERRF]) or with progressive myoclonic ataxia (PMA). (See "Mitochondrial myopathies: Clinical features and diagnosis".)

SYNDROMES OVERLAPPING WITH MYOCLONUS — Syndromes that overlap with myoclonus include exaggerated startle syndromes and psychogenic jerks. Jerks associated with sleep or sleep transitions are discussed separately. (See "Classification and evaluation of myoclonus", section on 'Physiologic myoclonus'.)

Exaggerated startle syndromes — Sporadic and hereditary forms of hyperekplexia (exaggerated startle reflex) can produce generalized myoclonus [56]. In addition to a nonfatigable startle reflex, the clinical syndrome may include hypertonia in infancy, hyperreflexia, falling attacks with retained consciousness, and tonic spasms. (See "Hyperkinetic movement disorders in children", section on 'Hyperekplexia'.)

Autosomal dominant inheritance exists in the hereditary form, and multiple genetic mutations have been found in the inhibitory neurotransmitter glycine receptor. A brainstem reticular formation source for the myoclonus is established and demonstrates subcortical-nonsegmental physiology.

Psychogenic jerks — Jerks that occur in patients with a conversion disorder or malingering may appear quick enough to be confused with myoclonus. The characteristics of psychogenic jerks include the following [75]:

Inconsistent character of the movements (amplitude, frequency, and distribution) and other features incongruous with typical "organic" myoclonus

Associated psychogenic symptomatology

Marked reduction of the myoclonus with distraction

Exacerbation and relief with suggestion and placebo

Spontaneous periods of remission

Acute onset and sudden resolution

Evidence of underlying psychopathology

EVALUATION — The evaluation of a patient with myoclonus is reviewed here briefly and discussed in detail separately. (See "Classification and evaluation of myoclonus", section on 'Evaluation'.)

The evaluation of myoclonus may be conceptualized into four parts (table 2) (see "Classification and evaluation of myoclonus", section on 'Evaluation'):

Syndrome identification

Ancillary laboratory testing

Clinical neurophysiology

Testing for rare causes

Most myoclonic movements can be diagnosed by clinical observation. The examination of a patient with myoclonus should delineate the distribution, temporal profile, and activation characteristics of the myoclonus (table 3). Ancillary testing should be performed if the etiology remains unclear. (See "Classification and evaluation of myoclonus", section on 'Syndrome identification' and "Classification and evaluation of myoclonus", section on 'Ancillary studies'.)

Clinical neurophysiology testing is useful to determine the physiologic classification of myoclonus (table 4). In addition, it is helpful when clinical observation alone is unable to distinguish myoclonus from other involuntary movements such as chorea, dystonia, and tremor. Simultaneous electroencephalography-electromyography (EEG-EMG) polygraphy is the most important clinical neurophysiology study, since it can show the approximate relationship of EEG activity with myoclonus, and determine which muscles are most frequently involved with the myoclonic jerks. (See "Classification and evaluation of myoclonus", section on 'Clinical neurophysiology'.)

For hospitalized patients with new or recent onset of myoclonus, toxic-metabolic and drug-induced etiologies are most common. The initial evaluation should focus on these potential causes and look for subacute or acute systemic and neurologic conditions that are associated with myoclonus (algorithm 1).

Myoclonus that develops in a patient after transplantation may have multiple possible etiologies, and infectious etiologies require particular attention. (See 'Myoclonus after transplantation' above.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Myoclonus (The Basics)")

SUMMARY

Definition – Myoclonus that occurs secondary to a neurologic or systemic disorder has been traditionally termed "symptomatic myoclonus." Symptomatic myoclonus is the most common type of myoclonus and can occur in association with conditions that span the entire spectrum of neurologic disease (table 1).

Epidemiology – Posthypoxic state, neurodegenerative disease, and epilepsy syndromes are the most common causes. Toxic-metabolic and drug-induced etiologies are particularly common in the hospital setting (algorithm 1). (See 'Terminology and epidemiology' above.)

Causes – Symptomatic myoclonus is associated with the following broad categories of disease (table 3):

Progressive myoclonic epilepsy (PME) and progressive myoclonic ataxia (PMA) (see 'Progressive myoclonic epilepsy and progressive myoclonic ataxia' above)

Storage diseases (see 'Storage diseases' above)

Neurodegenerative diseases (see 'Neurodegenerative diseases' above)

Infectious, postinfectious, and autoimmune inflammatory disorders (see 'Infectious, postinfectious, and autoimmune inflammatory disorders' above)

Metabolic disorders (see 'Metabolic disorders' above)

Drug-induced and toxic syndromes (see 'Drug-induced and toxic syndromes' above)

Encephalopathies (see 'Encephalopathies' above)

Focal nervous system damage (see 'Focal nervous system damage' above)

Disorders affecting multiple systems (see 'Disorders affecting multiple systems' above)

Overlap syndromes – Syndromes that overlap with myoclonus include exaggerated startle syndromes and psychogenic jerks. (See 'Syndromes overlapping with myoclonus' above.)

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